Adjuvant Pembrolizumab for High-Risk, dMMR Endometrial Cancer
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Dr. Shannon Westin and her guest, Dr. Brian  Slomovitz discuss the article “Pembrolizumab or Placebo Plus Adjuvant Chemotherapy With or Without Radiotherapy For Newly Diagnosed, High-Risk Endometrial Cancer: Results in Mismatch Repair-Deficient Tumors” recently published in the JCO and presented at the 2024 International Gynecologic Cancer Society. TRANSCRIPT The guest’s disclosures can be found in the transcript. * Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours), the podcast where we get in depth on manuscripts and literature published in the Journal of Clinical Oncology). I'm your host, Shannon Westin, gynecologic oncologist and JCO* Social Media Editor by trade. I am thrilled because we are going to be talking about gynecologic cancer today. So, this is my jam. And specifically, we're going to be talking about a manuscript that's a simultaneous publication in the Journal of Clinical Oncology* and presented at the Annual Meeting of the International Gynecologic Cancer Society) on October 16, 2024. And this is “Pembrolizumab or Placebo, Plus Adjuvant Chemotherapy, With or Without Radiotherapy for Newly Diagnosed High Risk Endometrial Cancer: Results in Mismatch Repair Deficient Tumors.”* This is affectionately the KEYNOTE-B21 trial, also known as the GOG-3053 trial and the ENGOT-en11 trial. And we are joined today by the primary author in this manuscript, Dr. Brian Slomovitz, who is the Director of Gynecologic Oncology at Mount Sinai Medical Center in Miami Beach, Florida, and the clinical trial advisor in uterine cancer for the Gynecologic Oncology Group foundation. Welcome, Brian. Dr. Brian Slomovitz: Hey, thanks, Shannon, so much. It's a pleasure to be here. And thanks for giving us the opportunity to discuss this trial. Dr. Shannon Westin: Yes, it's a great trial and I'm so excited to talk about it. And I think we'll start just because this is a broad group that listens to this podcast, they're not all GYN oncologists, experts like yourself, so can you just level set a little bit and speak a bit about the incidence and mortality of endometrial cancer overall and the recent trends in this disease? Dr. Brian Slomovitz: Yeah, sure. So, and it is nice to speak about gynecologic cancers, as we know, endometrial cancer was and still is the most common of all gynecologic cancers. The numbers are going up. Right now, there's about 65,000 to 70,000 cases each year in the US diagnosed with endometrial cancer. The numbers are going up. A lot of its obesity related, some other factors, but as the population gets less healthy, those are some of the risk factors for the disease. The thing that, however, is quite surprising is that we're seeing the deaths due to endometrial cancer going up as well, while for other diseases, we're making slow, steady steps to try to decrease the mortality we're actually seeing an increase in mortality. And the most discouraging point, Shannon, as you know is the number of deaths from endometrial cancer is going to outnumber the number of deaths from ovarian cancer if it hasn't done it already. I mean, now's the time. So, we really need to come up with better treatment strategies to everything to decrease the incidence of disease, to help with prevention, but for those poor women who are diagnosed, to come up with better treatment options so we don't have to keep this increasing trend in mortality. Dr. Shannon Westin: Absolutely. And I think some of that is related and we don't need to get on a soapbox here, but the amount of funding that goes towards research in endometrial cancer, and of course you, you have been leading the way and really trying to get a ton of trials in this space and getting our industry partners and our government partners to really support this. So really just commending you on how much you've worked on, on this area. And to that end, we've had a huge renaissance with immunotherapy and endometrial cancer, a lot of really big trials. Why don't you give the audience a rundown of where, so far, this seems to be best utilized for people with endometrial cancer? Dr. Brian Slomovitz: Thanks for that. And as you sort of alluded to, it's been a revolution, really, with immunotherapy. We started off at immunotherapy looking at microsatellite instability or the dMMR patients. What we found is similar to other disease sites in the second and third line setting that we saw good activity with the single agent checkpoints, pembrolizumab dostarlimab, that's based on the earlier KEYNOTE data and the GARNET trial. Really, a landmark study in the second line was Vicki Makker and her colleagues put pembrolizumab and lenvatinib combination for those patients with the cold tumors. Not the dMMRs or MSI Highs, but the proficient mismatch repair. And that study in a second line setting found that it was better than chemotherapy for an overall survival advantage. So right there, we know that it works in the second line setting in the dMMR population, and we got an indication in the PMR population saying that immunotherapy works in all women with endometrial cancer at some point, then we really had the groundbreaking trials. And Shannon, thank you. You are the leader on one of the four trials that happened, to DUO-E, AtTEnd, GY018 and RUBY trial, all very similar studies showing that the combination of immunotherapy with chemotherapy in the first line, metastatic or recurrent setting had a better outcome for patients than if given chemotherapy alone. That actually led to amazing things. We had three of those drugs have FDA approvals, pembrolizumab for all comers, dMMR and PMMR in the first line metastatic setting with chemotherapy; Dostarlimab, PMR, dMMR in the first line or metastatic with chemotherapy. And Shannon, in your study, I think we still have to learn a lot from your study. DUO-E, chemotherapy plus minus dostarlimab. And you also added a PARP