Episodes
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Dr. Shannon Westin and her guest, Dr. Bryan Schneider discuss the article “ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer” recently published in the JCO and presented at the 2024 ASCO Annual Meeting.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncology Extraordinaire and also the Social Media Editor of the Journal of Clinical Oncology. And it is my great pleasure to present some really incredible work today that is going to be a dual publication in the Journal Clinical Oncology and a presentation at the American Society of Clinical Oncology Annual Meeting on Monday, June 3. And this is the “ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer.”
And I am joined today by the senior author on the presentation and the primary author on the manuscript, Dr. Bryan Schneider. He is the Vera Bradley Professor of Oncology, the Professor of Medicine and Medical Molecular Genetics at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center in Indianapolis.
Welcome, Dr. Schneider.
Dr. Bryan Schneider: Dr. Westin, thank you for having me on today.
Shannon Westin: We're so excited and we're really excited to really summarize this incredible work that's being presented today. So, first, let's just levelset. Can you speak a little bit about peripheral neuropathy and the most common causes in patients with cancer?
Dr. Bryan Schneider: Yeah, I mean, I think for those of us who treat patients using the taxanes, we recognize probably one of the most important and common side effects that we deal with is peripheral neuropathy, and one that can, I think, impact both quality of life, but also impacts the ability to maintain dose intensity. When we think about risk factors for neuropathy, historically, I think obesity has been reported as a potential risk factor, as has diabetes and other conditions which put people at risk for neuropathy.
Shannon Westin: And prior to your work that you'll discuss with us today, what do we know about the incidence of peripheral neuropathy in patients that identify as black?
Dr. Bryan Schneider: Yeah. So, interestingly, I think we've recognized that patients who self identify as black have disparate outcomes in terms of inferior survival and more aggressive subtypes of breast cancer, like triple negative breast cancer. But I think the idea of toxicity being a disparate factor as well is probably a more recent one. Interestingly, as we set out to identify biomarkers to predict outcomes in the large adjuvant trial E5103, we weren't really setting out to look at this by race. We were using at that time, genome-wide approaches to identify biomarkers for toxicity and also efficacy. But what was interesting as we did that one of the most important predictors, as we looked across a number of important toxicities, was ancestry. And really the science spoke to us, it was very clear that patients of African ancestry had higher rates of bev-induced hypertension, anthracycline-induced cardiomyopathies and also peripheral neuropathy.
Shannon Westin: That's so interesting. We have so much overlap in gynecologic oncology and breast cancer. And I don't know that I've ever seen work like this. And now it's making me very intrigued and making me want to move forward to that.
Can you talk a little bit more about this ECOG-ACRIN E5103, like briefly about the study and what it demonstrated specifically?
Dr. Bryan Schneider: Yeah. So E5103 was an adjuvant breast cancer trial that really set out to look at the impact of bevacizumab in the curative setting. This was a 5000 patient trial that randomized patients the standard backbone of chemotherapy. So everyone received four cycles of doxorubicin and cyclophosphamide, followed by weekly paclitaxel, and then with or without the addition of bevacizumab. So the parent clinical trial showed, as we know now, bevacizumab didn't add benefit, but certainly this was a fertile ground for us to use genomic markers to try to identify a number of other important factors and predictors.
Shannon Westin: And what did you find genomically in that study that led to kind of where we are now?
Dr. Bryan Schneider: Initially, what we found is that ancestry was a major predictor of neuropathy. And in that trial we saw essentially a doubling of the risk of grade 2 and above and a doubling of the risk of grade 3 and above neuropathy. When we then looked comprehensively across the genome for common variants that might put patients at risk for neuropathy, we had enough patients in the black population to identify some markers that seemed to differentially predict the risk of neuropathy in the patients of African ancestry. So there we found a variant in the gene FCAMR, which appeared to be protected from neuropathy, and FCAMR is known to have an immune modulatory effect. But importantly, we also found that rare variants, so we did this using an exome wide approach in a gene called SPF2, predicted an increased risk of neuropathy. Now, interestingly, that gene SPF2 is also thought to contribute to a hereditary form of neuropathy, Charcot-Marie-Tooth. Here, what we found, obviously, is that if you inherit two of these variants, you probably have a hereditary neuropathy, but if you inherit one, you may not have neuropathy at baseline, but if exposed to a neurotoxin, much more predisposed to that event.
Shannon Westin: That is so intriguing and makes so much physiologic sense. So, can you talk a little bit about how that led to the development of the current study, the objectives design, that type of thing?
Dr. Bryan Schneider: Yeah. I think, overarching question and concern is, and we see this with all clinical trials in the United States, is that we're seeing disparate outcomes in a population that are largely underrepresented in our clinical trials. And so one of the first things we wanted to do was really focus on the population that was being disparately affected. So EAZ171 was set out to accrue patients, and in fact, only accrue patients who were self described as a Bck race or African American. So the goal of this trial then was to see if, number one, we could further predict which patients were going to get neuropathy based on our germline genotyping, and then also to better personalize the type of taxane based, again on genomics, but also on the risk of dose reductions, risk of neuropathy, impact on financial toxicity, quality of life, and a number of other, what we felt to be, important clinical variables.
Shannon Westin: So let's get into the details. What did you find regarding the incidence of neuropathy in the study, and how was it impacted by the type of chemotherapy the patient received?
Dr. Bryan Schneider: Yeah. So the starting point, the primary objective of that study, was to try to validate a high and low risk composite score for neuropathy. And the trial was negative, meaning our genotypes did not predict significantly differences based on the germline genotyping. Now, interestingly, the genotyping did numerically separate, meaning those in the high risk category had about a 12% higher risk of neuropathy, but this did not meet statistical significance. Another major or key secondary endpoint, though, was to look at the type of taxane and its impact in this population. And indeed, what we found is that patients who received paclitaxel had a markedly and statistically significantly higher risk of both grade 2 and above and grade 3 and above peripheral neuropathy. And in addition, we saw more dose reductions, both because of TIPN and all causes in the paclitaxel arm.
Shannon Westin: So why do you think you were unable to validate the genomic predictors in the current study?
Dr. Bryan Schneider: This is an incredibly important question. So, number one, I mean, we were happy to see the directionality of our preliminary data be correct. But I do think that neuropathy is a very complicated toxicity, and it's probably a multigenic effect, and it probably is also impacted a lot by a variety of clinical factors. So some of the future work we'll be doing is looking at polygenic risk scores and other known genes that may be impactful, and also melding that with a number of really important clinical variables, because I still think we have the potential to predict this ahead of time.
Shannon Westin: I know that this was such a patient driven topic, really focused on the patient experience and how to improve not only survival outcomes, but also toxicities and quality of life. Can you speak a little bit about the role of patients in the design of this trial, and maybe with helping it be as successful as it was with accrual?
Dr. Bryan Schneider: Yeah. This has truly been one of the most exciting projects I've ever embarked on, and largely because of the incredible team atmosphere and contributions by so many people. Real thanks to the late Worta McCaskill-Stevens and also the late Edith Mitchell, who were two really fundamental disparities experts who really helped motor this trial to where it was. And also our patient advocates and the community at large really were part of the design and part of this from the very beginning, all the way through the publication, I think, have made it a clinically relevant study, and one that I think we're all very proud of.
Shannon Westin: Is paclitaxel typically, what is the go-to? Or are more people using, let's say, docetaxel?
Dr. Bryan Schneider: I think it depends a little bit on the disease setting and type. And again, is a function of historical clinical trials. One of the pivotal trials, E1199, actually compared a number of these. So it compared weekly paclitaxel to every three week paclitaxel to weekly docetaxel to every three week docetaxel in a two by two design. And essentially the conclusion there is that weekly paclitaxel and every three week docetaxel both outperformed what at the time was a standard of care, every three week paclitaxel. Now, weekly paclitaxel, at least through ECOG-ACRIN, has been adopted as kind of the standard reference therapy and schedule of choice, but largely because of the side effect profile. And again, this is based predominantly on white patients, where the tolerability is much better.
Shannon Westin: Well, I mean, I think that this leads to really great information around how we're designing these trials and how we're potentially making those differences. What are your next steps here?
Dr. Bryan Schneider: So I think one of the things this clinical trial did was first validate that we do see high rates of peripheral neuropathy in Black patients with breast cancer. This was a prospective study using both physician and patient adjudicated variables. So I think this is a really nice validation that this is a problem in this population. I think it also shows us that docetaxel is probably a more tolerable drug for black patients with breast cancer.
The goal, though, I think in our future work, is really going to try to bring equity in terms of outcome and side effects. So we're working with ECOG-ACRIN now on our second trial, where really the primary endpoint is going to be to nullify the disparities and try to bring equity in terms of toxicity. One of the other pieces of work we're really excited about is we're doing some ex vivo work. So from patients in EAZ171, we have a blood stick where we're taking white blood cells and differentiating those into peripheral neurons. And here we're hoping to look at really important changes in both gene expression and epigenetics that might lead us to a little bit deeper understanding of the mechanism of the disparities in neuropathy, maybe what's causing some of the neuropathy. And we hope ultimately, these may lead to nice drug targets to help prevent or treat neuropathy down the road.
Shannon Westin: Those are some really great ideas. The other thing that really caught my eye around your findings was what you all found regarding the physician reported and patient reported toxicity. I'd love for you to summarize that, because I think that's always a concern as well.
Dr. Bryan Schneider: Historically, I think we recognize that physicians probably underreport side effects. And so we felt, and our team felt, that having patient reported outcomes would be a really critical piece to this study. What was fairly astonishing to me, if you look at the CTCAE, both patient and physician reported outcomes, they were actually pretty similar. And I think what this is a testament to is if physicians are actually thinking about the side effect, they do a pretty good job of predicting it. Now, one thing we're looking very forward to is that we have a long term follow up out to three years. So it'll be interesting to see if physicians continue to pay close attention to neuropathy, because I know the patients will be. So we'll be looking at the discordance at these longer term follow up time points as well.
Shannon Westin: Well, great. This is such incredible work, and I’m like literally taking notes to get in touch with people I know that do this type of work and gynecological malignancies because I think that this is going to have far reaching consequences. So just thank you so much for taking the time to review this and congratulations on the JCO publication and ASCO presentation. It's very well deserved.
Dr. Bryan Schneider: Thank you Dr. Westin.
Shannon Westin: And thank you to all of our listeners. Again, we have been discussing the “ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer.” We're so grateful you joined us, and please do check out our other offerings wherever you get your podcasts. Have an awesome day.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Disclosures
Research Funding
Company name: Genentech/Roche
Company name: Pfizer
Company name: Foundation Medicine
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In this JCO Article Insights episode, Alexandra Rojek provides a summary on "Romidepsin Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Versus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Final Analysis of the Ro-CHOP Trial" by Camus et al published February 16th, 2024 and the associated editorial written by Dr. Mehta-Shah and Dr. Horwitz.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing a clinical trial update published in the May 10th issue of JCO addressing the long term follow up of the addition of romidepsin to CHOP chemotherapy for previously untreated peripheral T-cell lymphoma, or PTCL. This report by Camus et al discusses a five-year follow up of the original Ro-CHOP trial, which did not meet its primary endpoint of progression free survival. The original Ro-CHOP study, conducted by the LYSA group, was published in 2021 in JCO and was conducted as a one-to-one randomized phase III study of Ro-CHOP versus CHOP for patients aged 18 to 80 years with PTCL. 98 international centers were included, and the study enrolled patients between 2013 and ‘17. Nodal follicular helper T-cell, or TFH lymphoma was defined in this study follow-up as a PTCL expressing at least two of five TFH markers according to the latest classifications. The study's primary endpoint was PFS with secondary endpoints of OS and duration of response, or DOR. Five year follow up was reached in December 2022.
In the original study report, the addition of romidepsin to CHOP did result in a reduction of dose intensity of chemotherapy. However, in this updated follow up, there were no new safety signals reported. A total of 421 patients were enrolled in the trial with a median age of 65 years. Notably, those who were randomized to the Ro-CHOP arm had a higher proportion of IPI 4-5 scores at 33%, versus 24% of those who were assigned to CHOP alone despite randomization. Nearly half of patients carried a histologic diagnosis of angioimmunoblastic T-cell lymphoma. 30% were characterized as PTCL NOS, not otherwise specified, 10% ALK negative anaplastic large cell lymphoma, leaving 13% reported as other. Over 60% of patients had stage four disease at enrollment, with nearly half having more than two sites of extranodal involvement. Median follow up was six years with a median PFS of 12 months for Ro-CHOP and 10.2 months for CHOP, which did not reach statistical significance as reported in the original study publication. Estimated five year OS available as a part of this clinical trial update was 50% for Ro-CHOP and 43% for CHOP alone, and also did not reach significance. There was, however, a longer duration of response observed in the Ro-CHOP arm at 52 months versus 24 months for CHOP, which is a new finding in this extended follow up of the study.
In an effort to better understand whether there are subgroups which may benefit from romidepsin despite the overall negative outcome of this study, the authors are able to provide new insights from this Ro-CHOP study in line with our current and updated understanding of PTCL. When the authors evaluated the study population for subgroups which may benefit from addition of romidepsin, TFH lymphomas, which included angioimmunoblastic, follicular, and NOS subtypes, were noted to have an improved response to the addition of this HDAC inhibitor. This subgroup, numbering 201 patients, experienced a mean PFS of over 19 months with Ro-CHOP versus over 10 months for those who received CHOP, and this difference achieved statistical significance. Similarly, there was a higher complete response rate and longer duration of response for those in the TFH subgroup who received romidepsin.
The authors also make note that those patients in this subgroup with high IPI appeared to particularly benefit. However, those in the PTCL NOS group who did not fit the TFH subtype experienced poor outcomes with shorter PFS and OS as compared to other histologic subtypes, which is in line with other reported data in the field. The authors in this update also report on treatments and outcomes after first progression or relapse of disease, which includes a total of 274 patients, of whom 251 received second line therapy. The median PFS in OS after progression or relapse was only 3.3 months and 11.5 months, respectively, and again, patients with the TFH subtype experienced a longer median OS than other included histologies. Only 8% of patients proceeded to undergo autologous stem cell transplantation overall, and 5% underwent allogeneic stem cell transplantation.
While the authors note that they did not observe any notable outcome differences between various included second line therapies, they do note of a possible benefit of the antibody drug conjugate brentuximab vedotin or BV in combination with chemotherapy backbones. Those who received a BV containing regimen in the second line experienced a better CR rate and a longer PFS, too. However, the OS too was not significantly different. Again, the authors note that most of the benefit of the addition of BV to chemotherapy in the second line appeared focused on this TFH lymphoma subgroup. Of note, CD30 status was not recorded as a part of the study for included patients and could not be further reported on.
The findings of the authors present in this subgroup analysis of the negative Ro-CHOP study seek to find benefit in future lessons for patients with these rare lymphomas who do not have a multitude of effective treatments available to them. The subgroup benefit in this clinical trial update based on the TFH phenotype fits our evolving understanding of PTCL in the modern era. Mutations characteristic of the TFH subgroup, in this case often involved in chromatin modification and the tumor microenvironment, have been linked to improved responses when treating with epigenetic targeting drugs such as romidepsin, thus making the findings of TFH lymphoma in the Ro-CHOP trial confirmatory of what we would expect from correlative studies. Despite the benefit of Ro-CHOP for those with TFH lymphoma, this updated analysis of a major frontline study of PTCL highlights the critical need in the T-cell lymphoma field to, first of all, better understand and separate what we have come to recognize as the heterogeneous diseases historically lumped together as PTCL. This historic classification, based on a lack of deeper molecular understanding of disease biology is unlikely to represent the true biologic diversity of its component subtypes, including the focus on TFH lymphoma presented here. The second critical unmet need, which this subgroup analysis highlights, is the need to investigate the benefit of new therapeutic agents in these distinct subgroups of PTCL, where the need for improved survival outcomes is sorely needed when examining historical outcomes with currently available therapies, both in the frontline setting as well as those in the relapsed refractory group.
The associated editorial, written by Dr. Mehta-Shah and Dr. Horwitz, elegantly discusses the challenges of designing studies in rare diseases such as PTCL, which are both biologically informed as well as appropriately powered. As the authors discuss, it is rare to get a second chance for a drug, as is the case for romidepsin, where these negative results led to its voluntary withdrawal in PTCL, affecting availability of the drug for patients in the relapsed setting, as well as future clinical trials, which could have had potential for success. Additionally, better understanding of the biological underpinnings of PTCL needs to lead to better designed and appropriately powered clinical trials, as these subsets of patients are in great need of therapeutic advances. While none of these tasks is easy nor straightforward, this clinical trial update of the RoCHOP study suggests a path forward from learning from prior, promising yet failed attempts at moving the standard of care for frontline therapy of T-cell lymphoma forward.
This is Alexandra Rojek thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ascp.org/podcasts.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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Dr. Shannon Westin and her guest, Dr. Patrick Stone, discuss the article, Methylphenidate Versus Placebo for Treating Fatigue in People with Advanced Cancer, a Randomized, Double-Blind, Multicenter Placebo-Controlled Trial, recently published in JCO.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts and research published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for JCO and a Gynecologic Oncologist by trade. I am thrilled today to present Methylphenidate Versus Placebo for Treating Fatigue in People with Advanced Cancer, a Randomized, Double-Blind, Multicenter Placebo-Controlled Trial. This manuscript is a dual publication in the Journal of Clinical Oncology and presentation at the European Association of Palliative Care Congress here on May 17, 2024.
And to review this incredible research with us will be Professor Patrick Stone, the Head of Department of Marie Curie Palliative Care Research Department, Division of Psychiatry at University College London. Welcome, Dr. Stone.
Dr. Patrick Stone: Thank you very much. Thank you.
Shannon Westin: Let's get right to it, we’ll level set. Can you speak a bit about the definition of cancer-related fatigue and how common it is in people with advanced cancer?
Dr. Patrick Stone: Sure. I think fatigue is a difficult thing to nail down really and define it clearly, and there are lots of definitions out there. In many ways, the simplest definition is the EAPC, the European Association of Palliative Care's definition of just a subjective sensation of weakness, feeling tired, and exhaustion. The reality is that that symptom is very common in the general population. And so if you really want to get a handle on it, I think a good way to do it is to think about taking an operational definition and say, “Look, if fatigue is normally distributed approximately in the general population, then we should consider severe fatigue or pathological fatigue could be defined as fatigue that is worse than 95% of the general population. And if you think that definition, then prevalence of fatigue in patients with newly diagnosed breast or prostate cancer, for instance, is around 15%, so three times as common as the most severe fatigue in the general population. If you come to patients with newly diagnosed non-small cell lung cancer, it’s up to about 50%. And if you come to my area, which is palliative care and you go to a hospice and you ask people to complete a fatigue questionnaire, 78-80% of people complain of fatigue that is more severe than 95% of the general population. So that I think gives us a good handle on sort of the severity of this problem in cancer patients and how it progresses as disease progresses.
Shannon Westin: I love this because I think we always struggle with exactly how to nail down the definition and exactly how to treat it. So I think that it’s a really nice transition to existing treatment options for this issue and exactly how they might work.
Dr. Patrick Stone: The first thing to say is in medicine if you can find a cause then you give a treatment directed at the cause and obviously that applies to fatigue as well. So the first thing is to do a thorough assessment of your patient, and if you can find an easily remediable cause such as anemia, hypocalcemia, or hypomagnesemia, or maybe other things like depression, which might manifest as fatigue, then you should try and give a treatment directed at that cause. But, for many patients, there won't be a single clearly identifiable cause you can target.
And then people use more broad spectrum approaches if you like. The most well-studied I think is exercise. And exercise, there have been lots of randomized controlled trials in different types of exercise and it’s a well attested treatment, which I think has good evidence of effectiveness, certainly in patients who are on treatment and in disease-free survivors. There is less evidence in advanced cancer because the trials are fewer. I would still say that there’s moderate quality evidence that exercise is effective in advanced cancer.
The other group of treatments, broadly speaking, would be psychological therapies, cognitive behavioral therapy and psychoeducational approaches, mindfulness based stress reduction, that sort of thing. And again, in earlier stage disease and in patients on treatment and in survivors, there’s more quality evidence that that sort of approach can help, if not alleviate fatigue, allow people to cope better with fatigue. But the evidence in advanced cancer is weaker than for exercise. So I think the evidence for the effectiveness of those psychological therapies is not so strong.
And then you come on to pharmacological therapies and there have been lots of trials of different agents. I won’t list them all because most of them are negative and don’t show any benefit. A few things which perhaps still show promise from previous trials, there have been, for instance, a few trials looking at ginseng as a herbal therapy. One very good quality trial showed benefit. Although another trial in advanced cancer didn’t replicate that finding, so that ginseng is out there. Steroids, widely used in advanced cancer for general relief of many symptoms like fatigue, lack of energy, low moods, appetite. But although widely used, surprisingly little hard evidence or effectiveness, specifically for fatigue, but one relatively recent, well conducted randomized control trial, provides us with some firm evidence, also, that dexamethasone can help in the short term in advanced cancer patients. It obviously wouldn’t be a recommended treatment longer term because of its side effects.
And then we really come on to the crux of this study which is probably the most widely studied single agent beyond that, is methylphenidate, which is a psychostimulant agent, raises central dopamine catecholamine levels in the brain. And there’s probably a thousand or so randomized control trials sort of being conducted looking at that prior to prize of this study that we’re talking about.
Shannon Westin: I would love to hear a summary of the data that were pre-existing in this study. So how well does methylphenidate seem to work, or what were the conflicting results that were seen prior?
Dr. Patrick Stone: I think the rationale for this study was that it was the perfect background to justify another randomized controlled trial, which there have been– Well, I can’t remember exactly how many there were in existence before my trial started, but when I last looked, there were 10 studies, 10 randomized controlled trials in cancer patients. Most of those trials have been neutral. They've shown no benefit over placebo, so most of the individual trials are negative. But meta-analyses always tend to show a positive result. So when you count the trials together, it gets you over the finishing line and you can see a positive benefit. But individually, the trials were quite heterogeneous, they’re quite different. There were only four trials prior to the publication of this one that were done specifically in advanced cancer patients. One of them was published only a couple of years ago while my study was going on. And of those four trials, three of those have also been neutral, not showing a benefit over placebo. One study involving 28 patients and using a PRN as required dosing schedule showed some benefit. But the other studies with a total of about 330 odd patients have been neutral.
Shannon Westin: I think that brings us to a great transition, just to talk a little bit about the design and objectives of your current study.
Dr. Patrick Stone: Well, what we wanted to do was take the best bits, if you like, of the previous studies, and try to give ourselves the best chance of finding a clinically meaningful improvement in fatigue in patients with advanced cancer. And I was focusing on advanced cancer, principally because I'm a specialist in palliative medicine. That's the group of patients I'm most working with, whereas a lot of the studies have involved mixed groups of cancer patients or patient's disease-free or on treatment. But we looked at patients who were under the care of palliative care services, with incurable cancer, with a prognosis estimated to be less than a year or around a year.
We wanted to try to get the dose of the medication up to a good level because some of the other studies which have shown benefit have got up to quite high levels of methylphenidate, approximating to about 40 to 60 milligrams of methylphenidate a day or equivalent. And we wanted to give the drug in an individually titrated dose because that would reflect the way it is used in clinical practice. You would adjust the dose like you might with morphine for pain relief. You would expect to adjust the dose of this medication up to get a therapeutic benefit. So we had this titration period where we adjusted the dose of the drug every week. We reviewed whether patients were feeling better, worse, or the same. We asked about side effects. And on the basis of the response to those questions, we either went up with the drug or kept the dose the same, or, if necessary, would come down. The primary endpoint was designed to be fatigue after six weeks of dose titration, plus or minus a window of two weeks, accepting the fact that we might miss a few patients at the six-week mark, for whatever reason. So we had a little window around that. That's what we were looking to do.
Shannon Westin: And why did you choose the six-week time point?
Dr. Patrick Stone: Well, there was no obvious time point to choose. One of the biggest positive studies previously was by Lower and colleagues back in 2009, and they had found their maximum benefit at around four weeks, or it took rather four weeks to reach the maximum benefit. So we wanted to give the patients in our trial every chance of demonstrating the benefit, and they'd also escalated the doses in their study up to above 40 milligrams or equivalent. And so we wanted to go up as high as we could, and we didn't feel that if we were adjusting the dose every week, that we could get up to a sufficiently high dose in any shorter time span. So six weeks sort of fitted, allowing us to titrate the dose up to a maximum of 60 milligrams a day, which is where we wanted to get up to.
Shannon Westin: And what about a little bit more detail on the population you included, and maybe give us a sense of how well you think that represents your general population affected by fatigue in the setting of advanced cancer?
Dr. Patrick Stone: We recruited patients from hospices, so that's inpatient palliative care units in the UK, but also from hospital palliative care services, from oncology outpatient services as well, oncology patients who are under the care of palliative care services, and we also recruited from some community palliative care services. So we had quite a good spread of settings, and all of our patients had advanced incurable cancer under the care of palliative care services. But I would say, I think by the nature of doing this randomized controlled trial, inevitably we ended up with quite a selected population, just because of the inclusion and the exclusion criteria that we had to apply. And the regulators were quite clear about who we shouldn't be putting on the drugs. And I think by the time you've excluded all the potential adverse consequences of using methylphenidate, we probably have ended up with a group of patients who were relatively fit compared to the general run-of-the-mill palliative care population, I would say. So I think that that is a limitation with regards to the generalizability of our result.
Shannon Westin: How did you measure fatigue in this study? What was the mechanism for that objective?
Dr. Patrick Stone: It's a subjective rating scale. We use a very well-established and well-validated measurement instrument. It's the Functional Assessment of Chronic Illness Therapy FACIT-F which is the fatigue subscale of their anemia subscale, which is a 13-item questionnaire, very well validated and widely used in lots of previous studies. Higher scores represent better quality of life and, therefore, lower levels of fatigue. So that's the scale that we used.
Shannon Westin: Got it. So let's get to it. How well did methylphenidate work to impact fatigue compared to placebo? And were there any groups that seemed to have a bigger impact?
Dr. Patrick Stone: Well, the bottom line, of course, is that at six weeks, plus or minus two weeks, there was no statistically significant benefit for methylphenidate over placebo. There was a two-point improvement in fatigue scores, but it wasn't statistically significant. And two points on the FACIT-F did not reach our predetermined five-point difference that we regarded as representing a minimally clinically important difference. We looked at lots of secondary fatigue endpoints. We measured fatigue every week over the whole course of the study. And actually, at weeks 2, 3, 4, 5, and 6, there was indeed a statistically, nominally statistically significant difference in fatigue scores. But I really would not want anybody to read anything over much into that finding because it was not a pre-stated hypothesis of our study. It wasn’t a pre-stated endpoint, it was a secondary outcome. And moreover, even if this was regarded as a statistically significant finding, and as I say, it was only nominally statistically significant finding, the magnitude of the change was still not sufficiently large that I think it would want to influence your clinical decision making.
With other groups just to say, we did look specifically at whether patients with the most severe fatigue would experience benefit over and above other patients, because in a previous study, that looked at modafinil, an agent that promotes vigilance, although the overall finding was neutral in a subgroup of patients with the most severe fatigue, modafinil seemed to work. So we thought we better check in this study whether patients with the most severe fatigue had a differential benefit. But we found no such effect. We found no difference in patients who were on or off treatment or indeed among the patients who scored highest with the depression subscale on the hospital anxiety and depression scale. None of these subgroups showed any benefit over placebo.
Shannon Westin: How did patients tolerate methylphenidate? Was it tolerable?
Dr. Patrick Stone: That was the thing I think that I was most relieved about. I am a cautious and anxious investigator, and the last thing I wanted to do was to put palliative care patients at risk by giving them a drug which might cause some harm. So I was very relieved when we analyzed the results to confirm that methylphenidate was very well tolerated. There was no real pattern of evidence for any increase in adverse effects over placebo. In fact, when we looked at just people who self-reported severe adverse effects, we found a higher rate in the placebo group than in the methylphenidate group in fact. And in terms of serious adverse events, there were 25 serious adverse events in both groups, so there was, again, no pattern that suggested methylphenidate was causing harm. So, yes, it was well tolerated, but did not result in a clinically important improvement in fatigue.
Shannon Westin: Were you surprised by the results?
Dr. Patrick Stone: I honestly went into this with an open mind. I didn't come in with a real fixed agenda that I want to prove that this thing works. In fact, although methylphenidate was being used by some of my colleagues around the country and I know it’s used by some colleagues internationally, personally I was not using it because I didn't feel the evidence was strong enough to justify using it. So I was waiting for the results of my own trial before making my decision. And I don’t plan now to be using it on the basis of the results of the study.
Shannon Westin: Sounds pretty definitive. It's always frustrating, and I know our patients, when we tell them to exercise when they're exhausted, they’re like, “Are you kidding me?” Right? So it would be wonderful if there is like the perfect pill that we can give them. It's certainly disappointing. What do you think we should be exploring next for the resolution of fatigue in this patient population?
Dr. Patrick Stone: Well, I think one thing. Going back to your very first question to me about defining fatigue, I think one problem is we don’t really have a mechanistic understanding of what we’re talking about here necessarily with cancer related fatigue. And it’s a bit of an umbrella term, I suspect, for a lot of different things, and may have a common endpoint in terms of the symptom. But maybe if we could better define, if you like, for want of a better word, the phenotype of fatigue, it may be that we could actually target a treatment in certain subgroups of patients that may be of more benefit. So maybe some greater basic science pinpointing what is causing fatigue, so that we can design the treatments, rather than just try repurposing existing drugs on the off chance that they work. And the other thing is okay, maybe we can't pinpoint a particular cause, we think it’s multi factorial. If we think it’s multifactorial, then perhaps we ought to be using a multimodal treatment approach and maybe it’s actually exercise, psychological therapies, and diet, plus or minus a drug, and that’s the approach if we can’t pinpoint a specific cause.
Shannon Westin: I love the idea of incorporating the translational work to really try to understand the etiology better and then use something more targeted. It's that version of precision medicine but for palliative care as well. I really like that.
Well, this has been awesome. Thank you so much, Dr. Stone. I think that your insight is so much appreciated, and thank you for putting together this definitive work to help us treat our patients better every day. I really appreciate the time you took.
Dr. Patrick Stone: Thank you very much.
Shannon Westin: You're so welcome.
And thank you to our listeners. This has been methylphenidate versus placebo for treating fatigue in people with advanced cancer, randomized, double-blind, multicenter, placebo-controlled clinical trial. And again, this is a dual publication in the JCO as well as a presentation at the European Association of Palliative Care Congress on 5/17/24. And we are so thrilled that you could join JCO After Hours and we hope you will check out our other offerings wherever you get your podcasts. Have an awesome day.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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JCO Editor in Chief, Dr. Jonathan Friedberg interviews Dr. Pamela Kunz, Editor in Chief of the new premier open access journal, JCO Oncology Advances. Dr. Friedberg and Dr. Kunz discuss what is to come from the journal and the benefits of an open access journal.
