Welcome all. I'm Flora Backus. I'm a gynecologic oncologist and professor in the Division of Gynecologic Oncology at The Ohio State University and James Cancer Center, and I'm honored to be one of the co-chairs of the IGCS Education Advances and Updates Workgroup. I'm very excited to provide this educational recording titled, Mismatch, Repair, Endometrial Cancer, What to Do at First Recurrence and Beyond, which is in part sponsored by GlaxoSmithKline. Today I'm joined by Dr. Ramez Iskander, and Ramez, please introduce yourself. Thank you, Flora. It's a pleasure to be with you here this afternoon for me, evening for you. My name is Ramez Iskander. I am a gynecologic oncologist and a professor of gynecologic oncology at the University of California, San Diego, Moores Cancer Center. It is an absolute honor to join you for this session, and I'm excited about the topic. A very exciting and dynamic time. Excellent. We'll dive right in. You've done a lot of work in this space, and I'm really excited to talk and hear some of your thoughts about it. Would you mind give us a little bit of an introduction? And today we're only going to talk about mismatch repair deficient patients, mismatch repair deficient recurrent endometrial cancer. In a future session, we will take the time to go through the proficient patients because there's just so much to discuss and we really want to dig in here a little bit more. Let's go to that first slide and see what we can put together here. So it has been partly a dynamic and exciting time because we've seen data from multiple large clinical trials result. And as you can see summarized here, these trials looked at various populations. We're focusing specifically on the mismatch repair deficient or the DMMR patient populations. And we go from left to right, the GY018 NRG cooperative group trial and RUBY were the first to read out. Those were simultaneously presented and published in March of 2023. But then most recently, we also had the presentation and then of course now publication of DOE but presentation of ATEND and DOE. What was interesting about all of these trials, we could spend time of course talking about the schemas and some of the nuances, but really they look to determine whether or not the addition of immunotherapy to chemotherapy would improve clinical outcomes in patients with advanced stage metastatic or recurrent endometrial cancer. And on the very right, the DOE trial was unique because you can see that it had a third arm that looked at not just an immunotherapy with immune checkpoint inhibition, but looked at immunotherapy plus olaparib as a maintenance strategy, trying to capitalize on the premise that there's a population of endometrial cancers that may be sensitive to PARP inhibition analogous to ovarian cancer with homologous recombination mutations or homologous recombination deficiency. And what we saw across these trials really was a remarkably consistent signal, which gave us incredible confidence about the efficacy. We see from NRGGY018, RUBY, ATEND, and DOE that in the DMMR population, the mismatch repair deficient endometrial cancer patients, the addition of immune checkpoint inhibition to chemo and then continued as maintenance resulted in a dramatic and significant improvement in the median progression free survival across all of these studies. And when you look at these hazard ratios, they basically fluctuate from 0.3 to 0.4. So a 60% to 70% reduction in the risk of disease progression or death. And what many of us thought was really quite notable is when you get to about 12, 14 months out, those PFS curves flattened in the immune checkpoint chemo arms of the trial. So we're optimistic that what this is showing is not only are these efficacious regimens much more than placebo, but when patients respond, and if they get to that 12 to 14 months, the recurrence rate is likely very low. And our hope is that that's also reflective of a better cure rate. And I will just say that we know that the RUBY regimen, which was Dostarlimab with carboplatin and paclitaxel was approved by the US FDA on July 31st of 2023 for mismatch repair deficient primary advanced or recurrent endometrial cancer. So it ushered in this new era for us. And shortly after presentation and publication, both the Pembrolizumab carboplatin paclitaxel regimen and Dostarlimab carboplatin paclitaxel regimens were NCCN compendium listed category one. So really rapidly changing the landscape of how we treat the disease in the United States and beyond. Yeah. And it's just amazing to see how similar, like you mentioned, how similar these trials are. And also, even though there's somewhat variation in the population that's enrolled, but even for the chemotherapy with placebo, the duration of median progression-free survival is fairly similar around at six, seven months. And that's just very short for somebody who just finishes chemotherapy. It's just such a good reminder how much improvement we actually can and are making here. Now, when you look at all these different, so now we have all these