inhib, and those patients with a PARP did better. So I'm really looking forward to your data, to the subgroup analysis to figure out which of those patients, depending on the biomarker, do better with PARP therapy. And right now, you have a dMMR FDA indication. But who knows? The future is really exciting to see- to be splitters, not lumpers. And I really want to see how that data pans out. And so that's how it came into the first and second line setting and that led us really to come up with the idea for this trial to put it into the adjuvant setting. Dr. Shannon Westin: Right. And so, I think this would be really important because we're so ingrained in this. We see this on the day to day. Can you kind of tease out a little bit what's different about those patients that would be treated in that advanced recurrent setting versus the patients that would be potentially treated in this B21 study? Dr. Brian Slomovitz: Yeah, so the first step, we demonstrated the efficacy in patients that really the treatment options were an unmet need. In the second line setting, we didn't have good treatment options. Those are the patients with measurable disease, with symptomatic disease giving immunotherapy. And not only did we see the efficacy, which was better, but we also were able to give it with limiting the side effects as seen with chemotherapy, which is nice. And then we know that the first line therapy, traditionally for endometrial cancer with carboplatin paclitaxel, response rates about 50%, progression free survival about a year, really something that we needed to improve upon. So, adding immunotherapy to the platinum backbone therapy really demonstrated an advantage. But now what we want to do is we want to see if we could prevent, in the high-risk patients, those without disease, what can we do to help prevent the disease from recurring and help patients live longer without really the need for really lifesaving types of treatments? We want to prevent it from recurring. Dr. Shannon Westin: Yeah, I think that's essential. We know that if we can sit on that prevention side and kind of invest all the time and effort that we need to upfront, that really does yield the longer survival. So why don't you just walk through the overall design of this trial, please? Dr. Brian Slomovitz: Yeah. So, this was an all-comers trial, meaning in individuals that had high risk endometrial cancer, high risk for recurrence, that included, in endometrial cancer, we have aggressive histologic subtypes, serous histologies, clear cell histologies, any stage, as long as there was some myometrial invasion. We also, for the first time, included patients looking at the molecular subclassifications. So, if there was a P53 mutation and they were stage 1 with myometrial invasion, they were included. And then in all comers, any patients with stage 3 or up to 4a disease, as long as the surgery was for a curative intent, and they had no residual disease after surgery, then they were allowed to enroll into this trial. One of the things is that this is the first time we've done an adjuvant trial this large. I think one of the reasons that helped us succeed in doing a trial like this is that we left radiation as investigator’s choice, because a lot of times going into a trial like this, people feel strongly, we know our radiation oncology colleagues, rightfully so, feel that radiation could help prevent disease from coming back. And we also have the camp that says they don't need radiation. We took that question out of this study. We let investigators decide whether or not they're going to get radiation. It was for patients to get chemotherapy, who are going to normally get chemotherapy for their high-risk disease and randomize them to chemotherapy plus placebo or chemotherapy plus pembrolizumab, a PD-1 inhibitor, in order to see if we could prevent the disease from coming back. Dr. Shannon Westin: And the primary results of this study were just presented at ESMO and published in the Annals of Oncology.* Can you give us just a quick overview of what that was, what they found? Dr. Brian Slomovitz: Yep. So, we enrolled 1100 patients. The primary objective of the study was to look at the ITT population, progression free survival and overall survival. And the overall study was negative. Okay, so the hazard ratio in the ITT population was 1.02, not demonstrating a benefit of adding pembrolizumab in this population. I would say disappointing, but at the same point, something that we could really learn a lot from and somewhere that we know that in the whole population, we need to come up with better strategies to help prevent recurrence of disease, better adjuvant treatment strategies. But there's also information that we learned from this trial and that we're reporting on that we're actually super excited about and we feel may be game changing. Dr. Shannon Westin: Yeah. So, let's go to that. This is the good news. Your manuscript in the JCO*, thank goodness you published it here, was focused on that subset of mismatch repair deficient. So, tell us what you found. Dr. Brian Slomovitz: So, in this study, we found that the first stratification factor was dMMR versus pMMR. Now, in the pMMR group, those patients had further stratification factors, but dMMR by itself was a stratification factor. Amongst those patients that had dMMR tumors, we found the hazard ratio to be 0.31 benefiting those patients who received pembrolizumab in the adjuvant setting. Really something that when we look at the treatment studies, the GY018s, the RUBYs, the atTEnds, the DUO-Es, in a dMMR setting, we see a similar hazard ratio of 0.3, 0.4. But to get that hazard ratio, which was statistically significant, obviously, is something that we were quite pleased with and something that we felt was worthy of reporting further. I will say it was a pre-specified endpoint. We didn't allocate alpha to it. So, at the beginning, it was a pre-specified endpoint, but at the same time even