TRANSCRIPT
Dr. Jonathan Friedberg: Hello and welcome to another episode of JCO After Hours. I'm your guest host, Jonathan Friedberg, Editor in Chief of JCO, and today we have a very special episode with Pamela Kunz, Associate Professor of Medicine in the Division of Oncology at Yale School of Medicine and Yale Cancer Center. As the new editor in chief of JCO Oncology Advances, she is with us today to share a new opportunity for authors to submit to ASCO’s new online open access journal.
Pam, welcome.
Dr. Pamela Kunz: Thank you.
Dr. Jonathan Friedberg: I guess my first question to you is, why did you take this role of editor in chief? People have asked me the same question, and I'm still, I think, trying to figure out the answer. So how did you decide to do this?
Dr. Pamela Kunz: That's a great question, and I might ask you the same thing. I think as I've gone on in my career, I really like saying I think about what I say yes and no to, and like saying yes to things that I think can make a difference and have real impact. And as a clinical trialist and someone who really hopes to advance the field scientifically, I think it was really exciting to think about helping to craft the future of the science of oncology and to also do it in a way, as we will later talk about open access, but do it in a way that really thinks about a broad audience, because open access really requires us to think about meeting the needs of our audience, as the articles will likely have broader reach.
Dr. Jonathan Friedberg: So, I mean, I can say I'm very excited about this journal. We do have a number of outstanding papers that we're not able to accept at JCO and knowing that there'll be a good home for these papers is heartwarming for me.
Can you tell me a little bit about your vision and goals for this journal? You're really starting with a blank palette. It must be exciting to try to craft what this is going to be about.
Dr. Pamela Kunz: It is really exciting. It's a little scary, I'll be honest, to have a blank slate, but I'm appreciative of you and the other editors in chief and staff for helping to provide some guidance. I think that in the beginning, as you were speaking to, there's an opportunity for us to really keep some great science in the JCO family. And so at least early on, we're hoping to really attract and think about publishing some earlier phase trials that may not quite meet the bar of getting published in JCO. So, phase I, phase II trials, even secondary analyses that yield important data from some of the larger phase III trials. This will be an evolution, I think, also. I think that what we may look like this year may look a little bit different in future years, but at least initially, we'll be focusing on some of the earlier phase clinical trials. I'm now framing this around beyond the clinical trial of secondary analyses quality of life, PROs. One thing that's exciting, a new article type will be plain language summaries. So really interpreting the clinical trial for patients and the lay public, I think that's an initial way that we're going to be thinking about it.
Dr. Jonathan Friedberg: And who do you see as the audience for this journal?
Dr. Pamela Kunz: Well, the opportunity that we have with open access is that we really have a much broader audience than we will have had historically with some of the non-open access journals. And I think that means that we have an obligation to be thinking about who that audience is. So, it's a great question. I think our audience will certainly be some of our typical readers, really, the oncology scientific community, but it will likely also be other physicians, primary care physicians, community oncologists, global oncology, and even patients, patient advocacy groups. So, I think that we have to be, as we're crafting and thinking about new article types, those article types, and the content that we create really has to meet the needs of the audience.
Dr. Jonathan Friedberg: And to that end, I know we've discussed, you had some discussions with your group about brief reports as another article type that is somewhat differentiating for the journal.
Dr. Pamela Kunz: Yes, exactly. And I think this also speaks to really trying to attract science that may be earlier in its development. And maybe an author, a team has an idea or a smaller scientific report that they'd like to publish. It may not quite meet the bar for JCO, but maybe we think that this is something that's exciting, that will lead to future studies, and that's exactly what we're hoping to attract.
Dr. Jonathan Friedberg: And I guess folding into maybe some of the input from your new editor team and editorial board, what features do you look for when reviewing novel research for publishing? How do you decide what gets in and what doesn't?
Dr. Pamela Kunz: Well, we are newly open, so this is something that we are also really, as a team, thinking about in real time. And I think that we certainly want JCO Oncology Advances to be the premier open access journal. So, we really still want the bar to be high in terms of high-quality science. As we have crafted and are still building our editorial team and editorial board, we are developing diverse expertise. So, we want content expertise. We have expertise in biostatistics. That's really critically important. So, we still want the biostats to be strong, and we want to ensure that, I think, that the conclusions are still really valid. So, I think really having a bar that's high for the science is still going to be critically important.
I think another thing that we may be looking at, again, given that we're looking at earlier phase clinical trials, is really the potential for impact, because, you know this, but JCO will really be publishing the large majority of the randomized clinical trials, and we may be thinking about publishing some of the earlier trials. So potential for impact will be important as well.
Dr. Jonathan Friedberg: Yeah, and I guess that gets into the next question, and I'll give an editorial opinion, I can't resist, I guess, as an editor, on what authors should think about as far as submitting. I really like the way you framed impact, and impact of a manuscript might go beyond changing practice in clinic tomorrow, but an important negative study which changes the way the trials are done in the future, or a preliminary study that leads to important phase II and phase III trials are very impactful for the field. And I guess one of the things I always advise authors is to help the reader and the editor understand what the next step is for their work. That can go in the discussion, it can go in the cover letter, but because of these results, the field should do X, Y, and Z. I think that's a really important thread that the reader should be able to see. I trust you might agree with that. But do you have any other insights for authors as they're preparing manuscripts for this journal that you'd like to share?
Dr. Pamela Kunz: That's a great idea, and you just gave me an idea to really maybe formally include that. I think one thing along those lines that we've been thinking about as it relates to our audience is to formally have, even in our manuscripts that aren't formally a lay language or plain language summary, to really have a short section that translates it. And I think translating the science is critically important as we're thinking about bringing in other community members, whether it's patients, patient advocates, primary care physicians, or those who may not be experts in oncology, but are really hoping to learn about the science of oncology. So that's an element that we're thinking of introducing to the manuscripts.
Dr. Jonathan Friedberg: Yeah, I think knowing your audience is critically important. And that said, I think that oncology practitioners are interested in broad topics as long as you can distill it down, it's not only clinical trials.
Dr. Pamela Kunz: That's right.
Dr. Jonathan Friedberg: You've mentioned a couple of times this term, open access, and this has been a real, I think, revolution during a transformational time in publishing. Maybe just for the people who are a little bit less familiar, define that, and what's the potential benefit of an open access Journal?
Dr. Pamela Kunz: open access publishing is a way; I think there are both advantages and disadvantages. It's certainly been a trend in oncology publishing. And in fact, I think some of the research that the JCO staff did found that over the last five years, about 30% of manuscripts are now being published via open access. Open access means, practically speaking, that the authors take on an article processing fee. So, there is a charge to the authors. However, the downstream benefit of that, there are benefits to authors, there are benefits broadly to the scientific community, and benefits to society. They sort of fall in those three categories.
The benefits to the authors are that there is certainly a chance of higher citations to the scientific community. There's an opportunity for broader scientific dissemination of the science. And then for society, we talked about the audience really shifts when there is open access. There's no paywall for patients or patient advocacy groups or non-oncology providers to get access to the content. I think it is a real paradigm shift, and I think it's both an opportunity, but also as an editor in chief and as the publishing community, we have an obligation to also think very intentionally about where there may be some potential for disparity. So, for example, if there is an article processing fee, we need to be sure that that's not a barrier. And if it is a barrier, is it disproportionately affecting certain populations, like low middle income countries or under or unfunded researchers? So, I hope that we can really be deliberate and thoughtful about that, as we are tracking this.
Dr. Jonathan Friedberg: I guess just some of the nuts and bolts. I know that you've put a lot of thought into trying to keep the fees as low as possible. And can you just maybe talk about how you've benchmarked them and maybe groups that get discounts?
Dr. Pamela Kunz: Yes. So, we are really trying to target a little bit around the median or below. So, we will be very competitive in terms of our peer journals, and in addition, there will be discounts that are really based on World Health Organization standards for low-middle income countries. And we certainly, on a case-by-case basis, can discuss with authors if there are hardships that we need to be aware of. So, I think we really don't want that to be a huge barrier. And I think, and I'd love your thoughts on this, too. I think that with this paradigm shift in publishing, I think there's an obligation for our institutions to really think about how they're going to support authors at their own institutions for this.
Dr. Jonathan Friedberg: Yeah, I agree, and I know that the ranges that you've discussed are certainly in line with many other oncology journals. And to that end, given the number of papers that are being published in this space, I think it speaks to resources being appropriately directed toward that.
Dr. Pamela Kunz: Can I ask you a question?
Dr. Jonathan Friedberg: Sure.
Dr. Pamela Kunz: So, because I think this was one of your ideas of really getting this journal started, why was it the right time for JCO to have an open access journal?
Dr. Jonathan Friedberg: So, I've been at the job now close to three years, and we take a look at where papers that don't quite meet the bar for JCO go. It's a very interesting analysis, but although JCO has four other journals in the family, each of those journals are fairly specialized with a narrow scope that includes some of what JCO publishes. But I would say in total, only about 15% of the articles that we reject might be appropriate for one of those four journals. So that leaves 85% of the papers finding a home elsewhere outside of the JCO family. So, I think certainly we felt that there were a lot of great papers that we'd like to find a place for in the JCO family. And that was one source.
I think the other is an appreciation that I'm still learning about this transformative time in medical publishing. And the old model of people subscribing to a magazine that they get once a month, and what publishing is, is really being turned on its head. People consume content based on a tweet or a link. There's a lot of graphics and video that goes into presenting this content. Funders as well as sponsors of research are really insisting that papers be made available to the broad public immediately, kind of questioning the copyright model and the need for subscription journals. So, I think really getting involved in this space and having a robust open access journal in the ASCO family is a critical direction to go. And based on all of the research that we've done; we really feel it is a great time.
Dr. Pamela Kunz: Great.
Dr. Jonathan Friedberg: One last question for you, as we're kind of leaving the audience with something. So, in addition to those benefits, based on your very early experience working with the ASCO staff and knowing about ways that ASCO and the JCO journals can promote manuscripts, our websites and search functions, what's the hook that people should choose this journal over another oncology open access journal?
Dr. Pamela Kunz: Great question. I mean, I think there are a number. Certainly, the JCO brand is strong and really top in the field. And I think that that in and of itself should be a draw for authors. I think that also our link with a professional society, with ASCO, is critically important. And I think that many oncology professionals see ASCO as their professional home. And I think having a journal and a journal family that's really linked with that professional society is important. And you and I have talked about really doing more to really enhance that link with ASCO. And I think that we will be doing that some at the annual meeting this year with promoting JCO Oncology Advances.
And I think that also, given that oncology really has become this global community, and ASCO has certainly become a global community, and the spirit and philosophy of open access, I think that really aligns nicely, and I think that it'll help us reach a broader community by having open access. And I think that that's a real advantage for authors.
Dr. Jonathan Friedberg: Yeah, I totally agree. And I think that as we continue to survey the landscape and come up with new content and areas of new focus like artificial intelligence and machine learning, which has been a big new trend, I think you're going to be able to have access to these cutting-edge manuscripts that will impact the field for sure moving forward. Any last comments for our listeners?
Dr. Pamela Kunz: Just to please submit your work. We're open for business, and I'm excited. So, thanks, Dr. Friedberg and to the team. I'm excited for the opportunity and we look forward to our first publications, hopefully, will be out this summer.
Dr. Jonathan Friedberg: Well, thank you so much for taking the time and thank you to our listeners. To learn more about JCO Oncology Advances, how to submit, the scope of the journal, just go to ascopubs.org. There's a whole detailed section there. We look forward to seeing your manuscripts. Thank you so much.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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In this JCO Article Insights episode, Rohit Singh provides summary on two articles published in the April 10th issue of the Journal of Clinical Oncology. The first article, "Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)" describes a randomized, open-label, multicenter, phase III study evaluating the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. The second is the accompanying Oncology Grand Rounds.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Dr. Rohit Singh: Hello and welcome to JCO Article Insights. I'm your host, Dr. Rohit Singh. Today I will provide a summary of a Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04), by Dr. Park and colleagues from Seoul, Korea. The purpose of this study was to evaluate the efficacy and safety of the ABCP regimen based on IMpower150 in patients with EGFR or ALK mutated non-small cell lung cancer who had progressed on prior targeted treatment.
I will also discuss an Oncology Grand Round case titled "Management of Treatment Resistance in Patients with Advanced EGFR Lung Cancer: Personalization, Parsimony, and Partnership", by Dr. Vallillo and colleagues from Lahey Hospital Medical Center and Tufts University School of Medicine, Boston, Massachusetts. Oncology Grand Round cases help us to give a clinical context to the clinical trial.
While TKIs are the established standard of care for non-small cell lung cancer harboring driver mutations, most patients will develop resistance to these treatments. Immune checkpoint inhibitors, with or without chemo, have shown clinical benefits of immune checkpoint monotherapy in patients with EGFR-mutated non-small cell lung cancer. Consequently, platinum-based chemo is the standard of care for patients with EGFR TKI failure. This was a phase III, multicenter, open-label, randomized trial conducted at 16 hospitals across the Republic of Korea. Patients diagnosed with stage four non-small cell lung cancer with sensitizing EGFR mutation or ALK translocation were included in the study. Patients were randomly assigned to the ABCP arm or chemo-only arm in a 2:1 ratio. Eligible patients were stratified on the mutation type (EGFR mutation vs. ALK translocation) and the presence of brain metastasis. No crossover to atezolizumab was permitted.
The recruitment with T790M mutation was capped at 30%. Patients who responded continued to receive maintenance with atezolizumab until disease progression or unacceptable toxicities occurred. If a patient was identified to have an acquired T790M mutation after the failure of a first or second-generation EGFR TKI, the patient had to be treated with a third-generation EGFR TKI before enrollment. The primary endpoint was investigator-assessed objective response rate according to research criteria. The secondary endpoints included overall survival and progression-free survival at one and two years, and the duration of response, along with a safety analysis. Investigators also did an exploratory biomarker analysis based on PD-L1 expression and its correlation with the response. They also analyzed the distribution of tumor-infiltrating lymphocytes, and a cut-off of 20% inflamed score was used to compare the two arms. Overall, 228 patients were enrolled, 154 in the ABCP arm and 74 in the chemo-only arm. Most patients were female at 56.1% and never smokers at 62.7%. Brain metastasis was present in 42.7% of patients. Most patients had previously received EGFR TKI therapy, however, only 8% and 30% received third-generation TKI as first-line therapy in the ABCP arm and chemo-only arm, respectively. The majority of the patients were EGFR at 90%.
The median duration of follow-up for the study population was 26 months. The objective response rate in the ABCP arm was significantly higher at 69.5% compared to 42% in the chemotherapy alone arm. The median PFS was significantly longer in the ABCP arm at 8.48 months versus 5.6 months, and the duration of response was similar at around seven months in both arms. The median overall survival was also similar at around 20 months in both arms, with a hazard ratio of 1.01. In the subgroup of patients with brain metastasis at the time of study enrollment, PFS was significantly longer in the ABCP arm at 8.4 months compared to 4.4 months in the chemotherapy-only arm. In contrast, no difference in PFS was observed in the subgroup without brain metastasis. Regarding EGFR mutation status, there was no difference in PFS or OS between the two arms in the EGFR deletion 19 subgroup. However, a favorable PFS was observed in the EGFR L858R subgroup. For those with acquired EGFR T790M mutation, there was no difference in PFS between groups, whereas a favorable PFS was observed in the subgroup without EGFR T790M mutation.
In the exploratory biomarker analysis, interestingly, the impact on PFS was correlated with PD-L1 expression. The study found that the higher the PD-L1 expression, the better the PFS. In patients with PD-L1 expression of more than 50%, the hazard ratio was 0.24 for PFS. This is an interesting observation. As in previous studies, we have seen that PD-L1 expression does not have a strong association with response to checkpoint inhibitors in patients with driver mutations. Based on the distribution density of tails in the tumor bed, the inflamed score was calculated using artificial intelligence. For patients with 20% of the imflamed score, the ABCP arm has significantly prolonged PFS at 12.9 months compared to 4.8 months. The median number of ABCP treatment cycles was 4, with 12 for atezolizumab and 8 for bevacizumab as maintenance therapy, pemetrexed maintenance was administered for a median of 10 cycles. The incidence of grade 3 or higher side effects was 35.1% in the ABCP arm compared to 15% in the chemotherapy-only arm. Peripheral neuropathy, alopecia, and myalgias were the most prevalent side effects. Interesting notably, 54% of patients in the ABCP arm required treatment interruption or dose modification, and there were three reported deaths in the ABCP arm, two due to pneumonia and one due to cerebral embolic infarction. Around 10 patients or 13.5% of patients in the chemotherapy-only arm required dose interruption or modification.
In conclusion, patients with EGFR-mutated or translocated non-small cell lung cancer who had failed prior TKI ABCP regimen showed a statistically significant prolongation of PFS and response rate compared to chemo alone. Patients in the subgroup with EGFR L858R, without acquired T790M mutation, and presence of brain met showed more benefit. There was no difference in overall survival, though we need more mature data. Adverse events were higher in the ABCP arm. Interestingly, in the exploratory analysis, a high PD-L1 and an inflamed score of more than 20% showed PFS benefits. Though we need to take into consideration that this trial was done and all the patients were grouped from a single country considering Asian ethnicity. And most importantly, the majority of patients were treated with first- and second-generation TKIs, whereas third-generation TKIs are the standard of care in the United States.
Coming to the Oncology Grand Round, in this case, we will discuss the management of treatment resistance in patients with advanced EGFR-mutated lung cancer. A patient with a 20-pack-a-year history of tobacco use presents with weight loss and hip pain, found to have a lung mass, skeletal mets, and brain mets, and was diagnosed with lung adenocarcinoma. The patient goes with palliative radiotherapy for the brain mets. Comprehensive tumor Merkel profiling demonstrated an EGFR mutation exon 19 and alteration P53. The patient was started on third-generation EGFR TKI osimertinib. However, after 17 months, the patient has symptomatic disease progression. Usual approach, if feasible, re-biopsy at the time of progression to evaluate for possible new mutations which can guide treatment options. As mentioned earlier, in the trial, acquired resistance to the TKI is inevitable and heterogeneous. There were various mechanisms which have been proposed regarding resistance, including a second-site EGFR alteration, upregulation of bypass pathway, histological transformation to small cell histology, or suboptimal drug penetration.
There are various approaches after disease progression on EGFR TKI. Combining EGFR-directed therapies to address resistance is an option. Prime results from the MARIPOSA-2 study showed amivantamab plus chemotherapy with or without lazertinib in EGFR-mutated non-small cell lung cancer after disease progression showed a better objective response rate at 64% compared to 36% in the chemo-alone arm. It also showed improved PFS with a median of 6.3 compared to 4.2 in the chemo-alone arm. Combining immune checkpoint inhibitors, EGFR-mutated non-small cell lung, I say has been disappointing in advance of EGFR-mutated non-small cell lung, and combination therapy studies are needed to improve outcomes. Studies, as I discussed ATTLAS, have shown that combining a VEGF inhibitor with ICIs and chemotherapy can lead to a better objective response rate and PFS. However, further clinical trials are needed to figure out the better subgroup of patients who can benefit from this combination.
Should the TKI be continued beyond progression in EGFR-mutated advanced non-small cell lung cancer? Continuing the primary EGFR TKI treatment beyond progression may be considered for patients with indolent or asymptomatic progression or localized progression. We can consider radiation, surgery, or ablation. This approach will potentially delay the need to change systemic therapy in patients. However, for patients with multifocal disease progression requiring chain systemic therapy it may be more beneficial to switch to next-line systemic therapy options like platinum doublet with or without immunotherapy and VEGF inhibitors. In the case presented, the decision was made to continue osimertinib along with platinum doublet, deferring the addition of immunotherapy and VEGF inhibitor. This choice was based on factors like the patient's history of brain metastases and intracranial control. There is also a high risk of toxicity, especially pneumonitis, with immune checkpoint inhibitors after using targeted therapy, the patient showed clinical and radiographic improvement while on this treatment regimen.
The decision to continue or change therapy at cancer progression is based on factors like drug tolerability, patient preferences, and specific subgroups with different outcomes, such as those with brain metastasis or specific EGFR mutation subtypes. Choosing between combination therapy strategies that concept progression involves personalized decision-making to optimize treatment outcomes. Ultimately, the approach to management should be tailored to individual patient needs, preferences, and eligibility for different treatment modalities.
This is Rohit Singh. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You will find all the ASCO shows at asco.org/podcasts. Thank you.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions ofASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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Dr. Shannon Westin and her guests, Dr. Emily S. Tonorezos and
Dr. Michael Halpern, discuss their article, "Myths and Presumptions About Cancer Survivorship" recently published in the JCO.TRANSCRIPT
The guests on this podcast episode have no disclosures to declare.
Shannon Westin:Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Social Media Editor of the JCO, Shannon Westin, and also a GYN Oncologist by trade. I'm thrilled to bring a topic that is very close to my heart. We're going to be talking about a Comments and Controversies article published in the JCO on November 16, 2023, entitled "Myths and Presumptions about Cancer Survivorship." I know you all will find this topic as enthralling as I have, and the authors do not have any conflicts of interest.
I'm joined by two of the authors on this important work. The first is Dr. Michael Halpern, he’s the Medical Officer in the Health Assessment Research Branch of the Health Care Delivery Research Program. Welcome, Dr. Halpern.
Dr. Michael Halpern: Thank you for having us on.
Shannon Westin: We're also accompanied by Dr. Emily Tonorezos, the Director of the Office of Cancer Survivorship, and both of them work in the Division of Cancer Control and Population Sciences at the National Cancer Institute, National Institutes of Health. Welcome.
Dr. Emily Tonorezos: Thank you for having us.
Shannon Westin: So, let's get right into it. I want to level set first. I would love for one or both of you to speak a little bit about the state of cancer survivorship currently. What's the prevalence of cancer survivors here in the US? Globally? What do we expect as time passes?
Dr. Emily Tonorezos: Thank you for starting with this question. In the Office of Cancer Survivorship, we use a definition of cancer survivor that we got from the advocacy community many years ago. We use a definition that says “a person is a cancer survivor from the time of diagnosis through the balance of life.” That means in the United States, we estimate that we have a little over 18 million cancer survivors, and globally, it's a little more difficult to estimate those numbers. Not every country has a cancer registry to count the number of cases, but we think there are upwards of 53 million cancer survivors diagnosed within the last five years in the world.
Shannon Westin: Wow. And so this is why it's so important, such a large number, and that's just an estimate. And we know this is only going to be growing. I personally learned so much from your manuscript, which is critically based on the understanding that our beliefs as practitioners truly impact the way we care for our cancer survivors. I admit, I definitely held or hold some of these beliefs, and I'm certainly grateful that you're providing that objective evidence to support or refute these claims.
So, with that being said, let's tackle the first one that you all approached: Shared care results in the best outcomes for cancer survivors. I think first I'd love to hear about what your definition of shared care is. What does that really mean in the context of cancer survivorship?
Dr. Michael Halpern: Shared care is a deliberate process to coordinate and integrate components of survivorship care between specialty, in this case, oncology providers, and primary care providers. And part of the issues with this belief about shared care being the best have to do with the broad practice experience of survivorship care. While the ideal definition is this integrated and coordinated care, shared care can range from one extreme to being essentially oncologist-led care - where the oncologist also sends information to the primary care providers; and to the other extreme - care led by primary care providers and an oncologist is available to answer questions as needed. So part of the issue with the available literature is that there is a tremendous range in terms of the definition of shared care that's being used in studies.
Shannon Westin: So, understanding those limitations, obviously, based on what you just said, what have we seen in some of the studies that have been exploring shared care and what it might mean for cancer survivors?
Dr. Michael Halpern: So there have been some wonderful studies and some very well-done research in shared care. The majority of it indicates essentially no benefits, not any worse, but definitely not any better than other survivorship care models among multiple domains, quality of life, patient preference, clinical outcomes, in some cases, costs. So there isn't at this point a rationale for believing that shared care leads to better outcomes than does other types of models of care. And that's not to say that we don't think that shared care is a valuable model, that it's potentially very useful and beneficial for certain groups of cancer survivors. It's just that at this point, we don't have evidence to say who it is going to have optimal outcomes for compared to other kinds of survivorship care models.
Shannon Westin: And that makes sense. I mean, I think we're seeing this over and over again in all aspects of cancer care that one broad stroke or one broad plan isn't right for everybody, whether that's therapeutic or surgical or prevention, so it makes sense to me that that's what we're seeing here in survivorship as well. So I see this manuscript as a call to action about what are we missing, what data do we need to generate to really be able to move this care forward. So that makes total sense to me. And I guess in line with that, another belief, and I've heard this all the time from my patients, too, is this idea that primary care providers feel unable to provide survivorship care. They're not comfortable. “Oh, you have a diagnosis of cancer. You have to be seen there at the cancer center.” What does our evidence demonstrate here?
Dr. Emily Tonorezos: This is another belief that was found to be a presumption. So that means that this is a belief that we think was true, but which convincing evidence does not confirm or disprove. So what the available evidence tells us is that primary care providers do have challenges in taking care of cancer survivors, particularly with regards to certain cancer-related care needs. But at the same time, we found lots of evidence that primary care providers are more than willing and able to take care of cancer survivors. They express confidence in their skills. They think that they are capable of taking care of cancer survivors. And especially for survivors of more common cancers, primary care providers, in general, express a lot of confidence in their ability to take care of those patients. What they might lack could be things along the lines of survivorship-specific knowledge. So that is a gap that we identified. But this idea that primary care feels unable to take care of survivors really was not supported by the evidence.
Shannon Westin: I mean, and that makes sense, right? If we're seeing more and more cancer survivors, primary care is going to adapt to that. We adapt to the things we see commonly in our clinics, and that goes across all specialties. So that certainly makes sense. I guess you've already kind of said this, and I'll just highlight it for the listeners. You know, clear guidelines seem to be a clear, nice option to potentially improve this situation.
So let's discuss this next myth that you all identified, that oncology providers are hesitant to transition survivors to primary care. Now, I understand this one because I definitely, we get this a lot, and I'm a center medical director in GYN, and we've definitely tried to put patients that are free of disease out back in the community to be able to free up space for other patients. And we definitely get pushback because seeing patients that are in this state of being free of disease and they're living their life, it's inspiring. We remember why it is we're doing the things we do. What did the data show us about this myth? And are we creating barriers to this transition to survivorship care outside of the oncology centers?
Dr. Emily Tonorezos: Exactly. So this belief is a myth. We found evidence that this belief is not true, and it seems to be one of those things that feels true, that oncologists want to take care of cancer survivors, that it contributes to the joy of medicine. But that evidence really does not suggest that that's the case. In fact, the opposite is true in the evidence. We found when we looked at the available research Oncologists want to take care of people who are diagnosed with cancer and need treatment. That is really what they think their role is. That's what they feel they're contributing. And so, even though there is a pleasure in seeing a person who has finished treatment, most oncologists say that the amount of time that they spend taking care of people who are done with treatment is appropriate - meaning they're not looking to expand their panel of post-treatment patients. They really want to take care of people who need treatment currently and then perhaps have a little bit mixed in of people who are done with treatment or who are in that survivorship phase.
We found a lot of evidence, also hard evidence, that oncologists are, in fact, transitioning survivors to primary care. There is a lot of evidence that people who have been diagnosed with cancer are being seen in primary care and that that proportion increases over time. So if oncologists were really creating these insurmountable barriers to transition to primary care, we would not be seeing so many survivors in the primary care setting. But the fact is they're there, and they are being moved there by their providers.
Shannon Westin: I love hard evidence. I do have a few patients that have said, "Can I just come see you every once in a while?" And I love seeing them, but I agree, we can't fill our panels with that. So that makes good sense.
So the next topic centers around finances, and this is the idea that survivorship clinics lose money. What truth did you all discover here regarding reimbursement for this type of care?
Dr. Michael Halpern: We discovered that this is a presumption. It's a belief that there isn't compelling evidence one way or the other. Part of the issue with this is probably some confusion about what constitutes survivorship care. There are certainly difficulties in obtaining reimbursement for certain survivorship services, such as sexual health and fertility counseling, and wellness and exercise services. It's understandable that there may be problems getting reimbursement or appropriate reimbursement for those. But when looking at overall survivorship care, there are actually very few studies that have done a financial analysis of the cost of providing that care versus the reimbursement. And those that have done more detailed analyses generally show that the reimbursement for survivorship care is greater than the cost. Survivorship care clinics actually do break even or make money.
Now, it's also true that providing survivorship care likely doesn't provide the same level of reimbursement as providing oncology treatments, which involves administering systemic agents and different kinds of imaging or diagnostic procedures. And so there are other streams of reimbursement possible for that. But overall, there really isn’t compelling evidence to indicate that survivorship clinics lose money. There is a concern that having this widespread belief that they do may be a disincentive for hospitals or healthcare systems to start different kinds of survivorship clinics.
Shannon Westin: I think this is an area where it would really behoove us to do more work so that we can encourage institutions to do this. And, I know in our center, the things that you're mentioning, it's exactly like the problems that these people are having around sexual health and fertility and exercise, wellness in general, I mean, those are the soft things that I feel like it's harder to kind of gain momentum to really develop established programs that really make an impact. And so I was so glad to see that you mentioned that in this paper, and I hope it will encourage people to really move that forward.
So finally, I was interested in this presumption around the shared electronic health records and how that might help with survivorship care coordination. Is this our solution for smooth communication and care of these people?
Dr. Emily Tonorezos: This one was actually almost something that's sort of funny to think about, how naive we were about electronic health records. We found a number of examples from five or ten years ago where leaders in survivorship research and clinical care were saying, "Well, once we have electronic health records, we will not have these same problems of care coordination or communication." And that has just not been true, unfortunately. So this one was also a presumption, meaning the evidence of a benefit for electronic health records just was not out there. So we know that consolidation and transfer of diagnostic and treatment information can increase knowledge. So you can show that you can increase knowledge about diagnosis and treatment with a shared electronic health record. So the primary care provider is able to look, for example, at the pathology from the original diagnosis. But whether that actually results in anything in terms of improved care is an open question.
Shannon Westin:I think that's what we've learned a lot about electronic health records in general. I remember when we were transitioning to our new system, and everyone thought, "Oh, this is going to be the end all, be all." And it has been good in a lot of ways, but it certainly hasn't been the cure for everything that ails us.
Well, I'm just so thrilled. Thank you all so much. This has been really educational and so important, given what we've already talked about, about the increasing population of cancer survivors that we're seeing in the clinic and globally. I think just to kind of tie a bow on it, I would just love to hear each of your bottom lines regarding kind of where we are right now with the care of our cancer survivors and what we need to be addressing maybe in the short term to move things forward.
Dr. Emily Tonorezos: So I'll go first. I just want to say it's really important, I think, when we are around other investigators and in our meetings and talking about clinical care, that we think critically about the things that we hear people saying. This idea, especially the one that oncology providers don't want to transition their survivors to primary care, but the others as well. I think the way that we need to address this or carry this forward is to just be aware when we're in those settings and we hear people say things, to ask the question, "Is that really supported by the evidence?" And you may find that there are even more of these commonly held beliefs that really aren't supported by the evidence or that deserve a little bit of a deeper dive.
