Thank you everybody for joining us. My name is Ramaz Iskander. I'm a gynecologic oncologist at the University of California, San Diego. It's an absolute pleasure to be with you today virtually. We are going to talk about novel treatment options for the management of advanced stage or recurrent endometrial cancer. It is an incredibly dynamic time. Our first presentation today actually something that I'm very passionate about and will be presenting and discussing is an evolving treatment landscape for the management of endometrial cancer. We clearly know that in the past year there has been a tremendous amount of data that has emerged in the endometrial cancer space. Looking at immunotherapy, immunotherapy plus chemotherapy, of course immunotherapy plus tyrosine kinase inhibitors and when vatnib and pembrolizumab updated data and also an evolution and a growth of antibody drug conjugates in the management of endometrial cancer. And of course this data is going to both inform how we care for our patients but also help guide how we incorporate currently approved treatment regimens into the treatment algorithm for the patients that we care for. So we're incredibly excited we're excited to review this data, active clinical trials that may inform future treatment opportunities for our patients, and of course what the future might bring. It feels to me like an honor to be up here talking about endometrial cancer because it's reflective of the investment that we've collectively made to improve outcomes in a disease where for quite a period of time there was limited advancements. I just will briefly talk about the burden of endometrial cancer in the United States. Dr. Fogotti is going to talk about the global burden of the disease and of course the disparities in clinical outcome. But I really just want to highlight the fact that endometrial cancer continues to be a malignancy with a rising incidence in mortality which is actually discrepant for many of our other solid tumors. And it's anticipated to surpass ovarian cancer in mortality in the coming years which is really a paradigm shift when we start to think about opportunity for improving cancer outcomes. We're going to talk first about adjuvant therapy and frontline treatment. The table here for reference really reflects the evolution in treatment of endometrial cancer. And I want to highlight the fact that these were all trials that were principally investigating cytotoxic chemotherapy regimens. And importantly, this is before the era of our understanding of molecular classification of the disease. So these are endometrial cancer patients who were enrolled on these trials together and treated without any granularity around the identification of these patients beyond really basic histology and clinical stage. But we went from whole abdominal radiation, examining single agent chemo, comparing it to doublet agent chemo with GOG-177 led by Jeanne Fleming. The triplet regimen of TAP was incorporated. But then ultimately, David Miller on behalf of the Gynecologic Oncology Group helped run GOG protocol 209 which compared carboplatin and paclitaxel to TAP with a non-inferiority design, essentially showing similar outcomes with improved treatment-related adverse events profile. That study is summarized in this slide here. And you can tell from the panels on the right that the curves are definitively overlapping. So it suggests similar outcomes. And this ushered in to our practice carboplatin and paclitaxel as the chemotherapy backbone. But it's very important. You know, we tend to look at data on trials, and we try to extrapolate. What does this mean for contemporary data? And I want us to make sure that when we think about these trials, we understand that there are nuances. These trials are not all the same. GOG 209 excluded any prior adjuvant therapy, and it did not mandate measurable disease at enrollment. So that is a very different population than some of the trials that we're going to talk about in the frontline setting. Nonetheless, this emerged as our chemotherapy backbone for the management of endometrial cancer, understandably, based on the data that was shared, presented in 2012, published in 2020. I like this slide because I think it's really reflective of our shared passion in this room to go from the light microscope and pathologic adjudication of the disease to the molecular microscope. And really, in my mind, it can actually be a two-way arrow because it's not definitive, for example, that molecular classification is going to simply inform a priori what we do. We're going to have to look at this holistically and take in molecular classification with what we know about disease. The Sentinel TCGA paper that was published in 2013 in Nature Medicine really gave us the four molecular subgroups of endometrial cancer. And I'm excited that in a few years from now, I imagine we're going to be sitting up here, and this will go from