different drugs available. Here is four listed on here already. How do you decide which drug you pick for your patients? It's an excellent question. One, honestly, and quite frankly, is hard to define an answer based on science per se. We also know the data that was presented suggested that the adverse events for these trials, DOE is unique because they had the PARP and you saw more PARP-related AEs in that arm, hematologic adverse events. But for the other trials, we saw that adding immunotherapy, immune checkpoint inhibitors, didn't appear to amplify the chemotherapy-related adverse events, adverse events, nor did the chemotherapy appear to amplify the immunotherapy-related AEs. So we could justify the safety of these regimens, which was reported. When we decide on a checkpoint inhibitor, I think quite honestly, Flora, I think a lot of it is pragmatic. What do you have available at your institution? What is approved for use in your part of the country, or sorry, your part of the world, regionally, because ultimately you can use what you have access to use. And I've heard things like, oh, my institution has made a decision to use one immune checkpoint inhibitor, for example, across their solid tumors. So I'm incorporating that in my endometrial cancer. Other institutions are saying it's FDA approval, and we have the dostarlimab plus chemo FDA approval. So that's what we're using. And other institutions are leaving it up to the providers to choose. And quite honestly, I think a lot of that is driven by familiarity and use of a checkpoint, because we know that these drugs have been approved for quite a period of time, both in endometrial cancer and in other gynecologic and non-gynecologic malignancies. So there's a lot of use of immunotherapy for many years now, and that's just being adopted into this particular treatment course for endometrial cancer. Yeah, it seems fairly reassuring that most of these side effects also, like you mentioned, are very similar across the different drugs. How about in DOE? Should we be thinking about, so we have the chemotherapy with immunotherapy, should we be thinking about adding a fourth drug or a second maintenance drug here was elaborate in the DMMR population also? Yeah, it's important for us to remember that the statistical design of DOE was for the intent to treat population, so everybody together. And they compared the ARM2, the DERVA, to the control arm, and ARM3, DERVA plus Olaparib to the control arm. So they didn't allocate alpha to compare ARM3 to ARM2. And then, of course, they didn't allocate alpha in the DMMR-only cohort. So I think there is some objectivity and inference in this assessment. But I will say that based on the data that was presented in the DMMR, which you can see on the far right panel here, the curves essentially completely overlap for DERVA by itself versus DERVA plus Olaparib. And I believe that that simply is reflective of the fact that the immunotherapy is so beneficial in the DMMR population that the addition of Olaparib doesn't appear to be doing anything beyond that in those patients. So I don't think that there's a role for PARP plus immunotherapy in the DMMR. I think that this data suggests that the immune checkpoint inhibition plus chemo with immune checkpoint inhibition maintenance is sufficient. And again, you see that across these studies, where you can see these curves are very similar in morphology. And then 018, RUBY, and ATEND did not have a PARP, obviously, but have a very similar shape of that curve with the immunotherapy plus chemo arm. Yeah, thank you. And so for a lot of these studies, a question has oftentimes come up about, are there different subsets even within the DMMR population? And I want to go over something that you did present for GY018, which is the group with either hypermethylated MLH1 hypermethylation versus the unmethylated or somatic mutation patients or lynch-like patients. Maybe we can look at the next slide and discuss this a little bit more. Thank you. So yes, this was an important question for us. Why? Because there were some smaller retrospective studies that looked to determine whether or not patients who had an epigenetic mutation, meaning epigenetic promoter methylation, silencing gene expression, responded differently to immunotherapy than those who had a mutation in the mismatch repair genes. And we define that as the mechanism of MMR loss, either mutation or epigenetic alteration. And in some of the other studies, it suggested that it was quite dramatic, the difference, where you had no recurrences in the mutation cohort and much more substantive recurrence in the methylation population. So within the DMMR population in NRG GY018, we looked to try to define this or answer this question, I should say. And we took the entire DMMR cohort. We looked at those patients that had absent MLH1 and PMS2 expression. And then we looked at their institutional promoter hypermethylation assay results, direct assay results. And we pulled out those who had MLH1 promoter hypermethylation. And then for the