Dr. Michael Halpern: I very much agree with that. And it's critical that we be willing to question some of these beliefs, be willing to discuss them, and not accept them as facts in order to be able to develop new research programs, hypotheses, to explore really what can help produce the best outcomes for survivors, because that's really what we're all about.
The other bottom-line issue, I think, one, Dr. Westing that you brought up, is that survivorship isn't a one-size-fits-all. The best survivorship care is the care that is tailored towards the survivor - the individual needs and wants. What kind of supports will be most effective in terms of enhancing their health? So, we really need to pay attention to the individual and, most importantly, what outcomes for survivorship care matter most to the survivor? What do they want to see happen? What do they want their subsequent future to look like? And how do we measure those outcomes to ensure that they get the best care on the terms that they want?
Shannon Westin: Well, great. I think that's a perfect place to end. I just want to, again, thank my guests. This went by so fast, and I learned a ton, and I hope all of you did as well. Again, we were discussing the Comments and Controversies manuscript "Myths and Presumptions about Cancer Survivorship" published in the JCO on November 16, 2023.
Thank you again to our listeners for joining JCO After Hours. And please do check out our other offerings wherever you get your podcasts. Have an awesome day.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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In this JCO Article Insights episode, Alexandra Rojek provides a summary on two long term follow studies: "Long-Term Follow-Up of Rituximab Maintenance in Young Patients With Mantle-Cell Lymphoma Included in the LYMA Trial: A LYSA Study" by Sarkozy, et al published on December 18th, 2023 and "Long Term Follow Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma," by Kahl, et al, published January 9, 2024.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing two clinical trial updates published in the March 1st issue of JCO, focusing on the long-term outcomes of rituximab therapy for patients with lymphoma. The first paper discusses the use of maintenance rituximab for mantle cell lymphoma patients in the LYMA trial, and the second paper addresses rituximab dosing strategies for low tumor burden follicular lymphoma in the RESORT study.
The first article by Sarkozy et al. for the LYSA group is titled "Long-Term Follow-Up of Rituximab Maintenance in Young Patients with Mantle Cell Lymphoma Included in the LYMA Trial: A LYSA Study." The LYMA trial was designed to answer whether the addition of the CD20-targeting monoclonal antibody rituximab provided additional benefit for patients with mantle cell lymphoma who achieved a response to induction chemoimmunotherapy, followed by consolidative autologous stem cell transplant in randomized patients, maintenance rituximab for three years versus observation alone. The primary analysis of the LYMA trial was published in 2017 and showed that the primary endpoint of four-year event-free survival or EFS was met at 79% in the maintenance rituximab arm compared to 61% in the observation alone arm. Additionally, there was a four-year overall survival or OS benefit of 89% versus 80% in favor of maintenance rituximab. Thus, on the basis of the LYMA trial primary analysis, the use of maintenance rituximab after consolidative autologous stem cell transplantation has become the standard of care in the field for these patients.
The long-term safety and efficacy data presented in this clinical trial update for the LYMA study continue to demonstrate ongoing EFS and OS benefit for patients randomized to maintenance rituximab. Patients were initially enrolled between 2008 and 2012, and 240 patients were randomized to either arm. EFS in this study was defined as absence of disease progression, relapse, or death, severe infection, or allergy to rituximab. The data cutoff for this updated analysis was April 2019, with a median follow-up from randomization of seven years for living patients with a note that this is prior to the COVID-19 pandemic. For those in the maintenance rituximab arm, the seven-year EFS was 76% compared to 46% for those under observation. For those on the rituximab arm, the majority of relapses occurred within three years of randomization and thus while on maintenance rituximab, which the authors suggest does not show an increase in incidence of relapse after the end of maintenance therapy. The seven-year overall survival was 83% for those on the rituximab arm compared to 72% for those on the observation, with a log-rank p-value of 0.08. There was no difference in causes of death between the treatment arms noted.
Notably, the patients who received maintenance rituximab after induction and transplant experienced a shorter second OS after relapse therapy, with a median OS2 of 1.1 years compared to 4.6 years favoring those on the observation arm, without impact of the type of salvage therapy received. Although this study was conducted before BTK inhibitors were approved in France and thus used at a low rate for patients who relapsed after initial therapy. This suggests that those who relapse after maintenance rituximab were those with the most aggressive disease biology. The authors also identified a group of patients who experienced progression of disease within 24 months of initial therapy or POD24 and showed that a Ki-67 score greater than 30% and high MIPI score were prognostic of POD24 events. For those who experienced POD24 within the rituximab arm, they also experienced a shorter OS2 compared to those on observation, again suggesting that those whose disease relapses after maintenance rituximab tend to have more aggressive and difficult-to-treat.
While the interpretation of post-relapse outcomes and therapies needs to be interpreted in the light of a different era of available therapeutic options in more recent years, particularly the newest generation of BTK inhibitors, this updated follow-up of the LYMA study provides additional strength to the standard of care established through the trial's primary analysis of the benefit of maintenance rituximab after induction therapy and consolidative autologous stem cell transplantation for patients with mantle cell lymphoma. Although the extended follow-up was conducted prior to the COVID-19 pandemic, during which increased risk of infection was shown for those undergoing B-cell depletion with agents such as rituximab, this extended follow-up of the LYMA study continues to show that the optimal therapy for mantle cell lymphoma should include maintenance rituximab after transplant. Studies since the design of the LYMA trial have sought to address whether consolidative transplants are necessary when BTK inhibitors are added to induction therapy, and ongoing studies in this era of newer treatment agents will continue to challenge and potentially redefine this now well-established standard of care.
The second article by Kahl et al. is titled "Long-Term Follow-Up of the RESORT Study: E4402, a Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma." The RESORT study, conducted by the Eastern Cooperative Oncology Group, was designed to address whether rituximab-responsive low tumor burden follicular lymphoma patients benefit from maintenance rituximab until progression versus a rituximab retreatment approach at the time of progression. The primary analysis of the RESORT study, published in 2014, did not show a difference in the primary endpoint, which was defined as time to treatment failure. The five-year risk of treatment failure for those on a maintenance strategy was 53% compared to 50% for those on a retreatment dosing strategy. At the time of the primary analysis, letters were sent to participants and providers, and thus the data was locked for further primary endpoint analysis in late 2011. The data lock for long-term follow-up presented in this paper was continued through 2021.
The authors looked at several endpoints in this long-term follow-up. They found that freedom from first cytotoxic therapy, at a median follow-up of almost nine years, favored the maintenance group over the retreatment group, with 83% versus 63% of patients free from chemotherapy or radiation at year seven. When looking at response duration, the analysis also favored a maintenance over retreatment approach, of 66% versus 30% for 10-year response duration, with a median follow-up of 12 years. However, when looking at overall survival at 10 years, there was no difference between rituximab dosing strategies, with a 10 -year overall survival of 83% for those receiving maintenance versus 84% for those receiving retreatment. While this extended follow-up of the RESORT study was not able to assess the long-term follow-up of the primary endpoint, the secondary endpoints suggest that while a maintenance dosing strategy was superior for prolonging time to first cytotoxic therapy and response duration, this again did not translate to an overall survival benefit. The authors conclude that they continue to recommend a rituximab retreatment strategy for these patients instead of a maintenance strategy, in the absence of a survival benefit, particularly with the high response rates observed with next-line treatment strategies for follicular lymphoma patients.
Similarly to the LYMA study discussed in the first paper, the treatment arms of the RESORT study were completed prior to the COVID-19 pandemic. B-cell depletion, such as with prolonged rituximab therapy, is known to negatively impact the ability to combat viral infections such as SARS-CoV-2. Thus, the authors conclude that, in light of current and future infectious concerns, the extended follow-up of the RESORT study does not support the use of maintenance rituximab for patients with low tumor burden follicular lymphoma. Other studies have also evaluated modified and abbreviated maintenance rituximab dosing strategies for this same population and have also not shown a survival benefit, thus further strengthening this recommendation of favoring a retreatment approach over maintenance therapy.
Together, the extended follow-ups of the LYMA and RESORT studies, while addressing different questions regarding the use of maintenance rituximab in mantle cell lymphoma and follicular lymphoma, support the primary endpoints of each respective study. There is a clear role for the use of maintenance rituximab therapy to promote improved event-free and overall survival, as the LYMA study has shown for mantle cell lymphoma patients. However, this does not extend to low tumor burden follicular lymphoma patients in the RESORT study. The updated analyses of these two studies provide additional strength to the nuanced and targeted application of this stalwart of lymphoma therapy that is rituximab, in the modern treatment era. While ongoing studies will aim to address how we optimize therapies with new agents for each subtype of lymphoma patients, the LYMA and RESORT studies continue to guide best practice and standards of care.
This is Alexandra Rojek, thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.
The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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Dr. Shannon Westin and her guests, Dr. Herbert Duvivier and Dr. Richard Schilsky, discuss the paper “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study” published in the JCO.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth into articles published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. As always, it is my pleasure to serve and bring this information to you.
Today, we will be discussing, “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study.” And this was published in the JCO on August 10th, 2023.
None of the authors have any conflicts of interest to disclose.
Joining me today are two of the authors, Dr. Herbert Duvivier, the principal investigator of this arm of the TAPUR trial. Welcome.
Dr. Herbert Duvivier: Thank you.
Shannon Westin: And then, of course, many of you know Dr. Richard Schilsky, who is the former CMO and Executive Vice President of ASCO and a principal investigator on the TAPUR study.
Dr. Richard Schilsky: Thank you, Shannon.
Shannon Westin: So, let's get going. I think the first thing would be great is to level set and make sure everyone knows exactly what this TAPUR basket trial is, the Targeted Agent and Profiling Utilization Registry study. Can you guys give the audience a brief description of the objective of TAPUR and maybe how it came to fruition?
Dr. Richard Schilsky: Sure. This is Richard Schilsky. Maybe I can start with that. The TAPUR study is a prospective, phase II, multi-basket, multi-center genomic-matching trial. Its primary objective is to identify signals of drug activity for targeted agents that are already marketed. But in the TAPUR study they are being used outside of their FDA-approved indication. The study, as you may know, was conceived in 2014, launched in 2016, and is still enrolling patients across the country. Really, the genesis of the study came from the fact that it began at the time where genomic profiling of patients with advanced cancer was becoming more commonplace. Genomic alterations that could be targeted by already marketed drugs were being identified. However, patients and doctors were having difficulty accessing these drugs because they were not used on label and were unlikely to be covered by insurance. And moreover, even if they could access the drugs, there was no organized mechanism to collect outcome data and report on the results of the patient experience receiving that treatment.
So those factors led to the development of TAPUR, which attempts to solve both the drug access problem by having collaborating pharmaceutical companies donate their drugs to the trial so they’re available to patients at no cost, but also implements a structured data collection mechanism so all of the relevant clinical outcomes with the patients can be collected and ultimately reported. And that’s how TAPUR came about.
Shannon Westin: Well, it was so necessary, and I think we do so much of our oncology treatments off-label, but as we get more and more expensive drugs when we move away from chemotherapies and more targeted immunotherapies, it’s very hard to get those drugs off label. So this was such a relevant and necessary trial that had to happen, and it's a great example of leadership that you had the vision to put this together through ASCO.
I think the natural next question for me is having not put patients on the TAPUR study, how does a patient join this study? How do they get started? Walk us through that.
Dr. Herbert Duvivier: At our institution, normally, all the physicians are aware of the TAPUR trial through internal conversations. When they have patients who have been treated with multiple lines of standard therapy, usually the next step for them is to get NGS testing. We have a research team that reviews all NGS testing for these patients and knows the open arms of the TAPUR trial. And if there happens to be a particular patient who may match with one, they will inform the physician. It is then up to the physician to speak to the patient about that option.
Shannon Westin: Do you have people come looking for the TAPUR trial or are these generally more established patients?
Dr. Herbert Duvivier: From my perspective, I think it is usually established patients.
Shannon Westin: I think what I love about this trial, and I have spoken about this trial in lectures around baskets, it’s such a pragmatic design making it as straightforward as possible to really implement across different centers, whether academic or community, or wherever they are. I guess one of the questions always around these targeted therapies is the molecular selection. How do you make sure that people are being appropriately molecularly selected and how do you decide which testing to utilize?
Dr. Richard Schilsky: As you pointed out, Dr. Westin, the goal of the study from the beginning was to have a very pragmatic design, in a sense to have this study attempt to replicate the way oncologists were deploying precision medicine in their practice. The study has broad eligibility criteria, it has minimum necessary data collection, it uses conventional clinical evaluations, there are no additional clinical evaluations required that are not part of routine clinical care. And it just makes it easy to embed the study into the clinical workflow. The study is based largely at community sites, about 85% of the 268 participating sites are located in smaller communities. The study has a set of genomic matching rules that are listed in the protocol and baked into the IT platform for the study as a rules engine. For every treatment available in TAPUR, there is a set of genomic inclusion and exclusion criteria.
So in essence the way it works, the physician determines that NGS testing is appropriate for their patient and can use any NGS test they want, as long as the test is performed in a CLIA certified, CAP, or New York State-accredited laboratory. They select the test, they select the biospecimen to be tested, they get the results, they look at the results, and they determine if there is a genomic alteration in the patient's tumor that is targeted by one of the study treatments in the TAPUR study. They can enter that into the rules engine, the rules engine will confirm or not that the appropriate alteration of treatment has been selected. If it is confirmed, then the patient can immediately be enrolled in the study if they meet the clinical inclusion and exclusion criteria.
If the rules engine does not confirm the treatment match is appropriate, or in some cases there are multiple possible treatment matches, if there are multiple alterations that can be targeted, or another case is the doctor is simply uncertain about which alteration is best to target, then the clinical site can send that patient case to the TAPUR molecular tumor board. A group of experts convenes weekly that reviews the clinical history, the pathology report, genomic test report, the prior therapy the patient has received, and they make a determination as to whether or not there is an appropriate therapy that’s available on TAPUR for the patient. And if not, then are there other potential therapies that are available that could be considered. That information is sent back to the treating physician who determines whether or not here she feels that treatment option is appropriate for their patient, and if so, the patient can then be enrolled and receive the therapy.
Shannon Westin: So awesome. I love the idea. If we don’t have an arm for you on our trial, we can help assist you potentially determine an option for your patient outside of that. That’s so clever.
Okay. So let’s get into this particular arm. Obviously, our audience is quite savvy and are aware of the role of immune checkpoint inhibition across a number of solid tumors. Could you describe what you sought to determine in this particular arm of the TAPUR study?
Dr. Herbert Duvivier: I think one of the most important things to remember about this study is that this study was opened and accruing prior to pembrolizumab becoming FDA approved in, I think, June of 2020. So prior to June of 2020, there was no indication for pembrolizumab in high TMB tumor types and the goal of the study was to determine if pembrolizumab had any overall response rate, duration of responses, progression-free survival, or overall survival advantage over what would be considered standard chemotherapy at that time in patients with high TMB.
Dr. Richard Schilsky: Yeah, that's exactly right. And in this paper that we're discussing, we're reporting on two different groups of patients. So there's a group of 28 patients, all with colorectal cancer, all of whom had high tumor mutation burden, as defined by the protocol. And that's one group. Then there's a second, larger group of patients, which is a very heterogeneous group of solid tumor patients. And the reason that that group is reported is there were patients who were being enrolled with multiple different tumor types with high tumor mutation burden. Each tumor type determined a specific, tumor-specific cohort in the study, and they were enrolling at different rates depending upon how common the particular tumor type was. But once the FDA approval for pembrolizumab, for any tumor with a high tumor mutation burden, was granted, then all of those cohorts essentially had to close to new enrollments because there was no longer an off-label use for pembrolizumab in that setting - everything was now on the label.
The result was that we then basically collapsed all of the open cohorts that were not then going to be able to complete into this one large, heterogeneous cohort that's being reported in this paper. And going back to the colorectal results, in the paper, we describe a disease control rate of 31%, an objective response rate of 11%. There were three patients who had partial responses lasting 12, 27, and 97 weeks each. And I think it's important to point out that in this particular cohort, essentially all of the colon cancer patients were microsatellite stable. So that's an interesting nuance here because we know that pembrolizumab is active and has an FDA approval in microsatellite high tumors. But this particular group of patients was essentially all microsatellite stable, suggesting that even in that population, if the tumor also has a high tumor mutation burden, the patient has the potential to respond and benefit from the treatment.
Shannon Westin: I found that very intriguing. And, of course, as a gynecologic oncologist that treats endometrial cancer, I'm always thinking about MSI and microsatellite stability. So I was very intrigued by this. We are not seeing a ton of TMB high in our population, but there are some patients that do have that.
So let's talk a little bit about the results for the collapsed all solid tumor group. What did you find there?
Dr. Herbert Duvivier: In the histology pool cohort, there were 47 patients representing 21 different tumor types, with a median tumor mutational burden of approximately 13 mutations per megabase with a range of 9 to 228. 40 of 47 patients had MSS disease, microsatellite stable disease. 6 of the 47, MSS was not reported, and 1 case was ambiguous. The disease control rate was about 45%, and the objective response rate was 26%. There were 3 complete responses: 1 in bladder, 1 in parotid, and 1 in squamous cell carcinoma. 9 partial responses and 9 stable disease 16 plus weeks. Of interest in the patients that were responding, 10 out of the 21 patients had POLE or POLD1 mutations, and 9 of the 21 patients had BRCA1 or BRCA2 mutations, although most of those mutations were classified as variants of uncertain significance.
Shannon Westin: That's really interesting. We've seen pretty good data for POLE and benefit from immunotherapy, although at least in the GYN tumors and especially in endometrial cancer, those patients usually do well no matter what you do with them. And so they don't often make it to get immunotherapy because they have a complete response up front to their surgeries. So very intriguing to see that driving benefit. I'm just interested to see because it seems like there's a range that you were quoting of what was considered to be TMB high. So did you see a correlation for response to therapy based on how high the tumor mutational burden was in a given tumor or tumor type?
Dr. Herbert Duvivier: Yes, actually we did see a moderately negative correlation between maximum percent change from baseline in a tumor and increasing TMB, which indicated an association between a higher TMB and greater shrinkage of tumor lesions.
Dr. Richard Schilsky: I should point out, by the way, that when we introduced this arm into the TAPUR study, this high tumor mutation burden arm, as Dr. Duvivier has already pointed out, it was prior to, of course, the FDA approval, and the FDA approval is for tumors that have at least 10 mutations per megabase. It was also prior to the adoption of that threshold of 10, based on work by Friends of Cancer Research and others as sort of the convention for what defined a high tumor mutation burden. So when we put this into TAPUR, we essentially consulted with some of the testing laboratories. We consulted with Merck, the sponsor for pembrolizumab and actually in the TAPUR study, we defined a threshold of 9 mutations per megabase as defining high tumor mutation burden.
Now, as Dr. Duvivier said, there's a broad range of tumor mutation burden represented in this population, and there does seem, if you look at, if the readers want to look at figure 4 in our paper, there does seem to be a general correlation between best response and number of mutations per megabase, which also holds true in a modest way for both progression-free and overall survival. So, TMB is somewhat predictive of favorable outcomes. It's not a perfect biomarker by any means, but generally speaking, if you have enough patients, you can define this sort of trend to support the notion that the more mutations, the greater the likelihood of benefit.
Shannon Westin: That makes a lot of sense. One other thing that I just wanted to comment on before we kind of bring the podcast to a close is I was really struck by the high proportion of underrepresented minorities in this arm of TAPUR, and I just would love to hear your thoughts on how the design improves recruiting in this population of patients.
Dr. Richard Schilsky: This was a goal of the study, very intentional. When you look at the overall study demographics, there are about 2800 patients now that have been enrolled on TAPUR overall. Almost 12% are black, about 6% are Hispanic, about 4% Asian. The median age is about 64. So it's a slightly older population. The goal always was to enroll a population of patients in TAPUR that was broadly representative of the patients that oncologists treat in practice. In the way we accomplished what we've accomplished, we still have work we can do to improve it. But the clinical sites were carefully selected and vetted. We focused on sites that served a significant fraction of minority patients. We made the eligibility criteria simple and broad, so many of the eligibility criteria that might typically exclude minority populations or older patients from clinical trials are not exclusion criteria in TAPUR. We made the operations of the trial simple, so patients really aren't asked to do much more than what they would normally be asked to do in the course of their routine cancer care. So I think all of those things together have made it possible to attract and enroll a more representative patient population in the study. And we're very gratified by that because when you look at many of the registration trials for many cancer drugs, minorities and older people are terribly underrepresented. So we feel that TAPUR is adding value there and adding useful information.
Shannon Westin: I think it's so generalizable and really the way people are practicing, and so to see similar results or concordant results, despite not as much of the rigorous testing and potentially exclusion of certain patient populations is really reassuring and certainly very exciting.
The last question is what's coming next? What other arms are coming soon? And can sites still join? Is this something where it's ongoing enrollment and participation?
Dr. Richard Schilsky: So sites can still join. There's a place on the ASCO website where sites can find more information about TAPUR, and there's essentially a form available where sites can indicate their interest in joining the study. And then those sites are then evaluated by the TAPUR study team to determine if they meet the minimum necessary requirements to qualify to join the study. There's a lot more data coming out, many more papers that are in press and being written. There are two abstracts that will be presented in April at the AACR meeting. There are three abstracts that have been submitted for the ASCO annual meeting. So a lot more data to come.
This is a study that, at least hypothetically, could continue in perpetuity as long as we're able to continue to attract new drugs and new treatment combinations onto the TAPUR study platform. So the TAPUR team is always on the lookout for drugs that are about to get an FDA approval and that could be appropriate for the TAPUR study and continue to talk to many pharmaceutical companies about their interest in potentially putting their drugs on the platform.
Shannon Westin: Well, great. Thank you both for taking the time. I know you're both incredibly busy.
Again, this has been “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study.” I'm your host, Shannon Westin, and I'm so grateful that you joined us on JCO After Hours. Please check out our other offerings on the website or wherever you get your podcasts. Have an awesome day.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Duvivier's COIs: Speakers' Bureau Company name: Guardant Health Company name: AstraZeneca Company name: Regeneron
Schilsky's COIs:
Leadership Company name: Clarified Precision Medicine Company name: Leap Therapeutics Stock and Other Ownership Interests Company name: EQRx Company name: Leap Therapeutics Consulting or Advisory Role Company name: Cellworks Company name: Scandion Oncology Company name: Bryologyx Company name: Illumina Company name: EQRx Company name: Syapse Company name: Zephyr AI Company name: AADi Research Funding Company name: AstraZeneca Company name: Bayer Company name: Bristol-Myers Squibb Company name: Genentech/Roche Company name: Lilly Company name: Merck
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In this JCO Article Insights episode, Giselle de Souza Carvalho provides a summary on "Pathologic Exploration of the Axillary Soft Tissue Microenvironment and Its Impact on Axillary Management and Breast Cancer Outcomes" by Naoum, et al and "Optimization of Breast Cancer Regional Nodal Management" by Braunstein et al published in the January 10, 2024 issue in Journal of Clinical Oncology. The original report discusses how the examination of axillary soft tissue beyond lymph nodes is often omitted and it predicts breast cancer outcomes and need for nodal radiation.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Giselle Carvalho: Welcome to the JCO Article Insights episode for the February issue of the Journal of Clinical Oncology. This is Giselle Carvalho, your host, one of the ASCO editorial fellows at JCO this year. Today, I'll be providing a summary of an article focused on “The Association of Axillary Soft Tissue Involvement on Outcomes for Breast Cancer Patients.” It was published in November 2023 and was partially presented at the 64th Annual ASCO in October 2022.
Although lymph node involvement in breast cancer patients is correlated with a worse prognosis, the impact of extracapsular involvement is still a matter of debate, and the implications of axillary soft tissue involvement are still not fully understood. There is some evidence indicating a decrease in disease-free survival for patients with less than four lymph nodes and with extracapsular extension, while other studies show that extracapsular involvement has no prognostic role in these patients and that the number of positive lymph nodes might matter more. Patients with node-positive disease may present with only lymph node involvement or lymph node involvement plus extracapsular extension and/or axillary soft tissue involvement. The axillary soft tissue involvement can result from either direct lymph node extension through the capsule or direct microscopic spread from the primary tumor. It is pathologically defined in this article as axillary lymphatic channel invasion, axillary soft tissue deposits, axillary blood vessel invasion, or any combination of these.
This was a retrospective study of patients with invasive breast cancer who received treatment at Massachusetts General Hospital in Boston, Massachusetts, from 2000 to 2020. Lymph nodes and surrounding adipose tissue were submitted in their entirety for histopathologic evaluation using hematoxylin and eosin stain, and immunohistochemical stains could be added at the pathologist's discretion. Eligibility criteria included primary breast cancer and positive lymph nodes without prior or contralateral breast cancer. 2,162 patients were included. They were divided into four groups according to their axillary pathology: the first group was composed of patients with positive lymph nodes with no additional axillary involvement; the second group of patients with positive lymph nodes and extracapsular involvement; the third group of patients with positive lymph nodes and axillary soft tissue involvement but with no extracapsular extension; and the fourth group of patients with positive lymph node and both extracapsular extension and axillary soft tissue involvement.
Primary endpoints were 10-year rates of local-regional failure, which was defined as recurrence in the breast or chest wall or ipsilateral axilla, axillary failure, and distant metastasis. Among 2,162 patients, 58% had lymph node involvement only, 25% had lymph nodes with extracapsular extension, 3.5% had lymph node involvement with axillary soft tissue involvement, and 14% had lymph node involvement with both extracapsular and axillary soft tissue involvement. 51% of cases of axillary soft tissue involvement were in the form of axillary lymphatic channel invasion. The median follow-up was 9.4 years, and 74% of the cohort had hormone receptor-positive breast cancer, 10% had triple-negative disease, and 16% had HER2-positive disease.
The groups with axillary soft tissue involvement, extracapsular extension, or both had more advanced tumor pathologic features when compared to the lymph node-only group, including a higher median size of breast tumors, a higher number of malignant lymph nodes, and an increased likelihood of breast lymphovascular invasion. Additionally, more patients in these three groups received mastectomy, axillary lymph node dissection, regional lymph node radiation, and systemic therapy.
The lymph node-only group had the lowest 10-year incidence of distant failure, 13%, while the group with extracapsular extension and the group with axillary soft tissue involvement both had a 23% rate of distant failure at 10 years. The risk of distant failure reached an impressively high rate of 42% for the group with both extracapsular extension and axillary soft tissue involvement.
Considering 10-year local-regional failure, the first group had a 6.2% rate, the second group a 5.7% rate, the third group a 10% rate, and the group with lymph node positivity with extracapsular extension and axillary soft tissue involvement had a 14% rate. The 10-year axillary failure rates were only 1.6% and 0.8% for the groups with no axillary soft tissue involvement but rose to 4.6% and 4.5% for the groups which did have axillary soft tissue involvement. In multivariable analysis, including tumor size, grade, number of positive nodes, and receptor status, axillary soft tissue involvement remained significantly associated with distant failure with a hazard ratio of 1.6, local-regional failure with a hazard ratio of 2.3, and axillary failure with a hazard ratio of 3.3. Of note, the number of axillary failures was overall low, only 4.6% in the group with both lymph node and axillary soft tissue involvement.
Delivery of regional lymph node irradiation, defined as treatment of axillary, supraclavicular, and internal mammary nodes, was associated with improved local-regional outcomes in patients with extracapsular extension or axillary soft tissue involvement with a hazard ratio of 0.5 and a p-value of 0.03 but was not associated with any improvement in distant failure.
The authors described the main limitations of this study as the retrospective nature and the absence of genomic marker results. In summary, although current guidelines do not emphasize axillary soft tissue examination, this study shows the importance of reporting axillary soft tissue involvement beyond the number of positive lymph nodes and the presence of extracapsular extension, as there is an increase in local-regional, and axillary failure rates for patients with axillary soft tissue involvement even without extracapsular extension. Therefore, both extracapsular extension and axillary soft tissue involvement should be consistently reported in large randomized trials as we continue to work to tailor local therapy to individual patient risk.
This is Giselle Carvalho. Thank you for your attention and stay tuned for the next episode of JCO Article Insights.
The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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Dr. Shannon Westin and her guest, Dr. Reshma Jagsi, discuss the paper "Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA" recently published in the JCO.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth with manuscripts that were published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the JCO. It is my pleasure to speak with Dr. Reshma Jagsi. Hello, Dr. Jagsi.
Dr. Reshma Jagsi: Hello. Thanks for having me.
Shannon Westin: I am so excited that you're here. Dr. Jagsi is the Lawrence W. Davis Professor and Chair of the Department of Radiation Oncology at Emory University School of Medicine, Winship Cancer Institute. She is going to be talking about her incredible work, "The Omission of Radiotherapy After Breast Conserving Surgery for Women with Breast Cancer with Low Clinical and Genomic Risk: Five-year Outcomes of IDEA," which was published in JCO in February 2024.
All right, let's get right to it. First, I want to levelset. Can you run us through some brief facts and figures about breast cancer just to make sure that all the listeners are on the same page?
Dr. Reshma Jagsi: Breast cancer is the most common cancer in the world. It’s 12.5% of all new annual cancer cases worldwide and is the most commonly diagnosed cancer among US women. About a third of all newly diagnosed cancers in women are breast cancer, and about 13% of US women develop invasive breast cancer over their lifetime. In 2023, there were nearly 300,000 new cases of invasive breast cancer. The median age of breast cancer diagnosis is 62, meaning an awful lot of people are getting diagnosed with breast cancer in the population that we specifically chose to study.
Shannon Westin: Wow, you're really good at this. That's like the perfect transition to move to the next piece. So, first, I think I'd love to hear about the standard of care for the population that you were studying and how we got to this point.
Dr. Reshma Jagsi: We offer women who are diagnosed with early-stage invasive breast cancer the option of breast conservation, and we encourage breast conservation because, of course, it is a better-tolerated surgery than mastectomy. Many women are eligible for breast-conserving therapy. And years ago, we as radiation oncologists encouraged our surgical colleagues to refer to breast-conserving therapy as lumpectomy plus radiation, just as one set. Because the studies that have been done in the 1970s and 1980s to establish that breast conversation was equally safe and effective in treating breast cancer relied on radiation therapy to minimize in-breast tumor recurrence rate, which one of those trials independently showed that there was no difference in survival. But the ones that compared lumpectomy surgery alone to lumpectomy followed by radiation therapy did show a pretty substantial improvement in local control with the addition of radiation treatment. And so radiation treatment became a part of a parcel of breast conservation in the early 1990s when consensus statements came out favoring breast conservation as a treatment approach.
And so the net analysis has combined all of these studies together and showed that overall, without radiation treatment, a patient treatment with a lumpectomy had a 30% risk of in-breast tumor occurrence in those historical studies. And it was reduced by about two thirds to about 10% when that lumpectomy was followed by radiation in those historical randomized trials. But of course, we’ve made many advances in our understanding since that time, and so that’s what this study is seeking to build on.