four to six or seven, because we're going to further subdivide some of these molecular cohorts, I imagine, as we learn more about the disease. But we have identified the DNA polymerase epsilon, pole E population, which appears to prognostically do very well. The DMMR or MSI-high cohort, which really, again, responds exquisitely well to immunotherapy. We'll review some of that data. And then we have the copy number high, serous-like, in quotes, P53 mutated, and the copy number low or NSMP population, mostly P53 wild type, where, again, there are opportunities to improve. This slide highlights those same molecular cohorts, but on the right side, I've added what I believe to be potential implications for treatment strategies based on these molecular classifications. And some of this is evolving, and some of this data, of course, we'll discuss today, and some ongoing trials. You know, Keynote 158 was a paradigm-shifting trial for us. And you may look at me and say, Ramesh, there was also the Garnett trial with the Starlimab. Absolutely. Keynote 158 accrued patients. They had a colorectal cancer cohort that was DMMR and a non-colorectal cancer DMMR population, of which the endometrial cancer cohort was the largest. And what we saw from this data was over 57% objective response rate, but perhaps most provocatively, the median duration of response was not reached. In patients who responded to chemotherapy at about a 10 to 15% rate based on historical studies, and if they responded, had a very modest duration of response. So this was immediately adopted after we had accelerated approval in the United States. It gained full approval. But again, this was paradigm-shifting. Why? Because this led to the first U.S. FDA disease site agnostic approval in DMMR solid tumors who progressed after prior therapy. So again, taking us into a world where the molecular information we have about tumor is guiding an effective treatment opportunity. And we've seen this now across multiple studies looking at immunotherapy in the biomarker-selected cohort, emphasizing the efficacy of this regimen. But in the PMMR population, we didn't see those results. We saw response to immunotherapy of about 5 to 12%. But we hypothesized that combining chemotherapy with immunotherapy may improve response rates. Why? Because we adopted this by understanding the rationale in the lung cancer space where cytotoxic chemotherapy can be immunogenic. It can lead to tumor cell death, neoantigen expression. But it can also reduce Treg and myeloid-derived suppressor cells in the tumor immune microenvironment, augmenting IO response. So in the first line, we've had several trials. And I apologize, some of this will be review to many of you in the room. But NRG GY018 was a prospective. Phase III international clinical trial that randomized patients to either carboplatin and paclitaxel, the chemotherapy backbone from GOG209 with placebo and placebo maintenance, or carboplatin, paclitaxel, pembrolizumab, and pembrolizumab maintenance for up to two years. Some key points. Number one, carcinosarcomas were excluded from this trial. Number two, the trial was statistically designed to examine the DMMR and the PMMR patients independent of one another, because we understand that the immunotherapy may have a more biologically profound effect in the DMMR population based on all of the data that we previously discussed. Prior adjuvant therapy was permitted as long as it was at least a 12-month chemo-free interval. And the stratification factors were MMR status, ECOG performance status, and again, prior treatment. You can see the clinical characteristics in both the DMMR and PMMR populations. And the analogy I give is this is really like two clinical trials run simultaneously in the DMMR and the PMMR cohorts. And the primary data was presented and published in March of 2023, showing a very profound reduction in the risk of disease progression or death in the DMMR patient population hazard ratio of 0.3. On the left side, 70% reduction in the risk of progression or death. But perhaps more interesting to many of us was that the hazard ratio in the PMMR population was 0.54, 46% reduction. And you can see the morphology of those progression-free survival curves shows a separation, and what appears to be a maintained separation in this patient cohort, suggesting a benefit in the PMMR population with respect to PFS. Recently at ESMO, for the first time, we reported the objective response rate data. And consistent with the primary PFS analysis in the PMMR population, we saw an improvement in the objective response rate. But also, if you look at the CRs, it was a doubling in the PMMR from 8% to 15% and in the DMR from 15% to 32%, highlighting the efficacy of this regimen, again, in both patient cohorts. And as anticipated, when you looked at the median duration of response amongst those responding, you saw, again, a meaningful benefit that was