others, meaning they had absent MLH1 expression and no hypermethylation, fell into the mutation cohort. Or if they had an isolated MSH6, for example, or isolated PMS2, those were defined as mutations. And what we saw was two things. Number one, the first panel on the left in the middle panel are intended to say that whether there was methylation or mutation, there didn't appear to be a difference in the response to chemo itself. So response to chemotherapy wasn't impacted by the presence or absence of promoter hypermethylation. Both of those populations actually did relatively poorly, as you discussed earlier, when they were given a placebo. But on the very right, when you look at the population that received pembrolizumab, specifically received PEMBRO, you can see that there was similarity whether there was methylation or absence of methylation, which suggested mutation. And that 12-month arbitrary, 12-month assessment was about 85% versus 74% progression-free between mutation versus methylation. But I will caution everybody. Why? Because if you look at these curves, this was a large study. GY018 was a large study. We had basically 225 DMMR patients. 72% of those were promoter hypermethylated. A small proportion were mutated. We had unavailable information for 15% of these patients because we realized not every institution reflexively tested for promoter hypermethylation, which was interesting on its own. But the vast majority of DMMR is driven by methylation, that we saw recurrences in the mutated and methylated populations. And it's a small number of mutation patients, only 13. So I don't think we look at this and draw definitive conclusions. My take-home message from this is the vast majority of mismatch repair deficiency is a result of promoter hypermethylation and epigenetic silencing. We know that immunotherapy with chemo and immune checkpoint maintenance in 018 had a dramatic benefit in the DMMR population, the large proportion of which are hypermethylated. And maybe, maybe the mutation do really slightly better. So it's like you take an outstanding population and you make it even better. But I don't look at this data and believe that it would suggest that we need to do something differently for the methylated. Like they don't benefit. No, they dramatically benefit from this intervention. And I think the take-home message is, we have this data, we can do some more research looking into this, certainly from the other studies that were reported. I'm interested to see whether we see similar signals in the frontline metastatic trials. But summing it up, I would say, in my mind, I wouldn't distinguish these two populations just yet, but more research needs to be done. Yeah, I think that's such a great point that these populations are so small. The no-methylation group is incredibly small, 13 patients here that received PEMBRO. So that's excellent, just how you described that. And absolutely, we need more research. But at this point, we should be offering this immunotherapy to all our DMMR patients and not really be selective. There's another subset. We don't really have a slide on that here. But I do want to bring it up, because in some of the trials, and GY018M-RWBY were the first ones to be presented, but they didn't have much of an Asian population, whereas ATTEND and DOE had a much larger Asian cohort. There were some differences there, or maybe lack of differences in the DMMR population, well, not necessarily in the DMMR population, but in response to the addition of immunotherapy. What are your thoughts on this? Yeah, I think that it was provocative in terms of informing how we might want to think about this. I will say that even when we think about self-reported race and ethnicity floor, I think there's a lot that we're still going to discover. For example, in NRG GY018, there were 38 patients that were self-reported as Asian. But this was almost predominantly a US-enrolled trial. It did enroll in Canada, South Korea, and Japan. So there were small numbers. But these are quote, unquote, American Asian patients, for lack of a better descriptor. In RWBY, there were 15 that were self-reported as Asian. But in ATTEND, it was 112. And in DOE, it was 89. So there's discrepancies there. And those are the gross numbers. The percentages, of course, are different as well. So can we think about patients that are accrued where race and ethnicity may inform efficacy signals? And part of the reason that conversation came up, we're not focusing on it this session, but it's because of the differences in efficacy in the PMMR, the non-biomarker selected population. So I want to clarify that in the DMMR, it appeared there's benefit, big benefit. In the PMMR, this is where there was some signal that maybe race and ethnicity matter. So I think we do have to do more work there. And we have to understand, is it simply race and ethnicity, or are there environmental factors? Meaning the US Asian population, is that the same as patients that are accrued in Asian countries when it comes to response, yes or no? And if