Shannon Westin: It makes sense. We all know that radiotherapy can lead to other issues, acute and chronic morbidities, as well as cost and having to do the treatment itself. So we're all interested in de-escalation of therapy. Tell me, prior to your study, what data were out there potentially supporting the de-escalation and avoiding radiotherapy in that specific population?
Dr. Reshma Jagsi: In the ‘90s, after those landmark foundational historical trials have been completed, there was a lot of interest in seeing if we could identify a population of patients in whom the risk of local recurrence was sufficiently low that they might safely choose to omit radiation therapy. All of these randomized trials have shown very consistently that there is a relative risk reduction. Whatever your risk is without radiation, radiation reduces that risk. The overall disease recurrence risk is cut in half with the addition of radiation treatment. But, if I told you that your overall risk was 1%, and I could cut that in half with radiation, you might say, “I might be willing to tolerate the 1%.” At least some women might be willing to tolerate that. So can we find a population in whom the risk is low enough that at least some of those women say, "Look, I want to go without radiation." And of course, the balance of where that number should be changes as we get better and better at delivering radiation.
So you mentioned, radiation comes with toxicity, comes with burden and yet, there have been some tremendous advances, and particularly in recent years, to shorten the course of radiation. We have evidence that we can treat partial breast radiation safely in five treatment fractions. We have five-year data that we can treat the whole breast in five-treatment fraction. We certainly have long term evidence that we can the whole breast with 15 fractions from many patients diagnosed with breast cancer. So the burden has decreased. We’ve also found that with hypo fractionated shorter courses of radiation, the toxicities are much lower, patients tend to tolerate radiation treatment both in terms of acute side effects and long term side effects extremely well. So that balance of what is low enough is changing with time.
But the trials that were started in the 1990s included the CALGB 9343 trial, a landmark trial published in the New England Journal of Medicine, with its five-year results showing only a 4% risk of recurrence at five years in patients who were 70 or older with clinical stage one disease that was hormone receptor-positive if they received a lumpectomy and tamoxifen alone, not receiving radiation - that risk, if we added radiation in this randomized trial, was only 1%. So there was still a substantial relative risk reduction with radiation treatment. This was published in 2004 in the New England Journal of Medicine.
At the same time, there was a Canadian trial that was published, and in that trial that included women who were 50 years of age and older, there were more concerning results with, even in a very favorable prespecified subgroup of patients who had node-negative breast cancer and T1 hormone receptor-positive tumors, the risk of ipsilateral breast tumor recurrence was 15% at eight years. So that started to feel excessive for women 50 and older.
Meanwhile, we went on to get the update of the CALGB trial, and the 10 -year results showed that the risk was, in the women 70 and older, was only about 10% without radiation. It was 2% with radiation. So again, there was a benefit from radiation, and it's up to each individual woman to decide whether they'd prefer to proceed and minimize their risk, or would be willing to tolerate something like a 10% risk. More recently, just this past year in the New England Journal, the PRIME 2 study from the United Kingdom, looking at women 65 and older, again, early-stage node-negative hormone receptor-positive tumors, and very similar results - 10% versus 1% local control at 10 years.
So you get an improvement with radiation. But there are some women who are 65 or 70 and older who say, I'm willing to tolerate the 10% risk. And so the question was, could we identify some patients who are younger than 65 to 70, but still postmenopausal, like in that Canadian trial, who might actually have similar outcomes - low risks at five and ten years - such that they might want to entertain the option of omitting radiation therapy, which right now is not standard or in any guidelines? So we have some promising information from some retrospective analysis of that Canadian trial that suggested that looking at biology might help. And in fact, the LUMINA trial, published just this year from Canada, did a prospective cohort study selecting patients based on immunohistochemistry, and suggested very low risks, five years in patients who were somewhat younger, although it ended up that the median age of the patients in that study was 67. So we still sort of had this question of what about the younger postmenopausal patients? And that's what took us to IDEA.
Shannon Westin: And just for my education and for the education of the listeners, when you have an in-breast recurrence, how likely are you to be able to cure that? Is that tough to cure, or can you usually get control again?
Dr. Reshma Jagsi: It's an excellent question. And so often these recurrences are caught early and are still completely curable with additional intervention. Now, there can be an impact, of course. You can talk to any survivor about the devastating impact of being diagnosed with breast cancer recurrence, and no one wants to go through that. And so there are reasons that people will want to reduce that, and there are implications for breast conservation because it may be that the remaining breast tissue is insufficient to allow a second breast conserving surgical procedure. It may also be that when one experiences recurrence, one decides, "I'm done with this. I'm having a mastectomy at this point." So, in-breast recurrences are very meaningful to patients and something that we should not take lightly.
Shannon Westin: It seems, though, the majority of the studies that you were talking about, aside from the LUMINA study, were predominantly based on those clinical features like stage and things like that. So, can you talk a little bit about the role of molecular features, genomic testing, things like that, to select patients?
Dr. Reshma Jagsi: Yeah. So, we have seen a tremendous change in the way we think about breast cancer in recent years, with a real focus on tumor biology, rather than classic clinical pathologic features alone to help us make decisions about systemic therapy. And so, there is a body of work that suggests that genomic assays, including the 21-gene recurrence score, that's commonly used for treatment decision making already ordered in many of these patients and available to us, that it may be useful in understanding patients' risk of local recurrence, both when they are treated with radiation and when they are treated without radiation. So, Terry Mamounas did some wonderful work looking at NSABP data where you know that the mastectomy patients at the time of the studies that were included were not receiving radiation treatment. And it did appear that the 21-gene recurrence score was helping to discriminate for local regional recurrence risk, suggesting it might be useful to use that to select patients who might be at lower risk.
Shannon Westin: All right, perfect. So, that leads us to your study. So, let's talk a little bit about the design and the population and kind of how you put it together.
Dr. Reshma Jagsi: This was really a true collaboration, a partnership across multiple 13 collaborating sites, where my colleagues, the lead investigators at each site, were extremely committed to this question. And we sought to do a preliminary cohort trial, really involving 200 patients. And over the course of three years, we enrolled those 200 patients who were aged 50 to 69 years old and had unicentric invasive breast cancer and lumpectomy surgery that led to negative margins of 2 mm or greater. And their disease needed to be PR positive, HER2 negative, it needed to be node negative, pathologically node negative, and the Oncotype DX 21-gene recurrence score needed to be less than or equal to 18. And then these patients were offered the opportunity to consent and register on a trial to receive five years of endocrine therapy as standard of care alone, and 10 years of surveillance on study, or to proceed with the standard of care treatment off trial, which would have been a recommendation to receive radiation treatment. And so, we ended up with patients with a mean age of 62 years, which, as I said, that's really more mapping the overall population of patients in the country. And we were able to report our results at the San Antonio Breast Cancer Symposium and with simultaneous publication in JCO, with a median follow up of 5.2 years.
Shannon Westin: Okay, and let's talk about a little bit about your major findings. Tell us what your good work demonstrated.
Dr. Reshma Jagsi: So, the overall and breast cancer-specific survival rates at five years were both 100%, and the five-year freedom from any recurrence was 99%, with a 95% confidence interval that went from 96% to 100%. But I want to emphasize that these are five-year data in a younger postmenopausal population, where five-year data are not typically sufficient to guide decision making. So, I really want to emphasize that these are very early results. But really, what happened here was we only had a couple of patients who had recurrences before five years, two patients, and that was one isolated ipsilateral axillary recurrence, and one ipsilateral breast event. But we also did see six additional patients who recurred later than five years after breast conserving surgery. And because we don't have much long-term follow-up, it makes it incredibly important for us to continue to follow this cohort over time before people make any Monday morning practice implications of offering this cohort of patients, or patients like this cohort of patients, omission off trial.
The good news is that there are ongoing trials that are building on this work, including NRG-BR007, the DEBRA ,that includes a population of patients really similar to those enrolled on IDEA and randomizes them to radiation or no radiation, which is actually incredibly important. Because what we want to understand is also the quality of life effects of omitting radiation therapy because what we don't want is to inadvertently cause an increase in worry about recurrence. Or, you could imagine that patients who omit radiation treatment then feel really stuck with their endocrine therapy. Now, endocrine therapy is the standard of care, but if they're experiencing terrible endocrine therapy side effects and they didn't get radiation treatment, are they more likely to persist with that endocrine therapy and to be miserable because they omitted a treatment that, as I mentioned earlier, can be administered now in five days or less?
And one of the questions that keeps coming up from older patients that I treat, where we already offer the option of omitting radiation, those CALGB and PRIME II patients, those patients will often say to me, "I’ve got to say, Doc, that whole experience of radiation that you described for five days, and the toxicity, and that doesn't sound so bad to me. What sounds bad to me is multiple years of endocrine therapy." And so, there are also ongoing trials in Europe, and I hope one day in the United States, also looking at older women and offering them a de-escalation of a different sort. Now that we have made so many advances in radiation treatment, maybe the optimal monotherapy for an older adult is actually, for many patients, given their values and preferences, going to involve omission of endocrine therapy. And we need to find out if that's safe. And again, Europa in Europe is investigating that question, and I hope that the American cooperative groups take up something similar.
Shannon Westin: That’s awesome! And what else is going on in this space? Any other trials? That was like, such a great review of ongoing trials, and I'm sure our listeners would love to have your expertise. Anything else that you're looking forward to that might impact the treatment landscape here?
Dr. Reshma Jagsi: Absolutely, and if there are listeners in other parts of the world, there are trials going on also looking at this. There is PRIMETIME, which is a cohort study designed, but with a much larger cohort that's going on in the United Kingdom. There's the EXPERT trial that is randomizing patients to radiation treatment or not in Australia and New Zealand. So, there are many trials that are ongoing, again, looking at de-escalation of radiation therapy. And I want us all, regardless of our specialty, to think about ways that we can de-escalate and optimize the options that are offered to our patients. And I think there's a tendency for patients to be very scared of radiation, sometimes, for our colleagues to be very scared of radiation. I mean, we are the only specialty that has a special “danger radiation sign” that comes to mind when you hear the word radiation therapy. So, it can be this very frightening thing that we often leap to efforts to avoid.
And what I don't want to be the conclusion of this is, “Isn't it great? Radiation oncologists themselves recognize that radiation is terrible and that you should avoid it.” That's not the case. What I hope people will say is, “Isn't it great that radiation therapists are trying to offer as many options to patients as possible?” Because it means a lot to a patient who's had the sense of power and control and autonomy ripped away from them by a breast cancer diagnosis, to be given many options to articulate their values and their preferences and to decide what treatment makes most sense for them. I think, for a lot of patients, that involves radiation treatment. And I think what we need to do as physicians is think about what other things are our patients really concerned about.
Our medical oncology colleagues have done tremendous work to de-escalate systemic therapy in the form of chemotherapy. Our colleagues in surgery have, again, de-escalated mastectomies, axillary dissection. So, there are these ongoing efforts, and I do honestly believe that the next frontier is endocrine therapy and optimization of endocrine therapy. It is so powerful. It is why we have such wonderful outcomes. We know that we should have a healthy respect for ER-positive cancer, which can recur in the long term. We don't want to throw out the baby with the bathwater, but baby steps towards understanding what happens if we peel back our treatments is our obligation.
Shannon Westin: I think this is a perfect place to end/ I agree - less is more is really becoming a resonant statement across all of our different subtypes. We're certainly seeing it in GYN oncology, and just like you said, systemically or even surgically. So I agree. I think we have a call to action to really assess what we've always done and make sure that we're not over-treating patients for whom it's inappropriate.
So I think this is great. And I just want to commend you again on your work. These types of multicenter trials are really hard to do, and getting it done in such a short period of time and really getting the data out to patients is so important. And I appreciate what you're saying about needing more follow-up, but it is certainly very reassuring and very in line with what we've seen. So congratulations on your work.
Dr. Reshma Jagsi: Thank you. And I just again want to thank all the patients who enrolled, the Coleman Foundation for their support, the University of Michigan for doing the multi-site coordination and the biostatistic support, and all of the collaborating investigators. I mean, this was a labor of love for everyone involved.
Shannon Westin: Yeah, these types of trials definitely take a village. Well, great work. Thank you for taking the time. I know how busy you are. So again, we are so honored and so excited to talk about "The Omission of Radiotherapy After Breast Conserving Surgery for Women with Breast Cancer with Low Clinical and Genomic Risk: Five-year Outcomes of IDEA,” just published in print, February 2024 in the JCO. Definitely check it out. And please check out our other episodes of JCO After Hours. We'd love to have your feedback. Take care.
The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Dr. Jagsi:
Stock and Other Ownership Interests
Company name: Equity QuotientResearch Funding
Company name: Genentech" -
Dr. Shannon Westin and her guests, Dr. Jeremy Davis and patient advocate Kathryn Carr, discuss the paper "Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy" recently published and printed in the JCO.
TRANSCRIPT
Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, a professor of GYN Oncology at MD Anderson, and the JCO social media editor. I am so thrilled to have wonderful authors here today who do not have any conflicts of interest. We are going to be discussing the “Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.” This was published in the Journal of Clinical Oncology online on October 30, 2023, and in print on February 1st, 2024.
And I am excited. I am accompanied by the lead author, Dr. Jeremy Davis, who is an Associate Professor and Surgical Oncologist at the NIH, National Cancer Institute Intramural Research Program. Welcome, Dr. Davis.
Dr. Jeremy Davis: Thank you.
Shannon Westin: If it is okay with you, I'll call you Jeremy.
Dr. Jeremy Davis: Yes, please.
Shannon Westin: Fabulous. We also have patient advocate Kathryn Carr, who is a board member for No Stomach for Cancer. Welcome, Kathryn.
Kathryn Carr: Thank you so much.
Shannon Westin: So let's get right into it. I think this is really thought-provoking work. First, I'd love to level set. So this was work around hereditary diffuse gastric cancer syndrome. Can we get a little bit of information about what causes this and how common it is?
Dr. Jeremy Davis: So, hereditary diffuse gastric cancer syndrome, also referred to as the diffuse gastric cancer and lobular breast cancer syndrome, is basically early-onset diffuse gastric cancer and in women, lobular type breast cancer attributed to germline mutations in the CDH1 gene. If we look at all cases of gastric cancer in the United States, only about 1-3% may be considered hereditary in nature. But when we do study hereditary causes of cancer, it is by far the most common one that we are aware of.
Shannon Westin: What is the likelihood that someone who is a carrier of a germline CDH1 variant will develop gastric cancer?
Dr. Jeremy Davis: That's a good question. Early on, when the syndrome was first described, the estimates of cancer risk were quite high, probably upwards of 70-80%. The good news is that more current estimates published in the last few years suggest that that risk in a lifetime is probably in the 25-40% range. It’s interesting, we do have our own data that are under review right now, where in some families where there’s no history of stomach cancer, that risk of stomach cancer in a lifetime getting a CDH1 mutation might be as low as 10%. So I think the takeaway is that there’s clearly a spectrum and that spectrum of risk is probably based on factors that we don’t quite yet understand.
Shannon Westin: What are the options for management of this hereditary syndrome, really focusing on the gastric cancer syndrome portion today? How good does it do to reduce the risk?
Dr. Jeremy Davis: The options are really two. One is probably the prevailing recommendation that most people would be aware of, is to prophylactically remove the stomach, and we choose to use the term most often ‘risk-reducing gastrectomy’, but to remove the entire stomach and really eliminate the risk of cancer from ever developing. The other option is enhanced surveillance, and people might think of this as akin to other high risk cancer syndromes. But for this we would do yearly or annual endoscopic surveillance. Many people think that that may not be the best option, but it is certainly an option. We discussed some of that in the paper about what are the risks and benefits of gastrectomy, and then what may be the benefit of enhanced surveillance for some people.
Shannon Westin: Well, I would love to hear Kathryn. I think this is a perfect opportunity to hear a little bit about your journey with carrying this variant, as much as you are willing to share with our listeners.
Kathryn Carr: Yeah, absolutely. So I found out that I have this spicy little gene back in 2019. My whole family got tested so the gene comes down from my paternal great grandmother. There are five of us who actually all had our stomachs removed by Dr. Davis. Within a year, he had five Carr stomachs. For me when I found out, I was extremely overwhelmed. I mean, “You want to take my stomach out? Like, what do you mean?” But after talking to Dr. Davis and his entire care team, I knew for me, having the total gastrectomy was the only option simply because I know my personality type enough that I was not going to be able to move forward with life unless I got rid of this overwhelming worry.
Shannon Westin: Yeah, I think that makes sense. I'm a GYN oncologist by trade, so I often reference all things surgery around that. We have the same thing when we talk about risk-reducing surgeries for endometrial and ovarian cancers. This seems more like what we do in Lynch syndrome, where patients are at risk for endometrial cancer. Removal of the uterus is almost definitive in its ability to reduce that risk, but it's obviously a very large surgery. Jeremy, can you review the gastrectomy in general? What are the most common short-term and long-term adverse events? What did you have to discuss with Kathryn and her five family members around what they could expect from this surgery?
Dr. Jeremy Davis: Yeah, I think this is a great question because it's the thing at the top of most patients' minds. When I sit down to talk to somebody about gastrectomy, usually a lot of the conversation initially centers around ‘how long does the operation take, how long am I at the hospital, and what are the most likely risks of the operation?’ The good news is that as operations go, it can be done in two to three hours, and most people are in the hospital for maybe five to seven days. The risks of this operation, however, at least during the operation or immediately afterward have to do with how we have to reconnect everything and reconnecting the intestine to the esophagus so that people can continue to eat. Because I think a lot of people wonder, "Well, how am I going to eat?” The stomach's gone, but we recreate intestinal continuity. We put things back together in a way that people can eat and absorb their food.
But that connection we make between the esophagus and intestine is almost like the Achilles heel of this operation. It's the one thing that keeps surgeons up at night, and it's probably the one thing that causes the most trouble in terms of immediate risks, like leaking. If that connection leaks, it can lead to infection. There are other aspects of the operation that relate to any kind of intestinal surgery, such as leakage, blockage, or narrowing or something like that. So these are the things you need to worry about in the short term. But you mentioned the long-term consequences, and that was really one of the reasons why we wrote the paper. If you look in the literature, the focus is on the acute problems, things that happen within 30, 60, or 90 days of the operation. Which, yes, those are very, very important. But since we're talking about an operation that's supposed to prevent cancer and therefore allow the patient to live a long and happy life, I think it's important for us to think about what happens well beyond the time that the patient essentially heals from the operation.
Shannon Westin: It's so critical. And I think before we go into the work that you did and what you all found, Kathryn, I would love to get your perspective. Having gone through the procedure, what was your experience? Give us as little or as much detail as you want, whatever you're comfortable with. But also, what did you wish you had known? What surprises kind of came up during the course?
Kathryn Carr: I'm going to quote Rachel, who works with Dr. Davis at the NIH. She's the clinical dietitian. And my question to her was, "Seeing all the patients you've seen and knowing all that you know, what would be the advice that you would give me?" She told me to have the patience to get through the first year. I think that really set my expectation of, "Okay, this is not just a surgery where in a week or two weeks I’m going to be up skipping along." It is a marathon. I really worked hard with Dr. Davis in the hospital. I'm allergic to everything. I was convinced that my spleen was erupting. I think I scared many fellows, and they were like, "That's actually not where your spleen is. It's fine. You're okay. Stop getting on WebMD." But once I got home, those first eight weeks, they’re hard. There were several moments where I would just sit and stare off into space and think, "Oh my gosh, what have I done?" But for me when Dr. Davis called to tell me the pathology report and that they did find some signet cells, I was 100% sure that I made the right decision. I would have been worried every second of every day that my body was going to turn on me. So once I kind of had that relief, it was like, "Okay, my body can do this. We're built to do hard things." Then it was just getting through the first six months, learning what I could eat, what I couldn't eat, working with Rachel on different strategies of, “Okay, I’m going to maximize my protein in the morning and then maybe get a little more adventurous as the day goes on.”
But what I wish I had known before surgery, because I'm a planner, I want everything scheduled and figured out. I was in the hospital, I had a different outfit for every day, and I just wanted it to go perfectly. I think taking away the expectations of what your journey is going to look like would be the best advice I could go back and give myself. Because I am very competitive, and my dad and I were separated by seven months of this surgery. He can do things that I still can't do, and that's okay. Everyone's healing journey is going to look very different because everybody is going to respond incredibly different. It's like the body is doing roll call and the stomach is nowhere to be found, and everybody is going to respond totally differently to that.
Shannon Westin: That's so insightful. I really appreciate that.
I guess now it's a good time to turn to the work that you did, Jeremy, and you kind of already hinted at what your objectives were, but can you maybe walk through your primary objectives in the way you designed the study.
Dr. Jeremy Davis: You know, I think as somebody who trained to take care of people with cancer and do big operations to cure people, this was a little bit of a different experience in the beginning for me. Because here I was taking ostensibly normal people - Kathryn may argue with that statement - but normal people, and I was going to take them to the operating room and do something to them to prevent a problem. And this is not a minor thing, it's a big deal. What I learned pretty quickly was how much I was disrupting people's lives. And what I mean by that is that a patient comes to clinic three or six months after surgery. We all document the typical things. They are healing well, they are recovering as expected, their incisions are healed and all this stuff. But it was the stuff that didn't always go down in the medical record. The comments that the patients made to my team, the nurses, the dietitian, about how their lives were being disrupted. And this started to change my viewpoint on, “Oh my goodness, we're paying attention to important things, but we're really not paying attention to what's happening.” So, the idea behind the study was really to explore those consequences that don't get talked about a lot. That was the nature of the idea behind the study. It was easy enough for us to conduct the study because my research at the NIH is about gastric cancer, but more specifically, this hereditary form of gastric cancer. We have a natural history study that allows us to follow people for a long time, not just within three or six months of surgery, and then we're done. So that longitudinal aspect of the study is really what allowed us to accomplish that.
Shannon Westin: What I thought was really interesting here is how many different types of questionnaires you were able to utilize to really assess beyond kind of the straightforward quality of life Yes/No. Can you speak a little bit about some of the questionnaires you chose and why?
Dr. Jeremy Davis: My concern going into this was that I had read a lot of the literature related to quality of life after gastrectomy for gastric cancer. There are certainly these validated questionnaires out there. And my sense was, having read those questions and papers, that those validated typical questionnaires- I'm referring to the FACT-G or the FACT-Ga might not capture the things that we wanted to capture. So, I spoke to our palliative care service here at the NIH clinical center, which is the hospital here on campus in Bethesda. They had developed a questionnaire many years ago that they called the NIH HEALS or Healing Experience of All Life Stressors. They designed that to identify stress causing changes associated with chronic illness. You might argue that having a germline mutation that puts you at risk for cancer is kind of a chronic condition. So, we thought we would use that.
And then the last part was we just sat around the table and we thought, “Well, jeez, what are all these things that people are telling us that would never be captured in almost any questionnaire?” And that's when we designed a series of questions that we thought were relevant to our patient population because we wanted to capture all the things that people had told us. Those were things like, “I had to change my job because I couldn't do the same work anymore, right?” Or, “My partner, our relationship changed substantially, and we grew apart, and we ultimately got divorced.” How do you capture that? So that's how we designed it. We basically looked at all the patients that we had done the prophylactic gastrectomy on and applied all of those validated and unvalidated questionnaires.
Shannon Westin: That's so great. And I bet, Kathryn, you participated quite a bit in that, in addition to other people in the study.
Kathryn Carr: I did, and I'm so grateful that Dr. Davis is doing this study because it is so important to look at what life is like without a stomach. You have this immediate thought of, “Okay, I just want to save my life. I want to make my life longer. But how is it going to change my life? How is it going to alter my day-to-day?” Because even Dr. Davis has said it would be weird if it didn't change your life. I mean, you're taking away a very important piece of the puzzle. So, I think this study is going to help people make more accurate decisions. I don't doubt my decision to have my gastrectomy at all, but this is beautiful information just so that you can be more well-prepared to walk into the surgery of, “Okay, now I have a very clear understanding of what my life could look like.”
I've been very fortunate that I have not had a lot of the physical problems. I don't deal with a lot of bile reflux. My weight has stabilized, so I am very blessed in that way. But emotionally, this has been a really tough surgery. You start to feel misunderstood, like you have to walk into every day being very prepared of, “Okay, every two hours I have to eat something or else I get real hangry, not just a little hungry, real hangry. Also, my body will start to shake.” That's how I get my hunger signal. My whole body will start shaking, which is very scary. It's very unpleasant. I'm almost four years post-op, and so I lean into my schedule and routine.
One piece of advice for anyone walking into this surgery is to make sure you're anchored in something. For me, my faith anchors me, but if you're not anchored in something that is secure and true, like, you are going to float away, because this is a storm.
Shannon Westin: Jeremy, do you want to just pass on a few of the key findings? I encourage everyone to read the paper. There are so many different things that were explored and identified as part of this study. It's amazing with the number of patients that were involved, what the depth of the findings was. But perhaps you can kind of hit some of the major high points.
Dr. Jeremy Davis: Yeah, I think the key takeaways for me, and obviously I'm still learning from all of this, is that I think we talk a lot about the surgery, in this case especially, but we don't talk enough about what life is like afterwards. I've started to talk to people about how much you think your stomach plays a role in your life, and you think about how much of our life centers around eating and drinking and holidays and family gatherings. And you have to imagine that means those activities are potentially disrupted. So for me, the key takeaways from this are, number one, we have to be aware. We have to be aware that risk reducing surgery of almost any kind has consequences. Yes, we want it to have a positive impact on the patient, but we have got to be aware of the negative impact. This is like systemic chemotherapy. It can do a lot of good, but toxicities are real. In terms of the specific findings from this study, listen, 94% of people in the study, 126 of people, 94% had some long term consequence. And it wasn't just like some long term, “Oh, I don't like my scar.” No, it was 94% of people had a long term problem, such as “I have daily bile reflux that interferes with my activities of daily living.” Something like that.
And I think the range of consequences is really important, too. And so, again, they range from things like GI symptoms, which you would imagine would be quite typical for a gastrectomy, but mental health, right? People talking about worsening symptoms of anxiety or depression, some substance abuse. Whether it was alcohol or otherwise, disruptions in relationships, I mentioned earlier, and even occupation change. I can't physically do the job that I used to do. So I think as clinicians, as surgeons that walk into this, yes, we need to focus on the surgery and the immediate consequences, but we also need to think, “How am I going to change this person's life? Not just for the better, but how might I really impair their life in the long term?”
Kathryn Carr: Well, in one, just very simple example. So like going out to eat with people. There's a natural cadence of conversation. I take a bite, you talk and vice versa. But when you're chewing your food to the nth degree it interrupts that natural cadence. I avoid dinner dates because then I have to talk about my stomach on a first date or going out to dinner with friends. It's nice if there's a group of us because then other people can carry the cadence but then you kind of feel left out of the conversation because you're like, “Oh, well. I’ve got to eat, otherwise I'm going to pass out.” So that's just like a very simple, you wouldn't think of, “Okay, I'm going to dinner at 7:30 so I should probably eat a snack before I go because I might not get my food until 8:00 or 8:30.” So it's just like you're constantly thinking about, “Okay, I've got to make sure that I have food in my body.
Shannon Westin: It’s so critical.
Well, this has been an awesome discussion and I'm sad that it's coming to a close. I guess just final thoughts around what's next in this space. Like what are you working on now, Jeremy?
Dr. Jeremy Davis: I'm a cancer surgeon and a cancer researcher so my goal is to find a way for us to prevent stomach cancer that doesn't require me having to take out somebody's stomach. So in the laboratory that's what we're doing, right? We're working on finding a way to prevent stomach cancer so that I don't have to do this operation anymore. But on the clinical side of things, the next thing that we're exploring is how do patients think about, talk about, or express concerns to their physicians about reproduction - reproduction in the setting of a cancer predisposition syndrome. And I think that's going to be really important work.
Shannon Westin: That's great. Kathryn, any thoughts?
Kathryn Carr: I know that being four years out, I'm not like an old timer, but I do just want to help anyone who's at the beginning stages of this journey and just making other patients feel less alone. I told Dr. Davis I just entered the world of TikTok to talk about gastrectomy and just opening up a conversation of what does life without a stomach look like? And just making people feel less alone and more understood throughout this process.
Shannon Westin: Thank you both for the work you're doing, and thank you to all of our listeners for tuning in to JCO After Hours. Again, we were discussing the “Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.” Please do not be a stranger to our podcast. Check out our other offerings and reach out to us on X and Instagram if you have other topics you want us to cover. Have an awesome day.
The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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In this JCO Article Insights episode, Subodh Selukar summarized findings from the original article published in the January 2024 JCO issue: “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” and accompanying editorial “Patient Experience, Adverse Event Reporting, and Clinical Trial Design”. The summary provides information regarding low and moderate grade adverse events and the patient experience in clinical trials.
TRANSCRIPT
Welcome to the JCO Article Insights episode for the January 2024 issue of Journal of Clinical Oncology. This is Subodh Selukar, your host, and today I will be providing a summary on 2 articles focused on low and moderate grade adverse events. The first article, titled “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” by Dr. O’Connell and colleagues, investigated low and moderate grade adverse events and the patient experience in clinical trials. Their article is accompanied by an editorial entitled “Patient Experience, Adverse Event Reporting, and Clinical Trial Design” by Dr. Neuman.
In clinical trials, a standardized system for reporting adverse events is the Common Terminology Criteria for Adverse Events (or “CTCAE”) established by the NCI, the United States National Cancer Institute. The CTCAE categorizes adverse events at 5 severity grades across 26 system organ classes. However, some clinical trials may only report adverse events at grade 3 or higher, with one possible rationale being that low and moderate grades are unlikely to affect patient safety or key trial endpoints.
In Dr. O’Connell’s article, the team investigated how the numbers of grade 1 and 2 adverse events related to patient self-reported side-effect burden and treatment discontinuation. To do this, they analyzed data from the Phase 3 trial E1912 conducted by ECOG-ACRIN comparing two treatments for chronic lymphocytic leukemia. They chose this trial as an example because the study data included all adverse event grades throughout the duration of treatment for each patient.
The authors studied side-effect burden based on GP5, which is the fifth item in the FACT-G subscale in the Functional Assessment of Cancer Therapy. GP5 rates the patient’s agreement with the statement “I am bothered by side effects of treatment” in the past 7 days, and it has previously been connected with adverse event grade and treatment discontinuation.
For treatment discontinuation, the authors focused on those discontinuations that were recorded as being due to “adverse events, side effects or complications.” They found that, for each adverse event grade, there were, on average, more adverse events in cycles that ended with a patient discontinuing treatment compared to other cycles.
Next, they used Bayesian models to assess how the numbers of grade 1 and grade 2 adverse events in a treatment cycle were associated with the odds of higher side-effect bother and odds of treatment discontinuation, after adjusting for cycle number, treatment and occurrence of grade 3 or higher adverse events within the cycle. Baseline GP5 was also included in the models, and these models also accounted for the inclusion of multiple cycles for each patient.