significant in both the P and DMMR patient cohorts. There was some concern, based on prior clinical and preclinical data, that the efficacy of immunotherapy may be blunted in patients who are not MMR by mutation, meaning there are different mechanisms of loss, promoter hypermethylation, which is epigenetic and mutationally driven. We know from the Garnett trial, when they looked at this, they inferred methylation status, and it didn't suggest a difference. Well, we went to the NRGGY018 DMMR population, we looked at all of the institutional MMR IHC results, and then we looked at all of the institutional promoter hypermethylation assay results. So this is not inferential. This is promoter hypermethylation being done on the tissue for patients that had absent MLH1 and PMS2. And what you can see, really, is two main things here. Number one is the presence or absence of methylation did not appear to be prognostic in the placebo arm, meaning it doesn't impact response to chemotherapy. Those curves are almost identical in the placebo arms on the left and middle panel. In the very right panel, it suggests that whether you're methylated or mutated, the response is similar. The PFS at 12 months, 75 versus 85 percent, although we have to caution ourselves with the fact that only 13 patients in the PEMBRO arm of the DMMR cohort had a mutation. So the vast majority of these patients who have MMR loss and endometrial cancer is methylation, 72 percent. And I know that Dr. LaRue will also cover this in her conversation. I highlight here that even if you break down by histology in the GY018 trial, this is a surrogate for molecular testing potentially, although we'll talk about the RUBY data as well. But here in the grade 1 or grade 2, in an exploratory forest plot, there appears to be benefit with addition of PEMBRO to chemotherapy and as maintenance relative to placebo. And we saw the same in the endometrioid grade 3 and serous populations. RUBY was a similar trial that looked at Dostarlimab with chemotherapy and Dostarlimab maintenance for up to three years. Importantly, they did allow carcinosarcomas to enroll but capped at 10 percent. And also, the prior adjuvant therapy interval was six months or less, which is important for us to consider. The statistical design was intended in the DMMR and then a step down to the intent to treat population. The PMMR was exploratory in nature but reported, of course, and presented. We can see here, again, dramatic improvements in the DMMR patient population with a 72 percent reduction in the risk of disease progression or death. If you look at the overall population, D and PMMR, the hazard ratio was 0.64. Again, significant, highly significant based on the statistical design of the trial. This was the initially presented overall survival data, again, on the left in the DMMR, on the right in the intent to treat overall population, highlighting the benefits seen with addition of dostarlimab to chemotherapy and continued as maintenance. But you may astutely ask about the PMMR cohort, again, intended to be assessed not with alpha allocation but more exploratory, but you could see on the left here the PMMR-PFS population, and then on the right, the overall survival in the PMMR population. Recently, the molecular subgroup data was presented by Dr. Mirza at the ESMO meeting a few weeks ago. A few things to highlight. Number one, Pol E mutations were exceedingly rare, 1.25% of the population. That's very important to remember, because in the beginning when Ruby and 018 were presented, there was some thought that maybe in the PMMR population we're seeing some drivers of response via Pol E, but that doesn't appear to hold true, and we could see that's a very small fraction of these cohorts. The DMMR, of course, you can see the frequency, about 20 to 25%. That's consistent across multiple of our studies that were conducted, and then you can see the last two, the copy number high, P53 aberrant, and then the P53 wild type, which they defined here as NSMP, which is the largest of the patient populations. And you could see by cohort, again, Pol E appears to do remarkably well, which is consistent with the data that we had from prior retrospective reviews. The DMMR population holds up, as we anticipated, based on the primary efficacy assessment. The bottom two panels were what brought attention, because it appeared in the P53 mutated that the addition of Dostarlimab to chemo had a more magnified benefit, and then at the NSMP there was a benefit, but not as robust, and I will just say there's a few things. Number one, we have to remember, this data is hypothesis generating. There are many variables that are uncontrolled in these patient cohorts, and the largest population, of course, is NSMP. So we have to look at this, understand the potential implications, but this has to be validated before you would walk away and say, oh, in an NSMP, chemotherapy plus IO may not be