not, why might that be the case? Is it a pharmacogenomic issue with the drug? Is it an immune microenvironment? So many unanswered questions. I can't venture to say I have an explanation other than to admit that we need to look into this a bit more as we try to make sense of the discordant data in PMMR endometrial cancer patients. And of course, with how effective these drugs, the addition of immunotherapy has been, a lot of people are asking, should we be giving chemotherapy even along with it? We don't see any separation of the curves for those first four to six months while people are still getting chemotherapy in both arms. And really, those curves start separating much later, and we see the difference between the curves getting wider and wider. Should we be going to immunotherapy alone, or should we really wait for the next trial results? Yeah. We're a victim of our success here, I like to say. Why? Because we completed several large prospective studies that show really provocative data in the chemo plus checkpoint maintenance in the DMMR. But we also know that research has been done in colorectal cancer, for example, where there was a keynote trial, Keynote 177, if I remember correctly, that looked at replacing chemo with immunotherapy in colorectal. But that was different. That was immunotherapy versus chemo. It wasn't immunotherapy versus chemo immunotherapy. So we have, of course, large trials that are looking at this. The C93 study is looking at pembrolizumab monotherapy versus chemo alone, and the Dominica study is looking at dostarlimab versus chemo alone in the DMMR endometrial cancer population. And I will tell you, I think we're going to have to wait for the data. And although it's not right to do, we're human beings, and we're going to be forced to cross trial compare, because we're unlikely going to replicate a trial that's doing a head-to-head comparison between these strategies, although time will tell. So we're going to look at the data from immunotherapy alone, which we all hypothesize is going to outperform chemo in the DMMR patients based on what we know from RUBY 018 attend, etc. And we're going to compare that to chemo-IO-IO maintenance. And we're going to have to make an adjudication and an assessment about whether or not the chemo has a role in those DMMR patient populations. And it will be difficult to do because these trials are different, different patient populations, but we will make an informed assessment based on that data once it's available for us in its totality, and we can really adjudicate. Because the one thing we don't want to do is simply make a guesstimate that both are the same, don't worry about it, just give the immune checkpoint alone, because if that does somehow compromise efficacy even in the DMMR, that may affect patients. And why do I say that? Because if you look at all of the DMMR studies, meaning the DMMR cohorts in these studies, there are still recurrences, about 20-25% recur within 12 months. Is chemo doing anything for those patients or not? Meaning, is there some benefit in an a priori population that might need that chemo priming even though they're DMMR? These are all thoughts in our mind. So we have to wait for the data. We'll see what the data shows. We'll figure out how to adjudicate it between trials and then make an informed and educated assessment. But I will say, until that data comes, I'm not comfortable abandoning it altogether. I think we need to wait so that we can make an informed assessment. Yeah, I know. And the data is following up so quickly. We're coming out with all these new trials and all reporting similar trials. And hopefully, we'll see those results soon, both in the adjuvant setting, as in a recurrent setting, where we need to have the chemotherapy with it. But yes, we'll go with the data that we have so far. Now, I know that a lot of people are prescribing, especially in the DMMR population, I think, we really owe it to our patients to give them chemotherapy with immunotherapy. But what are we going to do after that? And we're starting to see some recurrences happening. Like you mentioned, these patients do still recur. They're not all cured. And so how are you approaching that patient who has completed maintenance immunotherapy on one of these trials? Probably, or maybe already standard of care, less likely. But say that they were on a trial, and now they've been off of maintenance immunotherapy for a year, and now they have a recurrence. What are you recommending for that patient? Yeah, it's an excellent question. So in my mind, that's a blessed circumstance to be in. Why? Because you have a patient that responded, responded to IO clearly, had a benefit, and then had a disease-free interval. So this is a space that we're actively trying to figure out. We're living in this world right now. And so just like we have historical platinum-free intervals, we're trying to make sense of what do we make of an immunotherapy-free interval. Now, in the population, in a patient like this who went a year, that patient who's DMMR