When adjusting for baseline GP5, treatment, cycle and presence of grade 3 or 4 adverse events, both the number of grade 1 and the number of grade 2 adverse events were each strongly associated with increasing side-effect bother. The adjusted odds of treatment discontinuation were also higher with more grade 2 adverse events. However, with the same adjustment variables, the odds of treatment discontinuation were actually lower with larger numbers of grade 1 adverse events.
In their primary analysis, they focused on adverse events that were attributed to treatment, so they excluded non-treatment-related adverse events from the counts. Sensitivity analyses including these adverse events have similar conclusions but with a weaker magnitude of effect. They attributed this to issues like existing adverse events not causing new bother.
Next, the authors analyzed whether symptomatic versus asymptomatic adverse events affected these results by re-fitting the models and separating the predictors into numbers of asymptomatic and symptomatic grade 1 or 2 adverse events.
In these results, they found no evidence for associations between numbers of asymptomatic adverse events at any grade and side-effect bother. On the other hand, they found strong evidence for associations with symptomatic adverse events of grade 2 and 3 or higher both for side-effect bother as an outcome and with treatment discontinuation. Asymptomatic grade 2 adverse events were associated with treatment discontinuation but not side-effect bother, and symptomatic grade 1 adverse events were associated with side-effect bother but not treatment discontinuation.
· The authors conclude that adverse events of all grades, especially symptomatic adverse events, should be recorded regularly in cancer clinical trials. Formal patient reported outcomes are not typically collected as frequently as adverse events are recorded, so identifying patients with a high number of lower grade adverse events could be used to facilitate early supportive care to improve patient quality of life and reduce the likelihood for treatment discontinuation.
· They also highlight their result identifying lower odds of treatment discontinuation with larger numbers of grade 1 adverse events. They provide one explanation that patients may perceive grade 1 adverse events being associated with treatment efficacy, but this perception changes with higher grades. In their call to collect more lower grade adverse events, the authors acknowledge that recording more adverse events may be time-consuming and burdensome for sites and recommend cost-benefit analyses to develop future guidelines.
· This balance between the benefits and costs of increased adverse event data collection is the focus of Dr. Neuman’s editorial. Dr. Neuman acknowledges that Dr. O’Connell’s article provides a convincing argument for how low grade adverse event information is valuable, but notes the clinical trial context that current efforts at the NCI are to more efficiently conduct cancer research, which could be supported by streamlining data collection.
· Requiring the collection of low grade adverse events could have important impacts to trial logistics. Due to the high volume of low grade adverse events, reporting all low grade events could delay reporting higher grade and more serious adverse events; and it would require an increase in the effort of clinical trial research staff, which would be difficult if not accompanied by an increase in reimbursement to sites.
· Dr. Neuman suggests 3 approaches to balance the costs and benefits of collecting low and moderate grade adverse events. First, investigators could consider limiting low-grade adverse event reporting to the experimental arm. The standard of care regimens may not always have low-grade adverse event data available, but this may still be justified when there is extensive clinical experience with the standard of care. However, this approach is only practical when the experimental arm is not blinded.
· A second approach for moderating the effort in collecting low-grade adverse events is to limit collection to symptomatic adverse events, connecting with Dr. O’Connell’s example E1912 dataset. This approach could be addressed by prespecifying types of symptomatic adverse events that would be most impactful during the trial design phase.
· Dr. Neuman’s third suggestion is to plan for a follow-up study after the phase 3 trial to collect low-grade adverse event data and their impact on patients’ experiences and treatment discontinuation. This would be beneficial by only requiring low-grade adverse events in an experimental regimen that has successfully passed phase 3. However, a new study would require funding and site enthusiasm, which could prove challenging.
· Overall, Dr. Neuman emphasizes that investigators should develop trial-specific considerations and engage with the relevant stakeholders during study design. Because of the complexity of adverse events in these patient populations, the best uses of grade 1-2 adverse events will likely continue to develop in the future. In their article, Dr. O’Connell’s team studied grade 1 and 2 adverse events as separate predictors, but I would be curious to know how the accumulation and trajectory of these adverse events affect the patient experience. For example, even if the severity does not rise to grade 3, an increasing trend in a patient’s adverse event severities could signal the treating physician to modify study dose or to discontinue the treatment. I’m not sure if that type of information was available in their trial E1912, but perhaps that could be a factor to consider for the future. And, of course, it will be important to assess how these grade 1-2 adverse events relate to the patient experience in different studies, especially across different cancer patient populations, acknowledging that this is inherently challenging to study because the data to inform this research is not universally available. As Dr. Neuman indicates, trial-specific goals and expertise will remain critical when considering the data collection for a given trial.
That concludes this episode of JCO Article Insights regarding a summary of the article “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” by Dr. O’Connell and colleagues and the editorial entitled “Patient Experience, Adverse Event Reporting, and Clinical Trial Design” by Dr. Neuman. This is Subodh Selukar. Thank you for your attention and stay tuned for the next episode of JCO Article Insights. -
Dr. Shannon Westin and her guest, Dr. Ash Alpert and Spencer Adams, discuss the paper "Debunking Sex and Disentangling Gender From Oncology" recently published in the JCO.
TRANSCRIPT
The guests on this podcast episode have no disclosures to declare.
Shannon Westin: Hello and welcome to JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, Social Media Editor and GYN oncologist by trade. I'm so excited to be discussing a very important manuscript. This is "Debunking Sex and Disentangling Gender from Oncology," which was published in the JCO Online on May 26, 2023. So I'm joined by two of the authors here today on the podcast. First is Dr. Ash Alpert. They are an instructor of medicine and hematology at Yale Cancer Center. Welcome.
Dr. Ash Alpert: Thank you.
Shannon Westin: And we also have Spencer Adams. They have a bachelor's in public health, are a certified health education specialist, and are currently pursuing a master's in public health at Western Michigan University. Welcome, Spencer.
Spencer Adams: Thank you for having me.
Shannon Westin: So let's get into it. I'm so excited. First off, I just want to say thank you because I learned a ton from this paper, and I'm hoping to be able to implement some of these changes that we're going to discuss over the next few minutes at my own institution. So I wanted to just make sure we kind of level set and everyone's on the same page. So let's start off by discussing ontological oppression. Can you explain to the listeners what this means and how it relates to sex and gender and oncology?
Dr. Ash Alpert: Sure. So, ontological oppression is actually a concept from one of my colleagues at Yale, Robin Demroff, who's a philosopher. Ontology is a way of thinking about what exists and how we categorize what exists. And so ontological oppression is discrimination or stigma that happens because of the ways people imagine us fitting or not fitting into social categories. For example, if we think that people are women or men based on their sex assigned at birth, then it makes sense that we would think of transgender people and nonbinary people as abnormal, weird, or pathologic. In oncology, if we think of ovarian cancer as something that happens to women and a man with ovarian cancer comes into our clinic, we may be confused or uncomfortable. We may respond to those feelings by denying his identity, for example, thinking he's actually a woman or using the wrong pronouns or name for him or even potentially denying him care. And we have some data to suggest that clinicians respond to lack of knowledge about transgender people by treating them as abnormal, weird, or bad in some way.
Spencer Adams: Yeah. And to add to that, when we consider how we classify people, first, there's a problem within that. There's an ethical problem within that, but it's an idea or a construct that society has created and wants people to fit into these nice little boxes just because it's easier to digest, or you make the person more palatable if they're able to do these things. And life is not like that. We have differences, and we have things that make people fit outside the box. And I believe that when we keep reminding people that a box exists or a social construct exists, you're stifling who they are, their personality, their guiding light. You're stifling a lot of things about that person and ignoring something that's incredibly important to them.
Shannon Westin: I think that along those lines, kind of taking that to the next step, it would be really helpful to discuss a little bit more around this interaction between sex assigned at birth and gender and what assumptions are made. And I think you kind of started along this, like, how that impacts oncology care. But in your paper, you did, I think, a really great job of really laying out a lot of the problems that happen in this space, and I'd love to explore that more right now.
Dr. Ash Alpert: So sex is a designation made when a baby is born by somebody viewing that baby's external genitalia. And so I think we all, as doctors, know that that designation doesn't necessarily tell us what that person's karyotype is, what their later hormonal milieu will be, what their internal anatomy is, and it certainly can't tell us anything about their gender, which is how someone sees themselves as a man, woman, nonbinary, or something else, and usually develops around the age of four. And even though I think that we all know that, we're so used to sex and gender being used interchangeably, not just in the ways that we talk to each other, but in everything about the way that we do our work. And so it becomes very difficult to disentangle these concepts for ourselves.
And we have used sex in particular as a proxy for so many other factors where it doesn't necessarily function. And parts of medicine are based on that. So it's very hard to start to unpack and disentangle those things. For example, the ways that we talk about certain types of cancer can be linked with gender, like we were talking about earlier, women with ovarian cancer, men with prostate cancer. And that's the way that we talk to each other. But it's also in our clinical trial eligibility criteria, sometimes, it's in our patient facing materials, it's in the ways that we name our clinics, the ways that we talk about our work. So then even just sometimes occupying space to get oncology care can be a form of being misgendered.
Spencer Adams: Yeah, I think it's dangerous to conflate the two, sex and gender. As Ash was saying, that one is a visual inspection, the other is who the person is. And if we claim to be an institution that does patient-centered care, how can we be patient-centered if we are not properly respecting the patient? And to do that, you have to respect their gender as well. I see also one of the things that I want to add to the list is clothing that the patient is offered, especially going to a "women's clinic." We can change that to "reproductive health clinic," but usually the clothing is pink and that may be dysphoria-causing for some of our transgender and gender nonconforming friends. So it truly is in everything that is client facing, that is how the structural building is made. It truly is not just how we talk to each other, but how society runs.
Shannon Westin: Yeah, let's talk a little bit more about training because I think that will be pretty important as we try to change these things. So the way we're trained in medicine and oncology, regarding sex, regarding gender, how does this negatively impact the health? We've talked a lot about the mental health, definitely impacts, but also, I think, overall physical health.
Dr. Ash Alpert: Well, I think something that we started to talk about, but didn't talk about in detail is not just the conflation of sex and gender, but the ways that this concept of sex is used as a proxy for a number of other factors, including anatomy, hormonal milieu, karyotype, and body size. One of the ways that this becomes problematic is in our laboratory values for example. Laboratory values are developed, as far as I understand it, based on looking at large studies of people that are categorized as women or men and looking at averages. So, averages are helpful, but they can't necessarily tell us about disease or no disease. So, for example, if a large number of cisgender women have iron deficiency that is undiagnosed, and we use their averages, then we're going to continue to underdiagnose iron deficiency anemia going forward.
So, the ways that we've tried to use sex as a proxy for a number of things doesn't just hurt trans people, but potentially leads to very imprecise data in general. Specifically for trans people, we know that many trans people have negative experiences with care, that this leads to people avoiding care and likely leads to decreased screening for cancer and delayed cancer diagnoses. So we don't have a lot of data about this, but we do have some data to suggest that transgender people may present later with later stage cancers, be less likely to be treated, and have poorer outcomes than cisgender people.
Spencer Adams: And I think it's important to add that there are physicians who will - we call it like, “the trans illness" - but they will blame everything that you're experiencing on the fact that you're transgender or the fact that you're on hormones or the fact that you had the surgery, and say that you need a specialist. So you can't just go to your primary care physician anymore for the flu because they'll just blame it on your medical transition. When we take that into consideration, I think there's a whole host of physical ailments that come from just being denied care. I don't know if that is from the physician's own personal stigma around trans people or just them not being trained in trans healthcare to where they feel confident in going into that room. So it's a twofold attack. First, we need to make doctors who are competent in trans healthcare, and then second, we need to have more inviting spaces for trans and gender nonconforming people.
Shannon Westin: I think the next step is really better understanding this idea around degendering care, specifically in oncology, but I could really talk about medical care as a whole, but let's focus on what you all brought forward in the paper. I would love to hear how we think this idea of degendering care will promote better healthcare. And then, I think, some practical actions. What can we do on a day-to-day basis? And you've already started peppering this through this discussion but I’d love to like bullet point it out for the listener.
Dr. Ash Alpert: Yeah. So the way we described it on our paper was: “disentangling oncology is a conscious and explicit disentanglement of gender, anatomy, hormonal milieu, karyotype, and other biological factors. In oncology, diagnoses, epidemiology, and knowledge production. As well as,” - and I think this is an important part and that's maybe the harder part of the paper - “eliminating sex from our conceptual framework of bodies and disease”. So, in other words, we're really trying to say that not only do we need to disentangle gender and sex, but we need to debunk the idea that sex is an immutable fact of the body that says something important about a person and their biology. Instead of thinking about sex as this immutable fact of the body, can we really break down and think about what exactly are we measuring? Is it anatomy, hormones, karyotype, size, or stigma?
In terms of practical actions, some of the things we had in our paper include that oftentimes, the words "woman" or "man" can be replaced with the word "people." So like a very easy change. And actually, ASCO and the NCCN, both in the last few years, have worked to degender their guidelines by doing just this simple change. Then we also need to do this on our websites, in our patient education materials, and in our clinical trial eligibility criteria. Because if you have a trial for prostate cancer that says that one of the inclusion criteria is being male, then whether or not you actually mean that as an inclusion criteria, a transgender woman or her physician may see that as a barrier to enrollment.
Ensuring that, as Spencer was saying, that gowns, binders, and wigs are available that are gender-neutral are available for all genders. Ensuring that people have access to bathrooms, so making sure gender-neutral bathrooms are available. And often, this is as simple as taking a one-style bathroom and putting a sign on it that says "gender-neutral." Ensuring the names of clinics, mammography suites, and titles do not contain gender. Ensure that intake forms don’t conflate gender with biological factors. For example, in a clinic I used to work in, one of the questions on the intake form was, "If you are a woman, when was your last menstrual period?" Which if I’m a man and I have a period, it might be hard to figure out how to answer that question.
Spencer Adams: One of the biggest barriers for trans and gender nonconforming people is that intake form. It is the first person that you meet or see when you go to any healthcare establishment because that sets the tone for whether or not this establishment is trans-friendly. If you have, as Ash said, a "for women only" box or descriptor on your intake form, that is a sign that maybe they're not as trans-friendly as they could be. Or if you see "women's clinic" instead of "reproductive health clinic" or whatever, that could be a sign that they may not be as gender-friendly as they could be. These little changes actually make such a big impact on the trans community, and it's something that I believe would be very much appreciated and would close the gap between trans and gender nonconforming people and the medical community.
Dr. Ash Alpert: I know that for me, going to a doctor's office, these small moments, although they may seem small to other people, really add up in terms of stress. People talk about microaggressions, and I think that's really a good way of conceptualizing what it's like to have these little irritations or hits that happen over and over again throughout a clinical encounter. And I think in particular, for folks who are dealing with a cancer diagnosis and treatment, which can be experienced as a traumatic event, having these recurrent denials of identity on top of that can lead to additive trauma in a way that can be very distressing and have negative sequelae for patients.
Shannon Westin: Yeah, we're trying to look around this idea of allostatic load and how we can actually measure this because I think when we talk to policymakers about this, around not just the trans community, but also around underrepresented minorities, and the stresses that impact their risks of cancer, and how it's not just their race or ethnicity that's driving it, it's all of these microaggressions and everything. We get a lot of like, "Really? That's not science." So, I definitely think doing a better job around being able to objectively measure these other things and move forward in a very objective direction is going to help. Because if one of those things we know it's there, but for people who aren’t as ready to believe or understand that, it helps to have and embed that objective data. So that gets into the epidemiologic potential and cancer prevention.
Dr. Ash Alpert: Yeah. In some ways, we can't do much about the data that have been collected in the past, but we can start to think about them more critically and describe what we think is really going on in what we were calling sex or gender categories. But going forward, we can really think about collecting data on our clinical trials and in our large population-based surveys that actually speak to biological factors. So, if what we're concerned about is whether or not someone has ovaries, we can ask for an anatomy inventory. And when we're interested in hormonal milieu, we can check hormone levels. When we want to know about chromosomes, we can check a karyotype. And if what we're interested in is stigma, then we can ask about stigma, or we can ask about things that we think may cause someone to infer stigma. Once we have data that’s much more nuanced and granular, we’ll be able to better extrapolate it to all people in a much more rigorous and precise way, including trans people.
Spencer Adams: When it comes to cancer treatment and diagnosis within the trans community, it's such a unique thing because we have to consider also the social determinants of health. And this built environment that we've created, such as a hospital or cancer wing, or whatever you want to call it is directly impactful. As you were saying before, this microaggressions that add on and on to our trans friends. So, I think that when we look at the data and we look at stigma, we also have to look at where people are– We have to meet people where they are. It's going to be very difficult to bridge the gap between the medical community and the trans community when it comes to stigma. But if we have competent doctors trained in trans care and not always pushing off for a specialist, then I think we'll get better data.
One thing that happens to trans people is doctors feel as if they cannot diagnose because being trans is seen as a disorder that they see as out of their wheelhouse. First, they classify it as a disorder, and secondly, they think it's outside of their wheelhouse. So they would refer to an endocrinologist or someone else to provide the care that the person is seeking. We call it the "trans disease" or the "trans injury,” because if I come in with a broken leg and the first thing you say to me is to go to an endocrinologist because we don't understand how hormones work, that's not care, and that's not patient-centered care. And that's what we're all moving towards, I believe. All hospitals are moving towards this patient-centered care. And to do that, to be patient-centered, you have to understand the person as a whole, and you have to be able to treat the whole person and then make a treatment plan that is specialized and custom to that person. This may involve different routes people take in order to feel comfortable or achieve what outcome that they wish to achieve. But it's really a patient-centered approach that we have to drive home in order to make some change.
Shannon Westin: My last question is, what's next, and how do we get this information out? How do we actually enact? I mean, obviously this podcast reaches a lot of listeners, but beyond that, how can we educate people so that we can make these changes? This is something that hits close to home for me. I recently took over the gynecologic cancer center, which is where we house all below the belt malignancies. But there's work in progress, and we're discussing an overarching center to cover breast and gynecologic malignancies. And there's a discussion around how to title that. One of the suggestions was that it should be a "women's center," or something like that and that is not in line with what we've just been speaking about. So I think, certainly, that kind of individualized, like boots on the ground, people that are willing to speak up and say things and try to change these types of things, and I fully intend to do that - fingers crossed that it won't be me just waving my tiny fists in the air.
But more broadly, I’d love to see more education at ASCO, large oncology symposia and conferences. It needs to go to the people who are not aware. It can't just be an echo chamber of people who have already been talking about this and are already knee-deep. It needs to reach the broader oncology community so that people realize that this is an issue that involves all of us and that we all need to be addressing. And like you said, even simple things around replacing language and saying people and making sure that the trial eligibility are broad, those simple things that individuals can do can. But I also think like NCCN and ASCO, we have to do something around the organizational levels to really make an impact.
Dr. Ash Alpert: Yeah. And I think that the things that we talked about the we can do as individual clinicians, there’s the things that large institutions like NCCN and ASCO can do to sort of send out the inclusive messaging that is needed. And I think in the middle, we can create teams that are institutions of folks who we can be in allyship with to think about what are the most urgent changes that need to happen and the most feasible changes and start with those and then just keep going. Some of the changes that we make now will help us in the years to come, so I think being focused on the now and the future at the same time is helpful.
Spencer Adams: I think that the teams within our individual institutions is really a great approach to this. When it comes to figuring out the next steps to be more gender-inclusive, I really think that institutions should get data from their community. They should understand the makeup of their community and see if that is something that aligns with the makeup of their hospital. Because we can go and talk about doctors getting training in trans care or more doctors of color being in your hospital to make the BIPOC community feel more accepting. But if we don't have teams whether it’s diversity, equity, and inclusion teams, or whatever you want to call it, that are willing to push to make policy change within the hospital, then there will be no movement. So, we really need to get people within their hospitals to give them the power to really push what has been taught for so long and really challenge the status quo and allow us to move forward with gender equity.
Shannon Westin: Well, I think that is the perfect mic drop moment, and I just want to thank both of my guests. Spencer, this was awesome and I always take copious notes when I talk with you all because I learn so much. It inspires me to try to do what I can at my institution and within the field of gynecologic oncology to make things better. So I hope that others who are listening are just as inspired as I am.
And to our listeners, thanks again for tuning into another episode of JCO After Hours. Please check out our other podcast offerings wherever you get your podcasts. Have a wonderful day.
The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and should not be used for the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experiences, and conclusions. These opinions do not necessarily reflect those of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an endorsement by ASCO.
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Dr. Shannon Westin and her guests, Dr. Judy Garber and Dr. Geoffrey Oxnard, discuss the paper "Germline EGFR Mutations and Familial Lung Cancer" recently published in the JCO.
TRANCRIPT
The guest on this podcast episode has no disclosures to declare.
Shannon Westin: Hello, and welcome to JCO After Hours, the podcast where we get in-depth on articles that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for the JCO and Gynecologic Oncologist by trade. And it is my great pleasure to speak today with you about an amazing manuscript entitled, “Germline EGFR Mutations and Familial Lung Cancer.” It was published in the JCO on August 14, 2023.
The authors have no conflicts of interest, and they are Dr. Geoffrey Oxnard, he's a Thoracic Oncologist and Associate Professor, Hematology and Medical Oncology at Boston Medical Center.
Welcome, Geoff.
Dr. Geoffrey Oxnard: Hi, Shannon. Thanks.
Shannon Westin: And Dr. Judy Garber, the chief of the Division of Cancer Genetics and prevention at the Dana-Farber Cancer institute in Boston. Welcome, Judy.
Dr. Judy Garber: Thank you. Hi, Shannon. Hi, Geoff.
Shannon Westin: So excited you both could be here. Let's get started. So first I just want to levelset for our audience. Can you speak just a little briefly about the incidence and mortality of lung cancer and how that's been changing over time?
Dr. Geoffrey Oxnard: Sure. Lung cancer is common and it's deadly, more than 200,000 cases a year in the United States, more than 100,000 deaths a year in the United States. But I think importantly, it's evolving. Its biology is evolving as smoking incidence goes down. We've identified these genomic subtypes of lung cancer that are sort of increasingly apparent and important as we think about its treatment. Outcomes are changing with emerging therapies, presentation is changing with lung cancer screening and with a growing ability to now find cancers early and prevent them. And so it's in that setting of a very dynamic disease that we chose to study a really unique little slice of it, which is germline risk.
Shannon Westin: So let's take that one step further because I think that's really interesting. You mentioned the genomic aberrations and kind of how you're using that to target. Can you expand upon that a little bit more for me?
Dr. Geoffrey Oxnard: Lung cancer that I've long studied is different than breast cancer when Judy has long studied because we think about its somatic alterations, we've always thought about KRAS mutations, EGFR mutations, and smaller and smaller splice limit. ALK, RAS, RET HER2, etc. And so tumor testing in lung cancer has one of the first to be standard across on solid tumor oncology. And the germline genetics was kind of an afterthought and is the flip, I think, of how genetic testing evolved in the breast cancer space for example.
Dr. Judy Garber: I might argue a little bit if breast cancer was earlier and it was subtyped some molecularly it doesn't have as many molecular subtypes yet perhaps as lung cancer. But we've all been studying the somatic space to look for targets for therapy. And the germline space, certainly in breast cancer, came much earlier. And everybody knows about BRCA1 and 2. Now, we hope everybody knows about Lynch Syndrome, but certainly not everybody's thinking about inherited lung cancer risk.
Dr. Geoffrey Oxnard: Yeah, these have converged. I think 10 years ago when this kicked off, I felt like a super outlier for thinking about, wait a second, what about the genetics behind all this that is leading to this strange variable presentation of lung cancer? For example, we know that in Asian populations, one type of lung cancer, EGFR mutant lung cancer, is more common. There must be some geneticness that leads to that. What explains the sort of pattern of presentation of these genetic subtypes in the populations we see in the US, that’s pretty unclear?
Dr. Judy Garber: So, I think, Shannon one of the clues about all this came from the fact that the EGFR mutations were being identified in the tumors. And then I really should let Geoff tell this story, but as the amateur thoracic person in the room here, to me, it was so interesting that there were the EGFR mutations, then there was treatment exploiting EGFR mutations, and the most common resistance mutation was this T790M variant. But when labs started testing EGFR, there was a small group of people who had that resistance variant without ever having been treated at all. So that was the obvious question, what was it doing there? And that's where Geoffrey came in.
Dr. Geoffrey Oxnard: Yeah, this is a patient I met more than a decade ago at my fellowship in MSKCC. She'd been living with a T790M mutation in her tumor for years and years and years. I was like, “Well, I don't understand. Why is this sitting there?” And she had this sort of slightly mysterious history of lung cancer in her family. And we realized, wait a second, this T790M was behind her cancer from the beginning, and in fact, might have been the basis of why she developed lung cancer. And so that actually motivated a career development award I submitted to the Conquer Cancer Foundation of ASCO, a grant I received, and that then led to a program that I led at Dana-Farber under Judy's mentorship, where over the past decade, we sort of focused in and studied this strange, rare syndrome, really to dig into inheritedness as a kind of different flavor of lung cancer genetics.
Dr. Judy Garber: Well, and now it's really a good time to think about this because we're recognizing there are younger cancers, colon cancer, like an epidemic, and lung cancers, and we're not sure how many of them are genetic or come from other exposures. Geoff talked about the differences in Asia, some of which are certainly genetic, some which may be environmental, especially in the lung, where that's such an issue. But trying to sort these things out, you have to be willing to think a little bit differently. And that was fun when Geoff came from the lung program, interested in the germline, we said, “Oh, we have to do this.”
Shannon Westin: Well, let's talk about what you did. I would love to hear and I know the audience would as well about the design of this study, so called INHERIT study. Very good name. I love a good name. This is a good one.
Dr. Geoffrey Oxnard: Yeah. So that stands for Investigating Hereditary Risk of T790M, INHERIT. I forget where we coined that. Let me give you a case example. A patient presents in his 40s. I remember this man. He has an EGFR mutation in his tumor. He has a T790M in his tumor as well. He had routine tumor testing that lung cancer patients were getting. And he says, “Oh, also, my brother had lung cancer in his 40s just a couple of years ago. He was a smoker, though. He never had genetic testing.” And so this patient we test on the study, we hypothesized that when patients present with T790M at diagnosis, that it would be a representation of an underlying germline EGFR mutation. Our hypothesis was that about 50% of the time T790M at diagnosis would be explained by a germline behind the doll. And that that could then empower families like this one to understand the kinds of lung cancer they're getting in their family, the kinds of treatment they should be getting, and the kinds of testing they should be getting to look for lung cancer at risk early on.
It really saddens me that in a family that doesn't know about this condition, the brother would never get testing and would never think that I might be getting or might never get testing, might not be disposed to getting testing, and might not realize there's a therapy available to target that EGFR mutation if he died young without even much treatment. But this individual, we tested his lung cancer, we found him a therapy, we put him on a pill therapy that could last a very long time. And so we set up a program with a consortium alchemy, the Addario Lung Cancer Medical Institute, where we enrolled at three sites, both at Dana-Farber in Boston, Vanderbilt, and Ohio State, with some motivated investigators there that we appreciate their collaboration.
But also, again, this is now more than 10 years ago, set up shop where people could enroll remotely, that if you found a T790M in your tumor, for whatever reason, you could reach out to the team at Dana-Farber centrally and get consented online and even get counseling. And this is one of the early ways of getting this remote participation. And you can imagine, over the course of the study, we quickly ran out of individuals at any given site, but that remote enrollment accelerated and really allowed us to get to the large population of remote study.
Dr. Judy Garber: We were lucky that things were happening. The things you don’t expect. So EGFR testing was not routine at that time. And the EGFR testing that had developed in Dana-Farber and NGH became standard of care at Dana-Farber so we were finding those patients, and then grew outside as well, at institutions and testing labs. And these people would somehow emerge so we were very lucky that we were able to set up remote testing. We could send and get a saliva sample and be able to test. Or these were people who got tested through their own doctors, found out they had this mutation and then went online and said, “Who knows anything about this?”
I would say that we and our amazing genetic counselors who spoke to all these patients, took their detailed family histories, got their other information, and were able then to really build out these cohorts so we can understand them. And to look at, for example, Geoff’s question, it was really his question, “Why did we have such clusters in certain parts of the country? Could it be that there were the so-called founder mutations that somebody had this mutation and they spread their genes around so that they’re around the country and that turned out to be true.
Shannon Westin: It's so fascinating, and I love how you kind of almost crowdsourced getting these patients to you because I was mystified because it's such a rare aberration and you had so many patients. Let's talk a little bit maybe about your patient population and who volunteered, and is it reflective of kind of you do think, the general population?
Dr. Geoffrey Oxnard: I want to give a shout out to the GO2 Lung Cancer Foundation. That really was a lot of the ‘rah rah’, getting people to know about this, having some word of mouth and spreading the word. And so certainly there are physicians around the country that have been like found patients that I've got to know because they sent us patients to study over the years. We ended up getting germline testing on 141 individuals who presented eligible for testing because of either a relative or a mutation that was suspicious for inherited. Most of those were enrolled remotely, in the end, as you might expect. We found what you might expect, that this was Mendelian in its inheritance, that if you had a first degree relatives, they had 50% chance of having this. And so we sort of slowly built these pedigrees of individuals who once they were positive, would refer in their relatives and say, “Please go get testing. Let's describe our family and help understand our risk.”
It ended up boiling down to six individuals with a germline EGFR mutation from 39 different families. I remember one family where two different cousins presented separately to the program, not knowing each other was participating. And so, of course, there's not that many of these families around the United states, but we're really very lucky to have touched so many different individuals. What did we find? That if you had a germline EGFR mutation, your tumor almost always had an EGFR mutation. That really is the dominant biology of lung cancer that presents in these affected individuals, that it presents young, that the likelihood of developing lung cancer is around 55% by age 40 to 50. So it really is– I'm trying to make sure I'm quoting that right, actually, Shannon, I'm looking at the numbers here, but it was a really broad range of diagnosis.
We had a 28-year-old who was affected and an 83-year-old who was affected. I saw a family where the grandson had lung cancer, but his father and grandfather who had germline EGFR mutations, did not. So variable penetrance. Judy, of course, told me, “Geoff, this is the way families present. Come on, Geoff.” But other families, incredible penetrance– not everyone having lung cancer, many of them smoking, some of them not smoking. But for these families, what a sense of empowerment to say, “Oh, this helps explain what's going on in our family, why this is happening at a younger age.” And helps explain the therapies that we had some concern about giving these potent EGFR inhibitors originally, understanding every cell in their body has this EGFR mutation. Are we going to somehow cause toxicity? No. These potent therapies can be effective, can be tolerated, and can work for many years. So we really feel hopeful that we've described a syndrome that's out there that people see and that has a distinct presentation, a distinct treatment pattern, and a clear association with lung cancer risk.
Dr. Judy Garber: And I think that now the opportunity is to say, can you find these people before they get their lung cancers? Some of them have abnormalities on scans. Think of it's like the APC, the polyposis coli of lung cancer. You can see these adenomas forming, but we can't really predict exactly who's going to develop tumor when. And that, I think, is a challenge that families have to help us with because we need to continue to identify some of these people who have not had cancer. They have children. They want to know what to tell them besides not smoking adamantly and maybe with some hopes that we're going to do some screening.