though we didn't specify alpha towards that outcome, it still, we feel is clinically meaningful and can definitely add to affect the standard of care and the management of these patients. Dr. Shannon Westin: Yeah. I'm very intrigued to see what kind of people do with this. It makes sense, mechanistically, it makes sense if there was a population that was going to benefit, if not everybody does, this is the group that will. I mean, do you feel like there's enough data? What are you going to do? FDA approval aside, obviously, those kinds of things. But how do you feel about this? Is this something you're going to offer to your patients? Dr. Brian Slomovitz: The first answer is yes. I think it's something that I would like to offer my patients. As you know, we need one of two things: we either need an FDA approval or for a lot of our payers required to be in the NCCN listings. I don't serve on the committee. I have no influence on NCCN. I'm excited to see how they'll respond to not only the Annals* article, but obviously in today's release of the JCO* article, I hope that they'll look upon it favorably. It's a drug that we’re used to giving. Pembrolizumab, we have a lot of experience with it. It's interesting. We didn't see any new safety signals, Shannon. Dr. Shannon Westin: Yeah, I was going to ask - that’s great. Dr. Brian Slomovitz: There was nothing, nothing additional that we found in this trial. So, I feel that it can definitely improve the outcome of those patients, in my view, with high risk for recurrence, treating pembrolizumab in this setting. Dr. Shannon Westin: Yeah, I think it's important, of course, to look at the safety. What about quality of life? Any new findings there? Dr. Brian Slomovitz: Yeah, we did that quality of life as part of the phase 3 trial. No difference between the two arms. No difference between the two arms. When we looked at a couple of the other analyses, we found that the benefit is the same on stage 3, 4 tumors. We saw that the benefit was there as well. So, there were less patients in the stage 1, 2 group. But I think really, for all comers, for the patient population, I would definitely consider giving pembrolizumab, again, for those patients with a deficient mismatch repair. Dr. Shannon Westin: It's really exciting, and I think you mentioned some of the statistical limitations. Anything else that gives you pause about the study or things you wish you did better? I know we always like to armchair quarterback ourselves after we do these kinds of studies. Dr. Brian Slomovitz: Yeah, it's interesting. When we designed the study years ago, we used the best information we had at that time to come up with the study design, and we're happy with it, and we really don't think that we could have done it much better. I should say, this was a great partnership that we had here between the GOG, ENGOT and with sponsor Merck, Toon Van Gorp was the lead PI of the global trial. When he gave me the good opportunity to present it at the IGCS and to be the lead author on this, it was really a great partnership. And when we came up with a trial years ago, it was the best trial that we thought at that time. And based on the information now, I think it's really something that we're excited about these results, even though the overall trial was negative. Dr. Shannon Westin: Yeah, I agree with you. I think it's interesting, it's informative to think about, “Well, what would we do now or then if we knew what we knew now?” But still, you design the trial the best way you can. I think the results are super intriguing. I'm hopeful at the way they'll be reviewed. I agree I don't have any inside information about the NCCN committee, but I do hope that they'll consider the overarching data to support immunotherapy and mismatch repair deficiency and the findings of this study. And then I guess the last question I would just ask, as you're an expert here, what are you looking forward to seeing coming next in this space? What's the stuff you're intrigued about in endometrial cancer? Dr. Brian Slomovitz: I think, Shannon, you and I have talked about this for a while. I think we're getting really close to eliminating chemotherapy for some of the patients who suffer from this disease. So, I'm not sure if we'll do a follow up to this trial, but I think a logical type of follow up would be to see: what if we just took away chemotherapy altogether and we did pembro in the adjuvant setting, pembrolizumab versus chemotherapy? We don't have that trial in the adjuvant setting, but actually, we completed accrual of that trial in the recurrent setting and we’re anxiously awaiting those results. That's KEYNOTE-C93, where in the dMMR population we studied pembrolizumab versus carboplatin paclitaxel. How those results may translate into this setting, I'm not sure. Right now, it's exciting what we have, but yeah. And I think future is bright for this. Just to highlight, in the two arms, there's 140 patients approximately in each arm; there were 25 recurrences in those patients who received placebo. Only eight recurrences in those that received pembrolizumab. Really, when we talk about numbers, it's really remarkable and it shows you the benefit it really had on the patients. Dr. Shannon Westin: Well, this was great. It flew by, as it always does when I'm having conversations with you. I just really want to thank you again for taking the time to share your knowledge with our listeners. Dr. Brian Slomovitz: Thanks, Shannon. Dr. Shannon Westin: And listeners. Thank you all for taking the time to hear about endometrial cancer. Again, this was “Pembrolizumab or Placebo, Plus Adjuvant Chemotherapy, With or Without Radiotherapy for Newly Diagnosed High Risk Endometrial Cancer Results in Mismatch Repair Deficient Tumors.” And this was the JCO After Hours.)* If you loved what you heard, please check out wherever you get your podcast to see what else we have to offer). 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.*