can probably get immunotherapy alone based on approved labels. They had a year without it. They can go back on label to chemo with IO because those studies allowed patients to months off of cytotoxic chemotherapy, although, of course, those studies didn't allow prior immunotherapy because we didn't have it available to us. They can even go on a Linvatinib-Pembro opportunity based on recurrent disease in this setting. But to your point, this is a whole new world, meaning we weren't giving IO in the frontline metastatic setting historically, and now we are. And so we're going to be forced to start to really think critically about when are these patients recurring. And if I have a patient that recurred and had a long treatment-free interval like that a year, I have many options. And if that patient's amenable and has a good performance status, they could go back, again, chemo, IO, IO maintenance. If I'm worried about how they're going to tolerate chemotherapy, for example, I could re-challenge them with single-agent checkpoint potentially or combination Linvatinib-Pembro. But that patient has, in my mind, many options because of their interval without treatment. Yeah. And I'll just add there's lots of good trials also available for IO combinations for that patient that doesn't want to go on back onto chemotherapy. It's exciting to see the combinations with IO, with PDL, with checkpoint inhibitors, PD-1, PD-L1, and CTLA-4 or anti-TIGID or LAG or any of those other ones that are out there. So yeah, really great. It's going to be really important that we get our patients on these trials about IO after IO to really get that data together. One last question, the even more difficult or probably the most difficult question, what if your patient is on maintenance immunotherapy and now about, say, 6 to 12 months on maintenance only is having a recurrence? What do you recommend for this patient? Are we really totally in no man's land here? You stole my thunder, clinical trials. So I'm not being facetious here. I'm saying that we really need to invest our resources in developing the right clinical trials for these patients. We are going to have an entire population of patients who progress on or after IO, to your excellent point, Floor. And we're going to have to have different trials for different patients. Those who have an interval without immunotherapy who might benefit, like you said, from IO re-challenge with monotherapy or combination, but those who progress on IO where the answer may not be necessarily IO re-challenge. We have multiple antibody drug conjugates that have promising results for which we have clinical trials that are open or opening where that patient might be an excellent candidate. But to your statement also, there is some data that's emerged that is informing a little bit of the IO re-challenge. I will just refer that Stephanie Leroux had her study about NEVO and CABO, CABO is the antonym of TKI and NEVO. There was also the LYO one, which was run by Clovis, which looked at TKI plus IO also. Both of those studies had patients who previously had IO and progressed who were re-challenged, who had a response to the TKI plus IO re-challenge. And then most recently, there was a paper, Peter Rose's group published a paper in Eight patients, understandably a small cohort, DMMR, who seven of the eight progressed while on IO, one of them had stable disease. They were re-challenged with Limbatinib and Pembro. And 75% had an overall response, but all of them had a reduction in tumor burden. So it just speaks to the fact that we are still figuring this out. And to your excellent point, and it can't be overstated, it's our obligation to design the trials to make sure that we can give our patients the right answer. And so I'm excited to see how these are going to evolve both with the ADC world, alternate IO strategies or IO combinations post-progression. And it may be a different world for the DMMR who progresses on IO versus the PMMR who progresses on IO in terms of what trials we design and how we design them. But at least we have options, which we didn't before. Absolutely. Well, thank you so much. We're going to wrap it up today. It's always such a pleasure to talk to you and to hear your insights. You're fantastic. You're brilliant and fantastic researcher. And thank you for all you've done and are doing for our patients with endometrial cancer and really opening the space and providing great data and great new opportunities for our patients. And really exciting that even in our current endometrial space, we're seeing some patients long-term cancer-free. And hopefully in the future, we can say that these patients are actually cured as we have more follow-up data. Thank you so much. And also thank you for GSK for supporting this recording. We wish you continued health and safety. Thank you all and have a great rest of the day. Thank you, Flora. It was an absolute pleasure. Appreciate you.

treatment

mismatch repair-deficient

recurrent endometrial cancer

immunotherapy

chemotherapy

patient outcomes