I am afraid there probably is not good data that EGFR inhibitors could be used for prevention, but it's tempting to think that way. So there's plenty of work to do still to sort out the questions. This is the nature of genetics. We often find inherited susceptibility and people want to know, “Well, why would I want to know? What am I going to do about it?” And here I would say, “We're going to figure out what's your risk more specifically, and how can we help reduce that risk, in addition to telling you not to smoke.”
Dr. Geoffrey Oxnard: I do want to allude to Judy's comment about founder effect. I didn't tell you exactly about the presentation, but these families, first off, we only found germline EGFR mutations in Caucasian individuals and in black individuals, and it was mostly in the United States and in fact, enriched in the southeast United States. And don't get me wrong, we had enthusiastic participation from Vanderbilt. But still it seemed like there was more southeast United States prevalence. And even families I met in the Boston area would say, ‘Oh yeah, I have relatives going back to Arkansas.”
And so we ended up with a bit of a suspicion for this geographic enrichment, studying the genomes of these affected individuals, and in fact did find a very large region of chromosome 7 that was shared in more than 90% of the folks we tested, suggesting a founder effect in the southeast United States, probably white and black. And that goes back hundreds of years, maybe 200, 300, 400 years, as far as we can estimate, making me think that this is a fairly unique syndrome that we're seeing in North America, but actually may not be prevalent in other parts of the globe. Though we did identify a single individual in Australia, it might be a unique phenomenon in North America.
Dr. Judy Garber: At least more common. But these days, people travel, so hard to know.
Shannon Westin: I don't know if you've gotten a chance to do this - any other cancer type seeming to be associated with this mutation?
Dr. Judy Garber: No, fortunately not.
Shannon Westin: Okay, very interesting. And what about outcome? What was the association, or was there any association of these mutations with cancer related outcomes?
Dr. Geoffrey Oxnard: I would say the survival of these cancers isn't that different than EGFR mutant lung cancers. If they get to effective therapy, they can live for years on therapy. If they don't, they can do quite poorly. One interesting finding is that they can present in a multinodular fashion that might be multiple primaries. And so you can kind of use an approach of eliminating individual clones. Sometimes it's been described these different tumors have different mutations, and so you might treat them like a stage IV lung cancer, but actually they lived for a long time because actually they had multiple stage I lung cancers, so it can present a little bit differently. And then we tried to collect CT scans on affected carriers who did not yet have lung cancer to see if they might develop lung cancer. It was not required on study, and it's sort of an area of future investigation. But as you can imagine, lots of lung nodules and certainly anecdotes of individuals where we found early precancers through the screening effort, motivating the investigation that Judy was alluding to.
Dr. Judy Garber: I think this is what you expect in inherited predisposition that you have an earlier chance. So some of them are younger, not the 84-year-old, but that they could be younger, that they could have multifocal disease, that their biology could be different, but could be the same, maybe accelerated, maybe not. Some of these are slower. And I think that's why we're excited to be able to continue this work with the group at Dana-Farber.
Now, Jaclyn LoPiccolo is going to lead the INHERIT study, but much of the team is the same. And now the focus will be even more on trying to really quantify the risk and help think about prevention strategies and screening for these patients. It's a little tricky to want to do too much chest CT screening. On the other hand, there are lower dose CTs now, and we hope the guidelines will clarify the role of inherited risk. At ASCO this year there were a lot of talks about inherited lung cancer risk, but nothing is quite as well characterized as, I think, the T790M population.
Shannon Westin: Well, thank you all so much. This was fascinating. I learned a ton and I know our listeners did as well. And thank you to our listeners. This was “Germline EGFR Mutations and Familial Lung Cancer.” Again, published in the JCO August 14, 2023. So go check it out and check out our other podcasts on the website or wherever you get your podcasts. Have an awesome day.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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In this episode of JCO Article Insights, host Dr. Soldato discussed with Dr. Knikman and Dr. Cats the findings of a study that assesses the influence of fluoropyrimidine dosing based on DYPD genotype on both progression-free and overall survival. The article, featured in the December edition of JCO, presents groundbreaking and reassuring data. Furthermore, it highlights emerging research challenges aimed at refining the prescription practices of one of the most widely utilized chemotherapy agents, striking a delicate balance between safety and efficacy.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Davide Soldato: Welcome to this JCO Article Insights episode for the December issues of the Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Knikman and Dr. Cats, respectively first and corresponding authors of the manuscript titled "Survival of Patients with Cancer with the DPYD Variant Alleles and Dose Individualized Fluoropyrimidine Therapy: A Matched-Pair Analysis."
Dr. Knikman is a clinical pharmacologist and assistant professor at the UMC Utrecht, while Dr. Cats is a gastroenterologist specializing in gastrointestinal oncology at the NKI in the Netherlands.
Welcome, Dr. Knikman and Dr. Cats, and thank you for accepting our invitation today.
Dr. Annemieke Cats: Thank you so much for the invitation.
Davide Soldato: So I just wanted to start by discussing the manuscript that you published. But before delving into the results of the manuscript that was published in the JCO, I just wanted to ask if you could give a brief overview of the DPD polymorphism and explain a little its relevance in the clinical practice.
Dr. Annemieke Cats: The DPD polymorphism is very important in the metabolism of fluoropyrimidines. Fluoropyrimidines have been in practice for over seven decades now in the world and more than 2 million people received fluoropyrimidines in the beginning of this millennium. The indications for fluoropyrimidines have only been extended since then, so a lot of people are receiving this fluoropyrimidines. But with the good side of that there’s also another side and that is that there are a lot of side effects encountered by this chemotherapeutic drug. In the 1990s, it became clear that DPD was a key enzyme in the metabolism of fluoropyrimidines.
Dr. Jonathan Knikman: To better understand the toxicity associated which fluoropyrimidines are accompanied by, we have to take a closer look at the metabolism of fluoropyrimidines, and more specifically at the key metabolic enzyme which is dehydropyrimidin dehydrogenase, DPD in short. This enzyme breaks down the main active metabolite into inactive metabolites because 5-fluorouracil is the main active metabolite which is metabolized into inactive metabolites. However, if this enzyme does not function properly, this could lead to higher exposures of the active metabolites and subsequently more toxicity. This can be caused by mutations in the gene encoding for the DPD enzyme, which is the DPYD gene, and single nucleotide polymorphisms, so mutations in this gene can lead to less functional DPYD enzymes, subsequently can lead to more toxicity.
Davide Soldato: So basically, patients that are harboring these SNPs in the gene encoding for the enzyme have a higher risk of toxicities. I think what is really important about the manuscript you published is that, apart from looking at the toxicities, side effects and pseudo profile among these patients who harbor these SNPs you also wanted to check whether this was associated with some reduction or at least with inferior clinical outcomes. The endpoints you selected were progression-free survival and overall survival. But I was really interested, and I think our readers and listeners would be interested in understanding a little bit the methods of the study. What was the cohort of patients that was selected? Was this a cohort composed only of patients with gastrointestinal malignancy or also different types of malignancies? And in this second case, if you included the patients with different types of malignancies, did you have any methods to be sure that there was not any differences among these patients at the very beginning? So basically, how you handled all the confounding factors that could potentially impact the analysis of clinical outcomes.
Dr. Annemieke Cats: To start your question, we have to go back to a previous study we performed, which was a prospective, multicenter study we performed in the Netherlands in 17 centers in which 1100 patients that had an indication for fluoropyrimidine therapy were included. In these 1100 patients, there were about 85 patients that were heterozygous carriers of a DPYD variant. What we did, we compared these two groups with each other, but before the DPYD carriers started, they had a reduced dose. The *2A variant carriers and the *13 carriers, they received a 50% dose, and the 1236 and 2846 they received a 75% dose. Those patients, a large amount of them consisted of patient with colorectal cancer, about 60%. And also breast cancer patients consist for a large amount of this group, it was about 20%. And then the rest were esophageal and gastric cancer mostly, and there was a group consisting of rare tumors as well like anal cancer.
The comparisons showed that toxicity in the variant carriers was higher in the wild-type patients that received 100% dose. So despite those reductions, toxicity was higher in the carriers. But when we compared the variant carriers with historical controls, we saw that, especially for *2A, there was a large reduction of toxicity to a lesser amount. This was also the case for the 2846 variant carrier. But to a much lesser extent, there was a reduction in the 1236 carriers which worried us and this was the basis for a Clinical Pharmacogenetics Implementation Consortium (CPIC) to give a recommendation for starting for all these variant carriers with a 50% dose when treatment with fluoropyrimidine was indicated.
Davide Soldato: Thank you very much for the clarification. So basically, you started from one previous prospective study that was composed of a mix of different cancer types. And then in the study that you now published in the Journal of Clinical Oncology, you also added an additional part of patients who were carriers of this variants. I imagine that there was some variability between patients who were carrying the variants and those were not carrying a variant. So I wanted to understand a little bit, did you perform a matched analysis or did you try to be sure that there was not any confounding factors that could impact the results?
Dr. Jonathan Knikman: Yes, we performed an exploratory retrospective matched-pair analysis and we used a matched-pair analysis to select patients which are comparable between the DPYD variant carriers and the DPYD wild-type patients to ensure that on the most important factors, they were comparable and outcome was also comparable. In this matched-pair analysis, we compared progression-free survival and overall survival between DPYD variant carriers treated with the reduced dose and DPYD wild-type patients treated with the full dose. We matched these patients on five matching variables which were primary tumor type, stage of cancer, age within a range of plus or minus 10 years, sex, and treatment regimen to ensure the these patients as comparable as possible.
Davide Soldato: And so now, moving on a little bit to the results, what were the results in brief regarding progression-free survival and overall survival for patients who were harboring a variant in the DPYD gene and those who were wild-type for this gene?
Dr. Annemieke Cats:The results of our study showed that there was no significant difference in progression-free survival and overall survival between the DPYD variant carriers pooled as one group, treated with the reduced dose, compared to wild-type patients treated with the full dose. This suggests that DPYD-guided dosing can be performed safely without compromising treatment effectiveness. However, when we take a closer look at the individual variants, our study showed that progression-free survival and overall survival were not negatively impacted by DPYD-guided dosing in the 2846 and the DPYD *2A variant groups. However, in the group of 1236 variant carriers, we did find a significant difference in progression-free survival with a hazard ratio of 1.43, indicating that progression-free survival was shorter compared to the matched wild-type patients treated with the full dose. However, no difference was found in overall survival.
So based on results on this study, we can conclude that DPYD-guided dosing can be used while treating patients with fluoropyrimidines without compromising effectiveness and improving safety. However, when patients do not experience toxicity or experience minimal toxicity, it is important to escalate the dose guided by toxicity to ensure maximum exposure to the treatment.
Davide Soldato: Thank you very much. That was a very comprehensive overview of the results. I was really wondering regarding the variants in the 1236. So the one that you said was associated with a shorter progression-free survival. At the very beginning, Dr. Cats very well explained that in the first prospective trial that was done, among these patients, toxicity was still higher or they experienced more severe toxicities, even with a 25% dose reduction compared to what was planned. So I was wondering if you could speculate a little bit. Do you think that this reduction in the progression-free survival might potentially be associated with these higher rates of severe adverse events, and that maybe this has created a little bit of a gap in the adherence to chemotherapy?
Dr. Annemieke Cats: We looked into the mean dose that the 1236 variant carriers received, and this was about 75% of the dosage. So the dosage was what the protocol prescribed for the study. And also the number of cycles did not differ from the wild-type patients. So, I think the patients did not stop earlier with their treatment than was intended to. What we did see however is that in the whole group, only 10% of the variant carriers had some kind of dose modification, which could be both an increase of the dose or a reduction of the dose. So, there were only a few patients where the dose was modified. We know that the 1236 variant carriers are a very heterogeneous group. DPD enzyme activity also shows a wide range, ranging from normal to very low dose even we described a patient with a homozygous 1236 mutation. And we would expect that there would be no DPD enzyme activity, but there was still some activity in this patient.
Davide Soldato: That's a very good insight on this particular topic. So, just related to the conversation that we were just having, do you think that in general, for all DPD variants, and in particular, as we discussed, for the 1236, do you think that genotyping is sufficient for now to understand which is the right dose for these patients, to balance toxicities and to obtain the best clinical outcomes? Or do you think that we need more sophisticated or more integrated types of monitoring? Should we, for example, in the 1236, look more carefully at pharmacokinetics and so understand if these patients can receive higher doses because maybe, as you were saying, the activity of the enzyme is really higher than what we are expecting based on the genotype? Do you envision something like this happening in the future, or do you consider it as a potential line of research on this topic?
Dr. Jonathan Knikman: It's a very interesting question, and it's something we've thought about a lot. At the moment, I think genotyping is the way to go and is the most robust and most validated method currently available with fluoropyrimidines. And I think it's a bit of both. Currently, as mentioned, I would recommend DPYD genotyping, and also in the 1236 variant carriers, as we have seen in previous studies, that toxicity is still increased even while administering 75% dose instead of a full dose. So we see that there's still more toxicity. However, our study also shows that progression-free survival is shorter compared to wild-type patients. So, it's quite a complex situation as we still have more toxicity, but the progression-free survival is also shorter, and that's where we would advise the dose escalation part. So, I think it's a combination of genotyping and escalating the dose when possible, if there is no toxicity or limited toxicity, to ensure maximum exposure and to minimize the effect on progression-free survival while still trying to reduce toxicity.
Dr. Annemieke Cats: This is a very important question because we do not completely understand why toxicity is higher in the 1236 with a 25% dose reduction that may compromise progression-free survival. So we have to look in closer detail, and currently we are looking in closer detail to what do we have for a pharmacokinetic analysis, that you mentioned. What about DPD activity, enzyme activity? Can you titrate on that? And I think for now, it still stands that we should start with a 50% dose, but with the possible effectiveness of the dose in mind, you should go with an early titration, and I would say something about 25%. Although having said that, I have no data to underline this. And if you have the possibility to go for DPD enzyme activity in addition to genotyping, that would also help you to titrate doses on that. And that's where we stand now. But we need to know why these 1236 variant carriers have such a large range in activity and toxicity.
Davide Soldato: I also think, and I can ask you if you agree with me, that this analysis is really very important because I think it's one of the first reports regarding the analysis, specifically of progression-free survival and overall survival based on variants of DPD. But at the same time, I think that we also have to underline for our listeners that this was still a retrospective and exploratory analysis. So it's true that you observed this association with shorter progression-free survival. But still, I think that we will need also more core studies to validate these findings and to be really sure and also to perform additional analysis as to what the mechanism is as you were saying. I don't know if you agree on this limitation of the study, despite its importance in regarding clinical outcomes.
Dr. Annemieke Cats: We certainly agree with you that we have to keep in mind that it is an exploratory, retrospective analysis. Having said that, a randomized controlled trial certainly has some difficulties in it as well. Nowadays, it is not feasible to give patients with a DPYD variant a full dose. In 2018, there was a lawsuit in Oregon, and now recently in Ontario, Canada. There's also a lot of rumor in the news because of patients getting a full dose while having a DPYD variant. So the lethality of the toxicity in some variant carriers makes it not ethical to perform a randomized controlled trial. So we have to look for different designs that reflect real-world data and learn more about the genotype and also in different ethnicities. It is also very important because what we have studied considers the white population mostly and that's also a direction that future research should go to.
Davide Soldato: Thank you very much. That was very insightful, especially the last part regarding ethnicity and the possibility that also these variants might be different according to that.
So I think that the main message that we should pass is that when prescribing fluoropyrimidines, genotyping of DPD is fundamental because toxicities among patients harboring these variants can be severe and can also be lethal. You performed this retrospective exploratory analysis that provided us with overall reassuring data. There is still more research to be done, especially for the 1236 variant. So I think that that probably is our bottom line and main message for our listeners.
And I just had one final question because in the manuscript that you published, you had localized, locally advanced, and also metastatic cancer that were all grouped together. Do you think that an additional line of research would be to specifically look at how these impactful outcomes only in the locally advanced and localized cancer compared, for example, with the metastatic?
Dr. Annemieke Cats: You raised a very good point because there is a lot of variety within this study, and now you're mentioning locally advanced, local, or metastatic cancer. It's also within the cancer types. We studied different cancer types as well to reach a large amount of patients. It would be good to have a more homogeneous population that you can derive your conclusions from. So, I think that would certainly help us in the future, and we should look into whether we could do this together because before we had such a large population, we would need several countries to work together.
Davide Soldato: Yeah, you're totally right. Thank you very much for underlining that last point.
Thank you very much, Dr. Knikman and Dr. Cats, for being here with us today and for explaining to us and our listeners the results of your research. That concludes this episode of JCO Article Insights. We discussed the manuscript titled "Survival of Patients with Cancer with DPD Variant Alleles and Dose of Individualized Fluoropyrimidine Therapy: A Matched Pair Analysis." This is Davide Soldato, your host. Thank you for your attention, and stay tuned for the next episode.
The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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Dr. Shannon Westin and her guest, Dr. Michael Anne Kyle and Dr. Nancy L. Keating, discuss the paper "Prior Authorization and Association With Delayed or Discontinued Prescription Fills" recently published in the JCO.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast that goes in depth on articles and manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the Journal of Clinical Oncology. And as always, I'm so excited that you've joined us, and none of the authors have any conflict of interest today. We are going to be discussing a very exciting piece of work, “Prior Authorization and Association with Delayed or Discontinued Prescription Fills,” recently published in the Journal of Clinical Oncology. And I'm thrilled to be joined by the two authors of this important work. The first is Michael Anne Kyle. She's a PhD research fellow in the Department of Healthcare Policy at Harvard Medical School.
Welcome, Michael Anne.
Dr. Michael Anne Kyle: Hi. Thanks for having me.
Shannon Westin: We're so excited. And the second is Dr. Nancy Keating. She's Professor of Healthcare Policy at Harvard Medical School and Professor of Medicine at Brigham and Women's Hospital in Boston.
Welcome.
Dr. Nancy Keating: Thank you. It's great to be here.
Shannon Westin: So, we'll get right to it. First, I always like to level set because we have such an interesting and diverse audience. Can one of you describe the process and goals of prior authorization? What does this mean for our groups that maybe haven't experienced this? Lucky them.
Dr. Michael Anne Kyle: Prior authorization is- the process can take many forms. Basically, what we're describing is before you can be prescribed a treatment, in this case, we're looking at medications, you have to submit a request to the payer, to the insurance company, asking for approval to receive that treatment, or in this case, that drug. The doctor's office does have to do a ton of work, but very often, the patient also receives a lot of the communication. So, there's a lot of work for everybody in prior auth often. And the uses of it- in principle, the purpose of prior authorization is to confirm that the reason this medication or this treatment is being prescribed is because the patient meets the criteria for need. So that can mean, you want to confirm that you have the right tumor markers for the drug that's being prescribed. You want to confirm that you are aligned with guidelines. And then I think the thing that's often on many people's minds is that in the US, we don't have a lot of controls on drug pricing, but drug prices are very high. And so, I think we often think about prior auth as being a mechanism to try and contain costs.
Shannon Westin: And this isn't new, right? So, this is a process that's been going on for a while. I'd love to hear you speak a little bit about, maybe, some of the changes, like how have the requirements for prior authorization been changing over time, especially for patients with cancer?
Dr. Michael Anne Kyle: That's a great question. And that was the first step we took in this work because we've heard from oncologists, from patients, from researchers, that prior auth has been increasing. And we did find, looking at Medicare data, that that is true, that the use of prior authorizations for oral oncology drugs, so that will be Part D outpatient drugs you get at the pharmacy, has been rising over the past decade. And I think what's really interesting to point out here is we found the use of prior authorization increasing both for branded drugs and for generic drugs, and for specialty drugs, which are high cost, as well as non-specialty drugs, which are typically lower cost. So, across the board, prior auth is increasing. And why is this happening really is the million-dollar question. Some of it is surely like we have accelerated approvals happening predominantly in oncology. So, you could imagine that you do need to verify some evidence of these newer treatments, but some of it is a little bit harder to interpret. And that was one of the things in our paper that we were very interested in because we also see a lot of prior auth on drugs that have a very well-established record of efficacy. And we know our first-line therapies often now include some generics, and yet we still see that they have prior auth. And the reason for that is less clear.
Shannon Westin: Yeah. Just as a gynecologic oncologist, coming from this standpoint of PARP inhibitors, which have long been established as a standard of care and for years now have been a frontline treatment, we're getting so much pushback around that, and it's a huge issue because that impact of delays and things, and I know that's your work. So, I think that's one of the reasons I was very enthusiastic about this because I think it has such broad-based impact across all of our patient populations.
So, I think that kind of definitely transitions into this. What are the potential negative impacts in this process of patients? And I would say not only patients with cancer, but what do we know also in patients with other disease types that are facing this prior authorization issue as well?
Dr. Michael Anne Kyle: What we were curious about is there's a sense that prior auth is increasing, the trends show it's increasing. And we were wondering, does that matter for patient care? And we could think about the benefits of prior authorization being like double-checking that you're getting the right treatment. But the negatives are that you can be delayed in getting treatment, and that can either be because you're going through the initial process or there can be some error or denial or dispute in a prior auth process that delays your access. And the clinical implications of that would vary by drug, how that would affect your treatment. In this case, in this paper, we're talking about drugs, but for any treatment, the implications would depend on what the treatment is and what the patient's condition is. But I really want to draw attention to this other piece, which is that it's stressful not to have your cancer medicine. And so even if you ultimately end up getting it, the time that you're on the phone trying to figure it out is time taking you away from other things. It's stressful. And very often, patients with cancer are taking multiple drugs and have complex health issues. So, they may be dealing with this for multiple parts of their care. And that can add up.
Shannon Westin: Perfect. Thank you. So, I guess next is to talk about how you address this. Let's talk a little bit about the overall objectives of the study that you just published and maybe briefly kind of go through the design for our listeners.
Dr. Michael Anne Kyle: What we were interested in doing, like I said, was trying to figure out what happens with prior authorization at the point of care. And our study looks at 11 oral anticancer drugs in Medicare Part D. And the reason for that is because data available to look at prior auth is fairly limited. And Medicare Part D for the outpatient formularies does have indicators for whether a drug has a prior auth. So, we were able to use that. The next piece is we're not inside the office understanding why these treatment decisions were made. So, what we decided to do was say, “Okay, let's look at patients who've been consistently taking this drug.” And we said, “Okay, let's say you've had to have at least three fills in the past four months.” And we sort of take that as an indicator that you're able to access this drug and it seems to be working for you. And then what we do is we look at who are patients in plans, same drug, same plan, where the plan introduced a new prior auth on this drug they're taking, as compared with patients in plans who did not have a change in their prior auth policy. And we said, “Okay, there's this new prior authorization introduced, does that affect whether you get that next fill or how long it takes to get it?”
Dr. Nancy Keating: I want to emphasize Michael Anne's point about these are patients who are already successfully filling and regularly taking their drugs. And unfortunately, due to data limitations and the inability to see prescriptions that aren't filled, we would love to look at the same question with people that are starting on a new drug but weren't able to do so but would imagine that you might even see bigger impacts in those patients. We both recognize from a health policy standpoint that there could be benefits of prior authorization policies. But it's also very unlikely to think that for a patient that's regularly filling an anticancer drug over a long period of time, that there's a reason that that patient should not be on that drug. And so, this is an area where we think that there may be really limited benefits of prior authorization, but potential harms.
Shannon Westin: Yeah, it makes sense. And of course, it would be. There's always the ideal way to set research up, and then a practical way. So, I was struck by what you chose. I thought it was really very practical and rational and made a lot of sense. And certainly, there are inferences that we can make based on what you found. So, let's talk about that. Let's talk about your primary findings. What did you see as the impact of a new prior authorization policy on patient care?
Dr. Michael Anne Kyle: We found that for the patients who had a new prior auth policy introduced in their plan, compared to patients who didn't have a prior auth change, their odds of discontinuation within the next 120 days increased by about 7.1 times higher odds of discontinuation. And then for delays, we found that people were delayed an average of 9.7 days from when we last saw that they were expected to run out of their drugs based on their last fill, we said, “Okay, what's the last day we expect you to have meds on hand, and then when do we actually see you fill again if we see you fill? And the average delay there was 9.7, about 10 days. And that's a fairly conservative estimate that we decided to make. And I'm sure you and Dr. Nancy Keating can elaborate on how that's not just passive time. There's a lot of people scrambling around, probably in that interval, trying to close the gap.
Shannon Westin: I mean, you said it, like, 10 days. It's a huge time. And it's not just time sitting there twiddling your thumbs. They're probably stressing, anxious. They might be having side effects related to stopping their medication. They might be taking other medications and reduce the efficacy of the combination. I mean, there's so many implications here of the impact.
Dr. Nancy Keating: They're also calling the office, trying to get through to the office. Then the doctors are calling, trying to get through. People are like, what's going on here? Why isn't this medicine there? And so, there's a lot of individual patient and clinician effort that's happening at this time as well.
Shannon Westin: And I think, of course, you were limited by the databases that you were using and what you're able to access, but I think it really does make me wonder, what's the impact on cancer related outcomes. We know about delays in certain therapies and things and how that can negatively impact survival and response and all of those types of things. And I wish we did have access to that kind of data because obviously the time and the things that you've been able to demonstrate are important, but the more objective data we can get around patient outcomes, I think will help us impact the actual policies that are being implemented here.
Dr. Nancy Keating: Right. And just to underscore too, Michael Anne highlighted the delays, but also there was a substantial increase in discontinuation within 120 days. So, there are some people that seem to not be able to get the med, maybe found another way to get it, or maybe were able to get samples from a drug company that we couldn't observe, but that's also concerning that there might be some people who fell through the cracks.
Shannon Westin: A very good point. I think that it's hard to know, but the potential there of losing the drug that's actually working for you is really distressing for providers and patients both.
One other thing I noticed that was interesting. Can you speak a little bit about some of the other factors that were associated with these findings with the treatment delays and what other things may be impacting these outcomes?
Dr. Michael Anne Kyle: We looked at some patient characteristics and insurance characteristics that may be associated with delays. And I just have to note here that our sample is fairly small because prior authorization is so prevalent. There aren't a lot of switchers. So, this sort of limited the amount of depth we could go into. But here's what we can tell you, which is that people who are under 65, so in Medicare that will typically be people who have eligibility through disability, were filling about a day later than that 9.7 average people, female sex also filling 0.7 days, nearly a full day later. Similarly, and this is compared to males and then compared to white, non-Hispanic patients, patients who are black and patients who are Hispanic Latino are filling about 0.6, 0.7 days later, which is, of course, quite concerning, given our desire to have a more equitable health care system. And then finally, we linked our data to census data. And for patients living in a residential zip code with higher rates of poverty, we found that for each 10-percentage point increase in proportion of residents in that zip below the federal poverty level, the delay was about 2.5 days. So, what you can sort of take from that is the risk factors in particular are in Medicare being younger, which I would say is having a disability, female sex, non-white, and people living in high poverty zip codes. And given what we know about racial segregation, I think the odds are likely that the patients themselves would potentially also be low income.
Shannon Westin: That's what's so important about this work, is it raises an awareness of, really, who's being impacted by this. Because I just want to draw back to kind of what you said at the beginning, that this is meant to do cost containment. It's meant to help the healthcare system. But what we're seeing in practice is it may be helping in some specific areas, but it's certainly creating quite a detriment. So perhaps there are other mechanisms that we could be exploring from a policy standpoint to try to work on cost containment, but not put the burden on the patients or on the people that are giving this health care. So, I think that's why I was so struck by this work.
I guess the next question is, what are your next steps for the research, and how can we use these data to help the patients?
Dr. Michael Anne Kyle: What a great question. I'll start, and then I'll let Nancy give her thoughts too. We're lucky that prior authorization is a very active policy area right now, both at the state and federal level. There's a great deal of interest in sort of certainly improving a lot of the information systems. Perhaps we can move away from the fax machine finally in 2023. I think there's a lot of policy relevant action happening around trying to make prior authorizations electronic, and you can automate them and make a lot of this move faster. There are also larger questions about what is the right price for a drug and how do we distribute it to people that I think are a lot more fundamental than any one study, but I think this is just another way. When we think about financial toxicity, there's just many challenges that come back to some way to this root cause of care is very expensive, and this is, I think, prior auth is one of the side effects of that.
And so, hopefully, to help patients, we can get this data in the hands of policymakers who are trying to bring us to a more modern prior auth system. And hopefully also to payers, I would be very excited to see a little bit more examination of, like when is prior auth appropriate versus when is it not. I think there are cases where prior authorization is very appropriate, and we shouldn't take it away. But one of the drugs in our study is generic imatinib, and perhaps that is a lower value prior auth. And so, I'd be very interested in seeing payers think more strategically about when is prior appropriate, both to improve access and improve equity, and then also to improve the provider burnout and the poor docs who are really struggling under the weight of this.
Dr. Nancy Keating: Yeah, I couldn't agree more with everything that Michael Anne said, but really, we'll underscore that last point. The prior auth policy seems like it's this very broad policy and the way that it's implemented, it's sort of like, let's just hit everything and not take a nuanced, thoughtful approach. But just like Michael Anne said, generic imatinib, really? And then back to this point of patients that are doing well on a drug, people are not going to be taking anti-cancer therapies if they don't need to. And so there just doesn't seem to be any reason to implement a prior authorization policy on a drug that is being well tolerated. And so really, I think there could be a lot more thought and nuance put into applying these policies within health plans.
Shannon Westin: Yeah, I think that's a perfect way to end this. I would just add, I think this is beyond anticancer therapy for our patients with cancer. I mean, we're seeing it now with supportive care medications. And to your point, I mean, generic antiemetics, and you're like, come on, this is ridiculous. So, I think that this type of work is- the best type of work always spurs more questions and gets us fired up about what to do next. So, I just want to again commend you on all of this important work, and we need to add more data here so that policy will change.
And so, thank you both for your hard work in this area and for taking the time to educate our listeners. I'm sure we're going to hear a lot of intriguing questions for you about this work, and hopefully that'll move our policy forward.
And thank you, listeners, for checking in again with JCO After Hours. Again, we were discussing prior authorization in association with delayed or discontinued prescription fills. I'm so grateful to Dr. Kyle and Dr. Keating for joining me today, and I hope you all will listen to our other podcast offerings wherever you get your podcasts. Have an awesome day.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and it is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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Dr. Shannon Westin and her guest, Dr. Nanda Horeweg and Dr. Carien Creutzberg, discuss the paper "Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer" recently published in the JCO.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. I'm your host Shannon Westin, Social Media Editor for the JCO and GYN Oncologist by trade.
And I'm so excited about today's topic because it is a GYN Oncologist dream. Before I start, please note that none of the authors have any conflict of interest. We are going to be discussing molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early-stage endometrioid endometrial cancer. And this was published in the JCO on September 20th, 2023.
And we're going to be speaking to two of the lead authors. First is Nanda Horeweg. She's a senior researcher in the Department of Radiation Oncology at the Leiden University Medical Center in the Netherlands. Welcome.
Nanda Horeweg: Thank you. Happy to be here.
Shannon Westin: And Dr. Carien Creutzberg. She's professor at the Department of Radiation Oncology at the Leiden Medical Center as well.
Carien Creutzberg: Thank you.
Shannon Westin: So, let's get into it. And I want to really level set because we have a mixed audience here. So, why don't you start by speaking about the incidents and mortality of endometrial cancer?
Nanda Horeweg: Yes, of course. Endometrial cancer is the sixth most common cancer in women with around 400,000 new diagnoses made globally each year. And a woman's lifetime risk to get endometrial cancer is around 3%, and the median age, the diagnosis is 61 years.
Most of the women who are diagnosed with endometrial cancer are diagnosed at an early stage, around two thirds, and they have an excellent prognosis. Actually, the five-year survival rates are around 92%. For stage 2 disease, this is actually already going down a bit to 74%. Therefore, stage 3 disease is only 48%. Women that are diagnosed with advanced disease have only a five-year survival, 15%.
Shannon Westin: So, given that we know the majority of endometrial cancers are diagnosed at this early stage, prior to your evaluation, what was known about the optimal way to treat this early-stage patient population?
Carien Creutzberg: Well, of course, the PORTEC trials were done … were started PORTEC-1 in the 19th of the last century, and PORTEC-2 in 2002. So, at that time, there were still many, many women treated adjuvantly with external beam radiation therapy. And we just developed risk factors to decide on their risk and the incidents for radiotherapy.
And in PORTEC-2, because in PORTEC-1 we had seen that most of the recurrences in these early stage cancers were in the vaginal fold, we compared local vaginal brachytherapy only three sessions within full course of pelvic radiotherapy and showed that it had similar pelvic control and survival.
Of course, this study, which Nanda conducted, was a long-term analysis with many new factors known from the translational research in the tissue samples of these patients who participate in PORTEC-1 and 2.
And in the meantime, we've developed much more knowledge on the molecular factors and other important factors such as LVSI, which tell us much more about the individual prognosis to patients. So, the treatment has been developing greatly in the past 20 years.
Shannon Westin: Yeah, and I think this is a great case of less is more, right? We were doing so much for so many people that really didn't need it. And so, really tailoring who needs less treatment, who doesn't need any treatment, and then also, conversely, who may need more treatment that would be missed by the traditional risk factors that you're speaking of.
So, I think that brings us right into my next question, which is just bringing the audience up to date on the cancer genome atlas and how that's changed the way we classify endometrial cancer.
Nanda Horeweg: Yes, I think the molecular classification of the TCGA has shaped the way we think about endometrial cancer, and has huge impact on decisions on adjuvant treatments in the years to come. The TCGA performed an extensive characterization of the endometrial cancers and found that in fact, this disease exists of four different groups.
And the first of the groups I'd like to discuss is the ultra-mutated group, which is characterized by POLE mutations. And this group is shown to have an excellent prognosis in many independent studies. A second group that also has a high mutational burden is characterized by microsatellite instability, and mismatch repair deficiency and has shown to have an intermediate prognosis.
Then there's another group that has a low mutational burden with high copy number alterations and frequent TP53 mutations, and these have a poor prognosis. And then lastly, there's a group that does not have any of the classifying features and is often called non-specific molecular profile or TP53 wild type. And this group also has an intermediate prognosis.
And then finally, there's a small group of cancers that has more than one of these classifying features, the so-called multiple classifiers. And the WHO 2020 has developed an algorithm which can be used to classify them into the four groups.
And that's first on the POLE status. And for the POLE wild type tumors, they are assigned according to mismatch repair deficiency status. And for those that are mismatch repair proficient than POLE wild type, they are classified according to the TP53 status into NSMP or p53 abnormal.
Carien Creutzberg: Yeah, that is because of in the ultra-mutated and hyper mutated groups, many of the other mutations are secondary mutations in the context of the ultra-mutated stage, and they behave like the first molecular group.
Shannon Westin: Yeah. So, that POLE mutation is going to trump anything else, and it's so important. And I will just say as a sidebar, it's been challenging with the price of next gen sequencing sometimes to get that for everyone.
So, sometimes for us when we see a p53 mutation, we actually go back and do the full next gen sequencing to make sure that we're not going to act on that core prognostic feature when it really is in the setting of that more simplistic or that more positive prognostic place.
So, this is great, we already kind of highlighted a little bit PORTEC-1 and 2, but if you don't mind, I would love to get the audience a little bit more information just maybe about the populations that were included as we were figuring out how aggressive to be with radiation just to remind people of that, or to teach them that if they haven't gotten a chance to look at those studies.
Carien Creutzberg: Yeah, that's important to know because PORTEC-1 was still in the era that we also treated intermediate risk stage 1 endometrial cancer patients. So, deep invasion with grade 1 and 2 or superficial invasion with grade 2 and 3. That's what we defined at that point.
Then we compared external beam radiation or no further treatment, showing no survival difference, but a higher risk of recurrence with higher risk being older age over 60, grade 3 for deep myometrial invasion. And we kept those high intermediate risk factors as also similarly found by GOG-99 at the time to do PORTEC-2.
So, at the time, about 50% of patients did not have an indication for adjuvant therapy anymore, and with a high intermediate risk population for PORTEC-2, we compare external beam or vaginal brachytherapy and found the benefit of vaginal brachytherapy. A simple outpatient treatment, very short with almost no side effects ensuring local control.
And nowadays, using the molecular classification of PORTEC-4a, we've compared achieving treatment with or without use of the molecular factors to designated treatment. So, the standard arm is vaginal brachytherapy and investigational arm is first, a molecular risk profile.
And then we give no radiotherapy for those with a favorable profile, then a brachytherapy for the intermediate ones, and for the small group is either extensive LVSI or TP53 mutation or L1 chem overexpression external beam. And we hope to show that less overtreatment and less undertreatment will benefit these patients.
Shannon Westin: Yeah, I'm very much looking forward to the results of PORTEC-4a. But let's circle back and talk a little bit about your amazing work here. So, how did you leverage those patient populations from PORTEC-1 and 2 for the current study?
Nanda Horeweg: Yes. Well, the PORTEC-1 and 2 study provided a unique opportunity to look into differential treatment effects for radiotherapy. And that is because these are randomized trials, so the groups are comparable, and we have long-term follow-up data that's of very high-quality.
In addition, as Carien said earlier, she had the vision already back in the nineties to directly ask the patients permission for the collection of the tissue. So, we have a broader complete biobank for both of these trials, which is quite unique. And our colleagues, Professor Smit and also Charlene Goseff from the pathology department, they have done extensive work on molecular classification, and have molecularly characterized all these cases.
So, this allowed us to include 880 patients in this study, which is the largest so far. And besides like the very good starting point that we have of PORTEC-1 and 2 is that we also chose a design that was optimized to conduct like real causes, the causal effects of the molecular class on radiotherapy response.
So, we tried to preserve this randomization effect, the exchangeability of the groups as much by working with the intention to treat population and not excluding any patients, except for when they did not have the molecular classification assessed.
And also, we looked at areas in the body that were irradiated in one group and not in the other one to really observe the effect of radiotherapy as much as possible. So, looking to the entire pelvis, so local and regional recurrences in PORTEC-1 and looking at pelvic recurrences in PORTEC-2.
Shannon Westin So, how were the intervention outcomes in this study different based on the TCGA classifiers?
Nanda Horeweg: Before I tell you the results of biomolecular group, I think it's good to have the starting point of the analysis here. So, the no hypothesis of my study was to see whether there was any difference, and no hypothesis is that there's no difference. So, if we find a significant effect, then we can actually say that we found something.
And if we start with the POLE group, we did not find any significant difference between the groups allocated to radiotherapy or not. But we did see not a single recurrence in any of the patients that we included from both of these trials.
So, technically speaking, we did not find a predictive effect of the molecular classifier, but a prognostic effect. There's no one's having recurrence, so we can deduct from that, that radiotherapy is probably over treatment.
Then for the MMRd group, we did observe some recurrences, but these were not significantly different between these three groups. So, based on this study, we cannot draw conclusions on which type of radiotherapy we should give to the patients or whether we should give radiotherapy at all.
This was very different for the p53 group. There, the patients had lots of recurrences, unfortunately, as we expected, but we saw a big difference in outcome compared between no radiotherapy at all if it's vaginal brachytherapy where we still had lots of recurrences, and EBRT where we hardly saw any recurrences in the pelvis. And that difference was significantly different.
So, that's an indication that these patients need more than just vaginal brachytherapy, even though it's only stage 1 endometrioid endometrial cancer.
And then in the last group, the NSMPs, we saw even a different pattern where patients who had had external beam radiotherapy or vaginal brachytherapy, both had an excellent local regional control, and the ones that did not receive any treatments had more recurrences. And this was also very significant.
So, there, you would conclude that both therapies are appropriate, but of course, the toxicity profile for vaginal brachytherapy is much more favorable than that of EBRT.
Shannon Westin: We really are getting kind of consistent data around p53 needing more treatment. And I think the natural question that comes here, for me at least, and I know we can't answer it with the work, is would chemo be — would that be that extra treatment, when we saw with PORTEC-3 that the group needed the chemotherapy the most.
So, I think we'll have to continue to work through that and determine is any more treatment what we need or specific treatments really the best. So, this is so intriguing and it's nice that it's consistent, that we're seeing that across these different studies that really kind of lends strength and validity, I think to what we're finding.
So, one of the actions that we're kind of moving towards and that you advocate certainly in your paper is omitting therapy for patients with POLE mutations. Are there any ongoing studies around that that will help us confirm that this is safe for our patients?
Nanda Horeweg: Yeah, that's a very good point. I think the evidence is strong enough now to conduct prospective trials. And of course, these are ongoing, the PORTEC-4a trial was already briefly mentioned there. The patients with poor mutations will be randomized between observation and vaginal brachytherapy. So, that will give us a good indication whether in this high intermediate risk early-stage group omission is safe.
And in addition to that, we are also conducting with the RAINBO Consortium, the RAINBO-BLUE trial, wherein patients also with high-risk features, so non-endometrioid isotypes, LVSI and higher stages are included. And also in those patients, we investigate whether the de-escalation of treatment is safe.
So, we're definitely looking forward to those results to be able to transfer this knowledge to clinical practice later on.
Carien Creutzberg: And maybe it's nice to add that RAINBO BLUE is connected to the Canadian Taper trial. Taper being a general de-escalation trial where the POLE patients in that trial are also feeding into the RAINBO-BLUE. And I know that in North America, many centers will participate in the Taper trial.
Shannon Westin: Yes, I think everyone is very excited and I think it'll be nice to have these two very strong studies that will help us really confirm that that is 100% a test that needs to be done, cost are not — and that will help avoid overtreatment of patients.
So, in line of that, have you all experienced any challenges with implementing molecular testing across patients with endometrial cancer? Any thoughts on how we could potentially simplify? You talked about the rational promise algorithm, which I think is excellent, but I'm just curious to hear your thoughts on this.
Nanda Horeweg: The implementation of the molecular classification can be challenging. We have to be honest about that. And usually, it's the assessment of the POLE status that's causing the problems because that's usually done with NGS, which is quite expensive. It requires a lot of knowledge in the laboratory and it's also a bit time-consuming.
So, that is the bottleneck for most laboratories and for most settings. But this is already changing in a couple of places, like in the UK and the Netherlands, it's being reimbursed by healthcare insurances, and also, in many tertiary care centers in other countries, they're already systematically performing this test.
But of course, there will always be places where this is not feasible. And luckily, there are also cheaper alternatives coming up and are already available at the moment. So, one of them is, for example, standard sequencing, which is not so expensive, but a bit labor intensive.
Some colleagues we work with from India have implemented that in their clinical practice and are perfectly able to molecularly classify the endometrial cancers in daily practice.
Another alternative is a test that we've developed in Leiden that's called the QPOLE test, which is based on qPCR, so that's a technology which we use for our COVID test around the world, so that can be done almost anywhere. And with that, you have a very high accuracy to detect unknown pathogenic variants.
And this is also published in JCO Global Oncology, and can be implemented in any center after a local validation step. And even like more companies nowadays are realizing that this is important. So, I think commercial tests are already becoming available and very more on the market soon. So, I am really hoping that it'll be more available to endometrial cancer patients.
Carien Creutzberg: And they'll offer them at a very low cost and also a rapid turnaround because NGS can take like 10 days. But realizing on a more national level, if you have found one patient with a POLE mutation, the omission of cycles of chemotherapy with all of the patient care around in the hospital is worth much more than just a few POLE tests.
So, we have to look at this and that's I think why our healthcare reimbursement came through that if you look at a population level, it is cheaper, and we'll do an extensive cost analysis in PORTEC-4 just to show this.
Shannon Westin: That is such a good point. I love that and all of the downstream issues that happen potentially with radiotherapy or with chemotherapy, that's really brilliant. And I'm going to take that back, I love these podcasts. I always learn stuff that I immediately start to use.
So, I guess then the last question is, what's next for this particular research and how might we validate what you found?
Nanda Horeweg: Yes. Well, as mentioned earlier, for POLE, we have already put the next step in place. So, PORTEC-4a has completed accrual almost two years ago, and we're very much looking forward to do the final analysis within one to one and a half years.
So, that will be one of the important next step. And of course, the POLE-BLUE trial is open at the moment, and within a couple of years, we also hope to learn more about this group. So, that's very exciting.
Then for the mismatch repair deficient group, while we did not find any particular sensitivity for radiotherapy, and I also don't think that we will conduct another large randomized radiotherapy trial in this group — I think the results that we've observed in the metastasized setting, were really impressive results with immunotherapy are the way forward for this molecular class.
And I think the next thing we should do now is prove whether this works or not in the adjuvant setting. And if that's starting with the high-risk patients, which is something we are currently doing in the MMRd-GREEN trial, which is ongoing in the Netherlands, and soon, will open internationally. And from there on, we can work forward if we see that also in this setting the immunotherapy works well.
Shannon Westin: And I think GY020 also — NCI trial is also looking at the addition of immunotherapy to radiotherapy in that irony at risk.
Carien Creutzberg: Absolutely.
Nanda Horeweg: Yeah. And the KEYNOTE-B21 as well — oh, well, already complete accrue.
Shannon Westin: The B21, yeah. So, I think those are good. Yeah, that's a really good point for that MMRd group that the immunotherapy really is the way to go, and then more work to be done with the no specific molecular profile.
Nanda Horeweg: The NSMP, I think like for the early-stage group, it's quite clear that vaginal brachytherapy is a therapy of choice. But you can of course, try to identify those at such a low risk that you could deescalate treatment. And that's of course what's being done in the Taper trial and also in part, investigated in the PORTEC-4a trial.
Carien Creutzberg: And those with higher risk NSMP that we are revisiting hormonal treatments because 90% are estrogen receptor positive, and they have a clearly better prognosis than those with estrogen receptor negative tumors.
So, those with estrogen receptor positive tumors can in RAINBO-ORANGE, which will be run led by the UK group, see if we can improve quality of life with less intensive adjuvant treatment. And then you came to the p53 group, that's a good one to stop with.
Nanda Horeweg: Yeah, we have very good indications that radiotherapy and chemotherapy is working well for this group. And this is also in line with the guidelines that have been issued in the last few years by many societies. So, I don't think we should change this base of the treatment consisting of radiotherapy and chemotherapy.
But since the prognosis is still rather poor, we need to add systemic agents to reduce the risk of metastasis. And preferably, this should be like well-designed based on a proper biological underpinning, plus something that's not too toxic since we're combining the three therapies together.
So, this is what we try to do in the RAINBO-RED trial where we will investigate the addition of a PARP inhibitor to chemoradiation in the p53 group.
Shannon Westin: Oh, I love that. That's been my whole career, is adding PARP inhibitors wherever I can.
Carien Creutzberg): We might also want to mention the HER2 inhibitors, which are also in about 20% of the p53 group has HER2 overexpression. And there is a trial being set up in NCI with trastuzumab and pertuzumab.
Shannon Westin: My only concern with that one is I think that the antibody drug conjugates are so much more powerful, the TDX data that we just saw from DESTINY is so impressive. And so, I do wonder, like if we need to move on from kind of some of the older HER2, and get with the program and use some of these more powerful drugs.
But with that, I just want to thank Dr. Creutzberg and Horeweg. This was such a great discussion, and obviously, near and dear to my heart talking about endometrial cancer, but I hope our audience enjoyed as well.
Just as a reminder, this was a discussion on molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early stage endometroid endometrial cancer, published in the JCO on 9.20.23.
I am your host, Shannon Westin, and I hope you'll check out more JCO After Hours wherever you get your podcasts. Have an awesome day.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions.
Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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In this JCO Article Insights episode, Davide Soldato provides summary on two articles published in the November issues of the Journal of Clinical Oncology. The first article provides data on the prognostic effect of physical exercise on overall mortality and cancer-related mortality in a pan-cancer analysis of the PLCO study. The second article provides data regarding the impact of BMI on treatment-related adverse events and adherence to Palbociclib in the PALLAS trial. Overall, results of these study support the need to conduct studies investigating lifestyle behavioral factors and their impact on outcomes in survivors of and patients diagnosed with cancer.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Davide Soldato: Welcome to the JCO Article Insights episode for the November issue of the Journal of Clinical Oncology. This is Davide Soldato, your host, and today, I will be providing a summary on two articles focused on the impact of exercise on cancer prognosis and of BMI on treatment side effects.
In the first article titled Pan-Cancer Analysis of Postdiagnosis, Exercise, and Mortality, Lavery and colleagues investigated whether higher exercise was associated with a reduced risk of mortality among individuals diagnosed with cancer. The authors conducted a pan-cancer analysis using data from the Prostate, Lung, Colorectal, and Ovarian cancer screening study or PLCO, using data from a questionnaire that was administered to participants in the study at a median of nine years after initial randomization.
The questionnaire including 12 questions related to physical activity, both occupational and non-occupational. Of these 12 questions, four were used to assess the prognostic impact of moderate and strenuous exercise evaluated both in terms of frequency, so a number of sessions per week, and duration of exercise sessions.
The exposure to exercise was defined according to international guidelines, and patients were so divided among those who had a moderate intensity exercise defined as at least four days per week with each session on average for 30 minutes in duration, and strenuous intensity exercise equal or more to two days per week with each session on average of at least 20 minutes in duration.
So, based on this definition, the patients were categorized as either exerciser, if they were meeting the recommendation or non-exercisers. Additionally, to assess the existence over those response relationship between exercise and mortality, the authors further categorize patients on a four level scale as reporting no exercise, exercise, not meeting recommendation, meeting recommendation, or exceeding recommendation.
The primary endpoint of the study was all-cause mortality, and secondary endpoints included cancer mortality and mortality from other causes. This study included more than 11,000 patients diagnosed with cancer. 38% of them reported meeting guidelines recommendation with a median of 44 and 19 minutes spent in moderate and strenuous exercise respectively.
Individuals belonging to the group of exerciser were more frequently male, non-smokers, and with a lower prevalence of cardiovascular diseases. The most common cancer diagnosis were prostate cancer, breast cancer, and colon cancer observed respectively in 37%, 20%, and 7% of the participants.
Patients who died within six months from the completion of the questionnaire were excluded from this study. A median follow-up time between this landmark point and the last follow-up was 11 years. More than 4,500 deaths were observed in this period, and less than half were related to cancer meeting.
Meeting exercise recommendation was associated with a 25% risk reduction in all-cause mortality, a 21% risk reduction in cancer mortality, and a 28% risk reduction in mortality from other causes. In particular, five-year cancer mortality rate was 12% among exerciser and 16% among non-exerciser.
Interestingly, the positive prognostic effect of exercise was observed starting within the first five years of observation, but persisted up to 20 years afterwards. An inverse to those response relationship between exercise and mortality was observed, so increasing exercise was overall associated with incremental reduction in the risk of death.
The authors compared patients reporting no exercise with those reporting exercise under at the recommendation or over the recommendation. For all-cause mortality, the risk reduction was equal to 25% among those reporting exercise below the recommendation, and increased to 35 and 36% among those meeting and exceeding recommendation respectively.
Similar results were observed for cancer mortality, risk reduction ranged from 19% in those reporting exercise below recommendation, up to 33% for those exceeding recommendation. Finally, the authors investigated the effect of exercise on mortality by cancer type, and observed a significant reduction in cancer mortality only for head and neck cancer and renal cancer.
While reduction all-cause mortality and mortality from other causes were observed across a wide range of cancer, including breast, endometrial, and hematopoietic and prostate. The study confirms previous findings by showing an inverse relationship between higher level of exercise and lower risk of all-cause mortality, and provides novel insights on the topic by reporting that those response association, data on other causes of death, and edited analysis by cancer site diagnosis.
All limitation of the study is related to the generalizability of the findings. The study included only patients that were alive at a median of 4.5 years after cancer diagnosis, which might have applied to selection of patients with good prognosis, and thus, reducing the number of cancer mortality events. Additionally, these patients were willing to complete an additional questionnaire in the context of the trial, which might be related to a higher motivation in engaging in healthy lifestyle behaviors.
The study did not replicate previous findings observing a reduction in cancer mortality for breast, colon, and prostate cancer, among those reporting higher exercise. Although this might be related to the inclusion of long-term survivors in the study.
In the second article titled Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial, Dr. Pfeiler and colleagues investigated the impact of BMI on side effects, adherence to treatment, and efficacy of palbociclib in the PALLAS trial.
Just as a reminder, PALLAS is a randomized clinical trial that investigated whether the addition of two years of palbociclib to standard endocrine therapy in patients treated for stage two, three hormone receptor-positive HER2-negative breast cancer could improve invasive disease-free survival. Previous report of the trial showed that palbociclib did not improve invasive disease-free survival compared to endocrine therapy alone.
More than 5,500 patients were included in this analysis, and among them, more than two third at a BMI equal or over 25 diagnoses with 32% being overweight and 30% obese. Overweight and obese patients were more frequently older and coming from North America rather than from Europe.
In line with the age difference, normal weight patients were treated more frequently with Tamoxifen alone or in combination with ovarian function suppression or with aromatase inhibitors in combination with ovarian function suppression.
No differences in tumor characteristics was observed according to BMI. However, there were some minor differences regarding the type of surgery and administration of chemotherapy. The authors observed that side effects of palbociclib were significantly different according to BMI and in particular, they observed a lower incidence of a hematological toxicity among overweight and obese patients.
Conversely, higher rates of arthralgia, nausea and diarrhea were observed among overweight and obese patients, both in the palbociclib and in endocrine therapy alone. In particular, regarding hematological toxicity, the authors observed that overweight and obese patients experienced a significantly lower incidence of overall neutropenia, grade 3 and grade 4 episodes of neutropenia.
For example, looking at grade 3 neutropenia, the incidence was equal 44% in the obese population versus 64% in the normal weight cohort. Differences in incidence of neutropenia remains significant even when adjusting for confounding factors, including previous administration of chemotherapy, age, ECOG performance status, and race ethnicity.
Furthermore, a lower incidence of overall thrombocytopenia was observed in the overweight and obese cohort. The lower incidence of hematological toxicity led to significant differences in those reduction, early discontinuation, and relative dose intensity for palbociclib. At six months, only 29% of obese patients reduced to those of palbociclib compared to 50% in the normal weight cohort. Similarly, only 20% of obese patients permanently stopped palbociclib compared to 35% in a normal weight group.
Finally, the risk of palbociclib early discontinuation was 25% lower for each additional 10 units of BMI, even when accounting for additional potential co-founders. As a consequence of a lower dose reduction and lower rates of early discontinuation, the relative dose intensity for palbociclib was significantly higher among overweight and obese patients compared to normal weight ones. Efficacy of palbociclib was not different according to BMI, neither in the palbociclib bar, nor when assessing patients in both arms. However, these analyses are performed with a relatively short, medium follow-up time, and a low number of events.
So, in conclusion, this report from the PALLAS trial shows that higher BMI was associated with a more favorable safety profile, especially regarding hematological toxicity, and a lower risk of treatment discontinuation. These findings are in line with previous data obtaining the metastatic setting with other CDK4/6 inhibitors, and support the existence of a different pharmacodynamic profile influenced by BMI that translates in a more favorable toxicity profile.
At present, differences in BMI do not seem to affect palbociclib efficacy, but further analysis with additional follow-up time and events, as well as by type of endocrine therapy administered are planned in the PALLAS study. That concludes this episode of JCO Article Insights.
In these episodes, we summarized findings from two studies, the first titled, Pan-Cancer Analysis of Postdiagnosis, Exercise and Mortality by Lavery and colleagues. This trial shows that higher level of exercise are associated with lower risk of all-cause cancer specific and other cause mortality, although with some differences according to cancer site.
The second article titled Impact of BMI in Patients with Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial by Dr. Pfeiler and colleagues observed a significant different side effect profile for palbociclib according to BMI, but no differences in efficacy.
This is Davide Soldato, thank you for your attention and stay tuned for the next episode of JCO Article Insights.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions.Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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In this "Podcast Takeover," Dr. Lidia Schapira guest hosts to discuss with Dr. Shannon Westin her own JCO paper, which reports on the DUO-E Trial. Dr. Ramez Eskander also joins in this lively discussion.
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor of the JCO and Gynecologic Oncologist by trade. And actually, I'm super excited today because we are going to have a podcast takeover because we are discussing my own work, which was simultaneously presented at the European Society of Medical Oncology 2023 Congress and published in the Journal of Clinical Oncology on October 21st, 2023. And this was the DUO-E trial, “Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer.” Because we’re discussing this work and we wanted you to have an unbiased podcast discussion, Dr. Lidia Schapira, who is a Professor of Medical Oncology at Stanford University and an Associate Editor of JCO and the Art of Oncology podcast host, is going to take over this podcast and really just pepper me with questions about this exciting work.
Welcome, Dr. Schapira.
Dr. Lidia Schapira: Thank you so much. It's such a pleasure to be with you.
Dr. Shannon Westin: And before I turn over the reins, I also want to introduce one of my colleagues, who’s going to be providing quite a bit of insight on this topic, Dr. Ramez Eskander, who is Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Diego. And you will know he’s the principal investigator of the GY-018 study, which established pembrolizumab and chemotherapy as the new standard of care in endometrial cancer. Welcome, Ramez.
Dr. Ramez Eskander: Thank you. Thank you, Dr. Westin. It's a pleasure to be here. And congratulations again to you and your study team for this exceptional work.
Dr. Shannon Westin: Thank you. And congratulations to you.
Dr. Schapira, thank you for being here and please do take it away.
Dr. Lidia Schapira: So let's start by having you tell us a little bit about the standard of care for women with endometrial cancer and advanced endometrial cancer prior to this study. Ramez, I'm going to direct this question to you first.
Dr. Ramez Eskander: For many years, actually since about 2012, carboplatin and paclitaxel, which ironically is a chemotherapy backbone really across all of our gynecologic tumors, emerged as the preferred doublet chemotherapy regimen for the management of advanced-stage metastatic or recurrent endometrial cancer. It evolved through a series of different clinical trials, in fact taking us from whole abdominal radiation, systemic chemotherapy, comparing single agents to doublets and then triplet regimen of TAP to carboplatin and paclitaxel, which ultimately, then, following the presentation of GOG Protocol 209 and its publication, as the chemotherapy backbone, being carboplatin and paclitaxel. And it’s been that way for many, many years.
Dr. Lidia Schapira: And how effective is the regimen?
Dr. Ramez Eskander: The response rates to carboplatin and paclitaxel are actually quite reasonable in the patients who have advanced-stage disease, particularly if they haven't had prior systemic chemotherapy. Response rates in the 50% to 60% range. The issue is that the responses tend to be limited and disease recurrence is an expectation in these patients who have advanced-stage disease. And so that really highlighted the importance of trying to continue to advance therapeutic opportunities in these patients to improve long-term outcomes.
Dr. Lidia Schapira: As we think about improved long-term outcomes, we're thinking about a better treatment and also a kinder treatment, perhaps one that is also less toxic. Can you talk a little bit about the population of women with endometrial cancer? Are these older women? Do they have comorbidities?
Dr. Ramez Eskander: What we’re seeing is, interestingly, there has been an evolution a bit in this space. Historically, we used to think about endometrial cancer as—the phrases we used to use are type I and type II. These type I tumors, we would say, are estrogen-driven malignancies; they tend to be seen in overweight or obese patients. And we would identify them in a theoretically younger patient population. And then we had these type II, or what we termed estrogen-independent malignancies, that we would see in an older patient population. Of course, with obesity came metabolic syndrome and other cardiovascular comorbidities, etc. But really, that narrative has evolved dramatically, and that’s really something that will be highlighted in, I think, our discussion of these studies today, where the nomenclature that we used to historically use has evolved because of our understanding of the molecular characterization of this disease. So we’ve really gone away from that, and now we understand that we’re seeing all of these different heterogeneous endometrial cancer types amongst patients of different ages, different comorbidities, different races and ethnicities. And so it’s created a more complex picture for us. But certainly, there are comorbidities that these patients face, and that’s important as we look to identify treatments strategies that are both effective and tolerable.
Dr. Lidia Schapira: My final question before we jump into this very exciting study is about the Cancer Genome Atlas work. Can you tell us how that’s changed the thinking and the design of the studies?
Dr. Ramez Eskander: It was a seminal publication, really, back in 2012/2013 looking at an assessment of endometrial cancers to try and determine whether or not all of these "endometrial cancers" that we used to enroll on a single study are similar or divergent. And it’s important because the study I referenced that really established the standard of care, GOG Protocol 209, as carboplatin and paclitaxel, there was no real consideration of molecular characterization at all. We enrolled all patients onto this study without thinking about these variables, of course, because it was designed, conducted, and completed before the TCGA data emerged. But what we learned from the TCGA is there appeared to be four distinct molecular subgroups. There were the POLE-mutated patient population. There was the mismatch repair deficient or MSI-high endometrial cancer population. There was the copy number-high or what we say are the p53-mutated. And then the last cohort was called the NSMP (no specific molecular profile). But now, that’s even evolved; some people term it TP53 wild type. That’s a bit of even a heterogeneous cohort amongst itself. So we’re going to take these subsets, independent of POLE and an MSI-high, and we’re going to look at TP53 or copy number-high, and that will probably be divvied out further, and the NSMP, and that will probably be subdivided. But really, it gave us these four components, which has then evolved. Many of you may have heard of the ProMisE algorithm or ProMisE Plus, which looked to take the data from TCGA so that we can start to really look at it in clinical practice. So it’s really revolutionized how we think about these patients, how we think about the disease, and how we design trials.
Dr. Shannon Westin: And I just want to add to that because I think that it's so important, what Ramez said about the way we were developing trials, the way we were designing trials. We knew that these classifiers—we were learning these classifiers are prognostic. Now what we’re really trying to hone in on is how predictive they are. And certainly, one of the major classifiers that we’re going to talking about today is mismatch repair status, and that is most definitely predictive of response to therapies. But we’re still learning about the other classifiers and how we might adjust the way we treat people, even deescalating care for certain patients. That is still being proven in clinical trials, although we suspect that it’s going to be borne out as other clinical trials report.
Dr. Lidia Schapira: It's a perfect segue to this current trial. Tell us a little bit about the objectives and the design of DUO-E.
Dr. Shannon Westin: As Ramez said, the standard of care was chemotherapy. And so we wanted to see if there was a way to improve outcomes for these women with advanced and recurrent endometrial cancer in a really clinically relevant, meaningful fashion for patients. And so we knew that this TCGA classifier, the mismatch repair, was so important, and we thought that the addition of immunotherapy to chemotherapy would most certainly work in that population but could even work in the entire population because, generally, endometrial cancer seems to be a little bit more responsive to immunotherapy and to activation of the immune system than, say, some of our other gynecologic malignancies. And so we set out to see what the addition of durvalumab, which is a PDL-1 inhibitor, would add to chemotherapy. And this was two chemo as well as followed by durvalumab maintenance.
But even further, we had some really kind of exciting science data from our lab that said that if we combined a PARP inhibitor with immunotherapy that we could accentuate on the response to therapy and we could get more benefit. And there's kind of a lot behind that, but essentially, what we thought was that the damage that's caused by the PARP inhibitors would create an activation of different immuno-pathways, like STING pathway and activating cytokine release, and that we would get this synergistic activity. So one of the other objectives was to see if the addition of the olaparib, the PARP inhibitor, to durvalumab in that maintenance setting could even further improve benefit. So we had a dual primary endpoint looking at progression-free survival, so the amount of time people live without their cancer coming back. And that endpoint was first, the durvalumab-alone arm to control, and then the second portion of that was the durvalumab/olaparib arm back to control.
Dr. Lidia Schapira: So before you tell us about the results, tell us a little bit about the study itself. I mean, I was very impressed that you did it in so many different locations. Tell us about that effort.
Dr. Shannon Westin: This was a huge collaborative effort both with the GOG Foundation, the Gynecologic Oncology Group Foundation, as well as ENGOT, which is our European colleagues that do amazing clinical trials. But in addition to that, we really worked very closely with our industry partner to really make sure we spanned the globe. And so we had groups from all over the world that participated and really were exceptional. The care that was taken and the hard work that went into this type of study across the world really can't be overstated. We were very lucky to have a wonderful infrastructure group. We met weekly for a long time, just keeping an eye on the data and making sure that everything was as positive as possible and, of course, that we were watching the outcomes of the patients very closely and making sure that there was no evidence of harm or issue. And so it really did take a village, truly, to run this study and to ensure that at the end of it, we got really great data that we can trust.
Dr. Lidia Schapira: So tell us the results.
Dr. Shannon Westin: So DUO-E was positive for both of its primary endpoints, which was very thrilling. So for the first analysis, which is the durva-alone arm to control, we saw a reduction in the risk of progression of 29%, so a hazard ratio of 0.71. And then the addition of olaparib seemed to further enhance this benefit, so a 45% reduction in the risk of progression for a hazard ratio of 0.55. But what's really exciting is our follow-up time was pretty long; it was about 17 months, so we were able to look at a couple of different analyses, including an 18-month landmark analysis where we saw approximately 50% of the patients were still alive progression free at 18 months, as compared to only 21% of patients being alive progression free in the control arm. So there was a doubling in that progression-free survival time point at 18 months, which is thrilling.
Dr. Lidia Schapira: So Ramez, as an expert in the field, what was your reaction when you read or heard these results?
Dr. Ramez Eskander: It's exciting, honestly. So we have gone a long time without seeing really significant successes in the endometrial cancer space, a testament to the fact that we hadn't yet developed our understanding of how we could move this needle forward. But Dr. Westin and the DUO-E team conducted an exceptional clinical trial, as you mentioned, international study, rational and important hypothesis to adjudicate. And what we saw here was both now we had other studies—the RUBY trial, the GY018 trial, the AtTEnd—and now here DUO-E, which added this hypothesis of PARP maintenance in addition to checkpoint to try to augment response and consistent, really provocative data, exciting, in line with what we've seen and hopefully will continue to drive the science in this space, most importantly.
Dr. Lidia Schapira: So let me ask you a follow-up question to that. What kind of scientific questions are in the air now as a result of this trial and what the trial found?
Dr. Ramez Eskander: Oh, goodness. Shannon and I could both take this, I'm sure. But I think in the dMMR population, we recognize that there's a ton of data that is supportive of the fact that these tumors are immune responsive, particularly in dMMR endometrial cancer, whether it's an epigenetic promoter hypermethylation, or a mismatch repair gene mutation. I think the data has emerged that immunotherapy is here to stay for these patients in the newly diagnosed advanced stage, even chemo naïve, who need adjuvant therapy.
The pMMR population, this is where we're seeing more and more questions emerge because we realize that that may be a cohort of different cancers. And I'll let Shannon speak to this briefly, but even the incorporation of the PARP inhibitor, in addition to the checkpoint, there's a biologic rationale for combining those two together to augment response. And to see the benefit in that trial—arm three and arm two, we can look at descriptively and look at the differences, but who are those patients? Where is the PARP and the checkpoint most effective? How do we expand that to a larger population of patients potentially? These are questions that emerged because, as Dr. Weston will allude to, I know we also talk about HRR mutations, which are captured, but we even have a lot to understand about that in endometrial cancer, where we've had more research in the ovarian cancer space.
Dr. Shannon Westin: Being mindful of time, because I have, like, 1,000 hypotheses that have been generated by this study, which, I think, shows it's a great study, right? Because you get some answers, and as our colleague Brad Monk says, “The only definitive study is the negative studies.” This most certainly was not that. But just kind of expanding on what Ramez said, the interesting thing about DUO-E is that really the biggest benefit for the combination of the durvalumab and olaparib was in that mismatch repair proficient group. And I personally thought that we were going to see accentuation of the impact in the mismatch repair deficient group based on the science, but that just wasn't borne out by the data. It doesn't seem that the combination has that much to add in that mismatch repair deficient group. And when we tease out the mismatch repair proficient group, I think that's where a lot of interesting information is going to come because, to Ramez's point, we're going to tease out: Is it driven by the P53-mutant population? Is it driven by the population that has homologous recombination deficiency? How do we even measure homologous recombination deficiency in endometrial cancer? So I'm super excited about what we found and how that may help us to make those decisions for the patient in front of us.
The other thing I think needs to be made mention of—and this was something we saw in DUO-E as well as AtTEnd—we had a large population of patients that were recruited in Asia, 30%. Interestingly, when we look at the forest plot, that group doesn't seem to benefit as much from the addition of the olaparib. So we really need to tease out what's different about that population because what Nicoletta Colombo presented around AtTEnd, it looked like they didn't benefit from the atezolizumab either in that study. So there's clearly something different about that population, and we have a really big opportunity to look at that since we had such a large proportion of patients that were enrolled there. So that's another, I think, really intriguing question.
Dr. Lidia Schapira: So how does this fit in the context of endometrial cancer treatment, and what are we going to do with patients in the clinic? I'd love to hear both of your perspectives, starting with you, Ramez.
Dr. Ramez Eskander: It's an evolving answer, to say the least. What we can say definitively is that we have a United States FDA approval for the regimen of dostarlimab plus carboplatin and paclitaxel in the mismatch repair deficient, advanced-stage/recurrent or metastatic patient cohort. And again, that's because the magnitude of benefit that we saw in the RUBY trial, which looked at that, was actually analogous to what we saw in 018, AtTEnd, and DUO-E, again, consistently highlighting the benefit of the IO and the dMMR. We have yet to see how this is going to evolve the landscape in the larger patient population, which is the pMMR patient population. And it may be that based on the data that we have, we will see immunotherapy plus carboplatin and paclitaxel as the new standard of care in the pMMR cohort, or it may not. That's yet to be defined. And I think Dr. Westin will add to this, but I think that's also going to depend on the perception of how we view the cohort. Is it one group of patients? Are we going to have to think about subsets within the pMMR population? That is an active conversation.
Dr. Shannon Westin: I would just add, having treated patients on this combo regimen with the durvalumab and olaparib, I have multiple patients that still remain on study, and this—we're looking at three and four years out. I just never saw anything like that before with standard chemotherapy, so there's definitely something here. So I want to know who those patients are, who benefits really the best from the combination, and who could we just give the immunotherapy to and get that same benefit. So we obviously always want people to live as long as possible. That's the bottom line. But we don't want to overtreat. And so I think balancing that is really important.
Dr. Ramez Eskander: The point that was made earlier: We have yet, aside from MMR response to checkpoint, within the pMMR population, we understand that there may be subsets, but we have yet to prospectively validate that these molecular cohorts within the pMMR population are truly defining response to a particular therapeutic strategy. So we have to be cautious not to limit the treatment opportunities for these patients without having the data that we need to do so because, as Dr. Westin mentioned, for us—whether it was the Gy018 trial, the RUBY, the DUO-E trial—what we saw is there are pMMR patients who have a dramatic response even though they are “biomarker negative.” They're pMMR, they're TMB low, they're not POLE mutated, but yet they still derive a dramatic benefit. And so that goes back to the hypothesis about why we're even combining checkpoint with chemotherapy in which, for example, in lung cancer, there's been established success and approval. So I think we're all eager to see these strategies emerge as treatment opportunities for the pMMR patients as we work to still develop additional effective opportunities.
Dr. Lidia Schapira: So, based on all of this and sort of the new twists on the scientific hypotheses that are now generated, what are the next steps?
Dr. Shannon Westin: Well, I think we have to see if these drugs are available for patients. So looking at things like compendium listing and regulatory approvals obviously is going to be very important. But from the things that I can control, we are looking at the different molecular subtypes and understanding the different mutation status and trying to tease out who may be driving the biggest benefits so that we can help advise and make sure that we're doing the right thing for the patients.
Dr. Lidia Schapira: And wearing my supportive care hat, I have to ask you, Shannon, about the tolerability. We often find that the quality of life and studies come out after, sometimes months or years after, the original trials are published. So let me take this opportunity to ask you now: How did women tolerate these drugs?
Dr. Shannon Westin: The bottom line, Lidia, is, as expected, when you add additional drugs, you see additional side-effects. I think the good thing is that we're very comfortable with immunotherapy and we're very comfortable with PARP inhibition in gynecology because we have had access to these agents and so we know how to manage the toxicities. And so, from a standpoint of incidence, there was a higher incidence of grade three and higher adverse events in the group that had durvalumab/olaparib. But this was primarily driven by anemia, which is as expected and is usually pretty time-limited at the start of olaparib. From a long-term standpoint, there was a slightly higher proportion of patients that discontinued therapy, but it actually wasn't as much as I was worried about. So we saw a 19% discontinuation rate in the group that was just the control arm, and that went up to 24% in the dual arm, so definitely higher, but not that much higher. And when we moved to maintenance, which is really where—that's where the arm becomes unique, it was much lower at about 12%. And so that's exciting to me, that patients were able to stay on a drug and were able to tolerate it.
And then, to your other point, we do have a very nice patient-reported outcomes plan, and that is actually being analyzed as we speak with the hope of presenting it at the next major meeting, our Society of GYN Oncology meeting in March. So not right away, but I think in a pretty timely fashion, we'll have those data.
Dr. Lidia Schapira: Congratulations, Shannon, on leading and presenting this wonderful study. So it's been a real pleasure to chat with the two of you.
Dr. Ramez Eskander: Thank you.
Dr. Shannon Westin: Thanks so much, Lidia. I really appreciate it. Thanks, Ramez, for being here.
And I will just say thank you to all of our listeners. We really hope you enjoyed this episode of JCO After Hours, where we discussed the DUO-E trial, which is a phase III trial evaluating durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer. And again, please do enjoy this publication that was online at the Journal of Clinical Oncology on October 21st, 2023. And do check out our other podcast offerings wherever you get your podcasts. Have a wonderful day.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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In this JCO Article Insights episode, Davide Soldato interviews Dr. Jacob Sands, medical oncologist at Dana Farber Cancer Institute (Boston, MA) and Assistant Professor at Harvard Medical School, on their paper “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01”. The interview offers a deep dive into the safety and efficacy data of this novel drug and puts these data in the context of the current treatment landscape of NSCLC and of the revolution that ADC are bringing into the oncology world.
TRANSCRIPT
Davide Soldato: Welcome to this JCO Article Insights episode for the October issue of Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Jacob Sands, co-author of the manuscript titled, “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.” Dr. Sands is a Medical Oncologist working at Dana-Farber Cancer Institute in Boston and Assistant Professor at Harvard Medical School. His main field of research and clinical interests revolve around improving screening and diagnosis of lung cancer and also on developing novel therapeutic agents for this disease.
So, welcome Dr. Sans, and thank you very much for accepting our invitation today.
Dr. Jacob Sands: Happy to join. Thanks for having me.
Davide Soldato: I just wanted to start with a very general question because I think that we are going to discuss a very important study and the manuscript that you co-authored is going to look at the safety and the efficacy of this novel ADC datopotamab-deruxtecan that is targeting TROP2. But I just wanted to have a little bit of context before starting to discuss the safety and efficacy data. So the population that was included in the study included more or less 60% of patients that received three or more lines of therapy and also 20% of patients who received five or more lines of therapy. So I think that this is a very particular population, especially considering that we are speaking about non-small cell lung cancer. And so I wanted to get from you like a general context, like what are the therapeutic options for these patients normally in clinical practice and what do we expect in terms of outcomes and in terms of toxicity?
Dr. Jacob Sands: Yeah, so as you point out, this is a highly pretreated population in general, which is to say that they've really gotten the most effective lines of treatment up to this point. Now, we certainly do see some efficacy from some of the later lines of therapies in some patients, but inherently there is a decreasing response rate and decreasing durability of these responses as patients get further along in their treatment courses as far as lines of therapy. So it's generally considered to be a challenging clinical scenario, which is part of what makes the data that we're going to discuss, I think, so meaningful.
Davide Soldato: Yeah, I think that especially if we look at the population that was included first, I think that the very particular thing is that included both oncogene-addicted and non-oncogenic addicted patients, and also the great majority of these patients received the most effective treatments that are available because they all received more or less immunotherapy and platinum-based chemotherapy, if I'm not mistaken.
Dr. Jacob Sands: That's right. And that's an important distinction that you're drawing in the patients with oncogenic drivers and, of course, there's plenty of data with this compound with Dato-DXD in that population as well. But broadly speaking, in the non-oncogenic actionable alterations where they've gotten chemo-immunotherapy, those really are the most meaningful. Of course, docetaxel has been a long-standing second line that I'd say there is less and less enthusiasm about that as a line of treatment as we've seen some of these other more novel therapies that have just a better toxicity profile in particular, but also some with really durability that we don't quite see with docetaxel as well. And so once you're getting past that, you're really now reaching a bit deeper to then have something that is well tolerated and has efficacy. That's a setting where we really need it even more.
Davide Soldato: So, going back to the results of the study, as we kind of pointed out, this was a very standard classic with a Bayesian design, phase I dose escalation and dose expansion study of this novel ADC datopotamab-deruxtecan. So I just wanted to go over with you and to provide our listeners a little bit with some data regarding the doses that were explored and then what were the doses that were selected for the expansion. And also to discuss a little bit the safety data. We were discussing the tradeoff between risk and benefit, especially in patients that are very pretreated, searching for these kind of sweet spots between the toxicity and the efficacy. So I just wanted to put in context a little bit the data that you reported in the manuscript.
Dr. Jacob Sands: Yeah, that's right. So, like phase I’s go, we started with a low dose at 0.27 milligrams per kilogram, and dose escalations occurred up to 10 milligrams per kilogram. The 10 milligram per kilogram dose did have toxicities that really made it not considered to be tolerable, and that mostly being mucositis and skin. And so it was then back down to 8 milligrams per kilogram. And then there was a dose expansion at 4, 6, and 8 milligrams per kilogram. The 4 and 6 milligram per kilogram doses had 50 patients enrolled within those cohorts and 80 patients within the 8 milligram per kilogram cohort to then get much more data, of course, for efficacy and tolerability within those levels. Ultimately, each of them really demonstrated some efficacy as well as general tolerability. The 6 milligram per kilogram dose was really the one selected overall for further testing and future trials based upon the data out of this one that we're going to discuss further.
Davide Soldato: What were the main side effects that you observed in the trial? And particularly, do you think that there is some kind of special toxicity that should be looked at when using this novel type of ADC?
Dr. Jacob Sands: Certainly there are some novel toxicities to really pay attention to. And maybe I'll just point out before diving into the toxicities, that this is in many ways chemotherapy. The antibody drug conjugates, as listeners probably know, are an antibody that has a linker bound to chemotherapy, what's called the payload. And in this case, it's a topoisomerase I inhibitor with the antibody, the TROP2. So the cells on the surface, when there's TROP2 expression, the drug binds to that, gets pulled into the cell and releases that chemotherapy intracellular, but it is still chemotherapy. And so some of the toxicities are things that we commonly see with chemotherapy drugs. Although, broadly speaking, I would say we're able to deliver higher doses of that chemo to the cells in this kind of targeted dosing of chemotherapy to give the chemo intracellular.
Now, that being said, some of the toxicities that we see from this drug in particular that are a bit different is the stomatitis, mucositis. That is something that has occurred. Now, I've found that if it's really severe, then with a dose reduction that has really substantially improved any toxicities with future dosing. And at a 6 milligram per kilogram dose, a dose reduction to 4 milligram per kilogram is still within a dose range where we saw plenty of efficacy within the trial that we're discussing. That being said, if one can help patients tolerate it better, if it's more mild symptoms, if it's not severe, then that's better in maintaining that dose. And interesting things like ice chips at the time of infusion, so cold within the mouth, kind of like the cold caps to try to reduce alopecia at the time of infusion of the chemo may help some steroid rinses also can be helpful. But really these are things to help prevent stomatitis from being severe. It's harder when that occurs, then the treatment for improving it is a bit different.
We do know, though, that that does improve with time. So even when it was severe with that infusion, it does improve as patients get further out from those doses. Of course, another one is dry eyes or irritation within the eyes. And if that is severe, then or even mild actually, I'd say when there's any known toxicity like this is to involve ophthalmology. Now, within this trial, ophthalmology was involved and patients had to get a baseline eye exam and they would get checked at different time points throughout the course of the trial. And so they were being monitored. I did not have anyone who needed to stop the drug because of this. The patient I had with the longest standing response to therapy did have some dry eye. It was not bothering him so much. And he had this real aversion to using eyedrops. It was very hard for him to make himself use these. But when I told him, “Look, if this gets worse, you might have to come off the trial, that it might not be our decision just by the way the trial describes it, if this gets worse.” And so for him, the fear of having to come off the drug was really the thing that helped him to then start using his eyedrops, which really helped to control that a bit more. And so that is something to monitor for.
But the biggest thing really is interstitial lung disease. This is something that is a complex topic, I think because it's something that we need to be very aware of and monitor for. At the same time, a diagnosis of interstitial lung disease can be challenging. There really were not cases where we had pathologic confirmation of this diagnosis. These are clinical diagnoses in the cases on this. Now there was an adjudication committee that would review all of the data and come to a determination of whether this looked like drug related ILD or not. But for clinicians, when you see a patient whose scan shows some inflammatory markings or inflammatory appearing markings on a scan, we see that all the time with other drugs too. And so determining what is potentially incidental versus drug related, I think in most cases on a trial when we're unsure, we lean toward drug related. And in some cases there are reported out severe cases of drug related ILD.
I think the really difficult thing that I'd want people to take away from all of this, though, the bottom line is, yes, we need to be very aware of the potential for drug related ILD while at the same time, we need to not reflex, just call things drug related ILD and really make sure that we're doing a workup when feasible rather than just that bottom line conclusion. We see it at a rate related to the drug, and I do think it's real. But we also need to, when treating individuals, try to identify any other potential etiology. I did have one patient that really looked absolutely classic for this diffuse drug related ILD that ended up ultimately really being what looked more like tumor progression in just a radiographic pattern that looked more like an inflammatory process than it did the way we would typically see cancer progression. And so this has really, for me, I think, highlighted this as a topic where I'm diving a bit more into that description.
Davide Soldato: And I also think that in the population of lung cancer patients, as you were saying, this is even more complicated because frequently these are patients who had a history of smoking, who can have concomitant infections where progression is easier in the lung. If I think, for example, other ADC that have already been tested, for example, in breast cancer, it might be far easier to detect and to adjudicate an ILD to the drug that we are using compared to what could be, for example, for lung cancer patients.
So if I understood correctly, the toxicity that in your opinion as a clinician, they are more complicated to treat, let's say on a more daily basis, are more stomatitis and inflammation, but maybe the one that you experience as potentially more severe are always related to lung toxicity.
Dr. Jacob Sands: Well, I think the scary thing about the ILD is that we have higher grades of ILD, and this is a toxicity that then can become life threatening. When we see a grade I or a grade II ILD reported in numbers, where we see, okay, this looks like it's really happening, and then see some really higher grade toxicities, I think the concern amongst clinicians then is if they're seeing lower grade, which of those can potentially progress to those higher grade, which then becomes life threatening toxicities. Whereas dry eyes certainly can become a nuisance, we didn't see any blindness or something like this, and the stomatitis resolves as you hold the drug, and in some cases, really before the next cycle even comes, it's just more a matter of controlling the discomfort, which can be severe. I'm not minimizing that. I think that's why ILD stands out so much, is that that becomes a potentially life threatening thing.
And to your point exactly, these patients with a smoking history on other drugs, we see these inflammatory findings. Now, in some cases, we know it can be from the drug. In other cases, we see it and know that it's essentially incidental. And I'll say to patients, “Hey, we see this. It's something we'll monitor on future scans, and these can wax and wane.” When you have a patient on a drug with a high attention towards something like ILD, there can be- what I'm cautioning against is a reflex attribution to that drug. In all cases. I'd urge clinicians to individually assess each of these patients to get a sense of whether they think that that's going on for that person, knowing that it's often not possible to say with 100% certainty in any of these cases. But we often see waxing and waning inflammatory findings. And in many of these patients with heavier smoking histories, in particular, there can be waxing and waning respiratory symptoms. So the question is, are there instances where there is what really is an incidental inflammatory findings and incidental respiratory waxing and waning that then suddenly we call a grade II?
At the same time on the other part of that, if there is something that seems like it really may be drug related ILD, is doing that work up and really evaluating and diagnosing that before it progresses to a point that really there are severe symptoms. And it's kind of trying to do both of those things on the opposite ends of the spectrum that I'm speaking toward at the same time.
Davide Soldato: Just on a personal note, do you think that, as we continue the development of these drugs that are associated potentially with lung toxicity, do you think that we also need to pay attention to the drugs that were immediately previously received by the patients? What I mean is, do you have the feeling that the previous treatment could potentially impact on the risk of developing this type of toxicity in the lung?
Dr. Jacob Sands: I don't know that we yet have data to draw any real conclusions around that. But you raise an important question within this, and what potential toxicities could be related to prior treatments or synergy across those. Of course, we see inflammatory findings within the lungs and pneumonitis with prior immune-related therapies, and that it would be a good prompt to the question you're asking. And that in particular, we also see this in some of the targeted treatments, although not nearly to the same percentages. I don't know that we can draw conclusions from this. I would speculate that the mechanisms of action of each of these drugs are so different that I would not hypothesize real synergy in those toxicities. But it is certainly something to be aware of and an important question that you're raising.
Davide Soldato: I think that, apart from the safety data that I think we dissected, the other end of the spectrum would be finding a drug that this very pre-treated population could still give us some efficacy data. So you already mentioned that, in the dose expansion cohorts, so 4, 6, and 8 milligrams, we had more or less signals of activity and of efficacy of these novel drugs. So the therapeutic options, as you were mentioning, are potentially docetaxel or other types of mono chemotherapy. But we know that the objective response rate is not that high, and that progression-free survival is not that long with these types of drugs. And potentially the safety profile could also be complicated in patients that are also pre-treated. So I just wanted to discuss a little bit the efficacy data and to see if there is really promise in this type of delivery of chemotherapy as you were saying with the ADC.
Dr. Jacob Sands: We saw response rates of about 25% across all three of those cohorts. The manuscript outlines the 4, 6, and 8 milligram cohorts within a chart showing the efficacy outcomes. And really it's around 25% across the three of those, which in this patient population, as we've discussed, heavily pre-treated, to have a response rate of 25% is really quite promising that there really is a substantial treatment effect. On top of that, we also see a duration of response of really around 10 months. So, in the patients that are having a response, there really is some durability. Now, it's tragic that 10 months is considered durable within this population and it really highlights the ongoing need for further drug development because I don't think anyone would say that 10 months is enough, we need dramatically better. But within the context of what we currently have, a 10-month duration of response is really quite meaningful and a response rate of 25%.
Now, it also describes a disease control rate. And I always have to put a little asterisk to this. I think we see this increasingly - the disease control rate being reported - and it always looks quite a bit better than the response rate. And that's essentially incorporating stable disease. And although I would never claim that everybody with stable disease is truly benefiting from a drug, across all of the studies where this is reported out, there is a spider plot which really highlights a number of patients that are not considered responders, but with responses, a handful of them beyond six months of disease control, even though they're not considered responders, and one of them beyond a year with still ongoing disease control. So, even within that stable disease group, I'd say there are some who are really clinically benefiting from the drug, which is to say that really, even beyond the 25% response rate, we are seeing some others that are truly benefiting from this.
Davide Soldato: Yes, and I also think that for these patients, especially when they can develop very rapidly symptoms that can potentially also impact quality of life, having a drug that achieves this level of stability - with maybe no deterioration in clinical symptoms - I think that it's still probably a very meaningful objective to obtain for this type of population. Of course, I think that with future studies we will also have probably health-related quality of life data that will tell us more about the impact of this type of drug in this setting. But I still think that this could be potentially a relevant endpoint, even if we don't achieve what we officially consider as a response as per resistor criteria.
So I think that we have talked a little bit about the efficacy data. So, we are kind of entering a novel area where more and more ADCs are being tested, are being included in clinical practice. For example, if I think about breast cancer, we already have two that are approved that can be used, the same in bladder cancer. So, as you participated in this phase one trial, I just wanted to have your opinion: if you think that, in the future, we are going to evolve completely towards this type of delivery of chemotherapy, using what we call now "smart drugs" in terms of delivery of these cytotoxic agents.
Dr. Jacob Sands: It'll be interesting to see. We certainly will see other generations of ADCs. I mean, I think we're really just at the beginning with this technology. We certainly have now a very solid foundation to build upon, where we have effective targets and effective payloads. We've highlighted some of the toxicities we're seeing from that. Also, I'd highlight within this drug with TROP2, the amount of expression has not seemed to really be a driver in this. And some of that may be the bystander effect, which I'd call a real benefit of the drug, where the payload as a drug goes through apoptosis and lysis, that payload that releases then into the surrounding- toward the surrounding cells is membrane permeable and crosses into other cells, leading to potentially more efficacy. That technology in itself, I'd say, is something that we may see incorporated further into next generations of ADCs. Whether there can be improvements in preventing toxic drug in other sites like the stomatitis, for example, with newer generations that evolve from this, we'll see.
I don't know that I would anticipate all chemotherapy ultimately going through ADC technology, but I certainly believe that this is the beginning of what I would call a whole new class. But would future cytotoxic treatment happen more so through ADC than just broad circulating payloads? If we can call it that. And I certainly think we'll see a lot more development like that. But you know, we may see other ways of developing the cytotoxic drugs in other forms of delivery as well. It'll be exciting to see as we go forward.
Davide Soldato: I also think that one of the major challenges that we probably will have to deal with, in probably not so long, is also the sequencing of these types of agents. We are starting to have, as I was saying, accumulating data regarding the efficacy of these drugs. And some of them share either the same payload or they target the same antigen on the cell. And so, do you think that we will need as a new line of research to really go into the field of cross resistance when we are using and trying to sequence these types of novel agents?
Dr. Jacob Sands: We're seeing that across various tumor types. I mean, to stick with lung in particular and small cell lung cancer, we've seen DLL 3 really be a demonstrated target for small cell lung cancer. And now we have a handful of drugs being developed that target DLL 3. How would we potentially utilize those drugs? In what orders and which ones over others is going to be an area for discussion, much like the area you're raising here, where we see TROP2 directed treatments. And so which one would you choose? On top of the fact that there are other targets, in this case, we're talking about TROP2, but of course, there's HER3 that we've seen, and especially when we're talking about an EGFR population, EGFR mutation population, we've seen good efficacy with this TROP2 antibody drug conjugate, as well as the HER3. And so how would we order those? And they both are using the same payload.
If we're talking about both of the deruxtecan compounds, this is going to take some sorting out. I think with time, it'll be tough. I don't know if we'll end up seeing head to head studies in this or if this is going to end up being shaped more by expert committees and their descriptions. But I imagine we'll see some heterogeneity in the treatment pathways at different centers just based upon preferences and familiarity with these different drugs. Of course, assuming that they all end up ultimately being approved and then that efficacy and tolerability that we're seeing continues to pan out in future trials.
Davide Soldato: So we were mentioning before that there is a very big line of development for this novel ADC. And I think that there are also some trials that are exploring the role of data DXD so the datopotamab-deruxtecan in lines where patients have received less therapy or in combination with other agents. So I wanted to ask you if you could give us some insights regarding the ongoing trials, if you know about them. And also what do you think could be the area of a met need where this drug could potentially give the most effect?
Dr. Jacob Sands: It'll be interesting to see. In the first line setting we have TROPION-Lung07 and TROPION-Lung08. These are studies with PDL-1 expression of less than 50% or greater than or equal to 50%, the greater than equal to 50% being plus pembrolizumab versus pembrolizumab alone. The less than 50% essentially being an incorporation with or instead of chemotherapy along with the platinum-based therapy plus pembro. And so that one is a more complicated three-arm study. Now, essentially what this is looking at is incorporating this antibody drug conjugate in place of chemotherapy for potential tolerability when given concurrently with the platinum and pembro. Whether or not we'll see some synergy with the chemo and the pembro, I guess I would hypothesize that we would likely see at least similar to when giving the chemotherapy, or at least that's the hypothesis driving the trial design.
If anything, whether we note improved tolerability relative to those getting, I'd say the carboplatin component, because certainly within non-squamous, non-small cell, pemetrexed is generally very well tolerated. And so that's a bit tougher to beat out from a toxicity standpoint. The trials are really designed based upon the efficacy that we've seen from this trial you're pointing out. I think by the time that this podcast is heard, we'll have the data from TROPION-Lung01 that'll be reported out as well in the second line setting versus docetaxel as that data is near release. These are areas for ongoing attention, certainly.
Davide Soldato: Thank you, Dr. Sands, for being with us today. This concludes our episode of JCO Article Insights. We discussed with Dr. Sands the results of the manuscript titled, “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.”
This is Davide Soldato. Thank you for your attention and stay tuned for the next episode.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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