as beneficial. We have to be very thoughtful about an interpretation like that. The DOE data was presented by Dr. Weston on behalf of the study team, again, at ESMO. Importantly, this trial added an arm to look at the relevance of PARP inhibitor maintenance in addition to IO, because of the preclinical data and some clinical data suggesting that there's a cohort of endometrial cancers that are mismatch repair deficient, and I will just emphasize here that the statistical analysis of DOE was unique. It compared arm two to the control arm and arm three to the control arm with an intent to treat analysis. So it didn't carve out in the statistical plan specifically to look at the DMMR independently, and it didn't compare arm three to arm two. So these are important things as we try to make sense of all of this data that's emerging in the frontline, but we could see, obviously, here in the intent to treat population for progression-free survival, provocative, again, positive findings, hazard ratio in arm two of 0.71 and in arm three of 0.55. And if you look at the subgroup analysis on the left, it appears to suggest that dervelimab by itself is sufficient in the DMMR population. You could see basically essential overlap between the dervelimab and the derva-olaparib arms. On the right, in the PMMR population, is where there's a suggestion that adding the PARP to dervelimab may augment and enhance response, although, again, importantly, as Dr. Ketel-Russo had mentioned in the discussion of this abstract, we didn't statistically compare arm two to arm three to inform that benefit or that difference, and that's going to be something we have to think about collectively. Dr. Colombo also presented at ESMO the ATEND study. This is a tezolizumab in a similar design overall, although these patients were treated indefinitely with maintenance therapy in this trial. There wasn't a defined cutoff. Again, look at the DMMR. It's incredibly consistent, the magnitude of benefit we see with I.O. in the DMMR populations, and it's for this reason I will say also it's important to mention that dostarlimab plus chemotherapy and its maintenance is FDA-approved in the DMMR patient population in the United States in the context of the benefits seen. Overall survival in the DMMR here was, again, positive. Importantly, post-progression I.O. is very important for us to consider as we interpret overall survival in these studies. So if we look here, the DOE, because it had the PARP arm, is a bit different than these three trials, but you can see the consistency across these studies when we're looking at adjudication of checkpoint with chemotherapy with checkpoint maintenance versus a placebo. I think this question has been answered. The more provocative question is do we even need chemo, but I'll leave that to my follow-up discussants. And then here we look at the difference between these three, and maybe in the PMMR population it has to do with the fact that the trials were designed differently. Why does this discrepancy exist? I think we're all challenging ourselves to make sense of this. Is it the statistical design of the trials? Is it the 12-month versus six-month prior adjuvant therapy chemo-free interval? Is it the carcinosarcomas? Is it the ethnic and racial makeup of the patients on the trial? You know, you may have heard conversations about potential blunted benefit in Asian populations, not in the United States, but ex-U.S. in the control arm. So these are hypotheses that we will have to figure out. Briefly, I want to highlight, again, we also have the opportunity for anti-HER2-directed therapy. This was based on studies that were led by Dr. Nichols Fader. This was a phase two trial in HER2-positive serous defined by breast scoring, so 3-plus IHC or 2-plus positive by fish. And what we saw was an improvement in median progression-free survival and a very provocative signal of overall survival, particularly in the advanced stage chemo-naive population. We currently have a trial, NRG GY-026, that's looking to ask this question in both the early stage and the advanced stage, looking at dual HER2 treatment. This is actively accruing in the United States right now with also, I think, ex-U.S. sites, and it's going to be informative and important for us. So now let's pivot to recurrent disease. Again, we talked about how poorly cytotoxic chemotherapy performs in the recurrent endometrial cancer patient population in general. So this leaves a significant gap and a significant unmet need. I've also alluded to the fact that single agent checkpoint doesn't perform as well as we'd hope, clearly, in these patient cohorts. But Dr. Macker and her colleagues, after a previous phase two trial, conducted the confirmatory phase three, Keynote 775, that looked at the combination of lenvatinib plus pembrolizumab versus physician's choice chemo based on the biologic rationale of combining TKI with immunotherapy to augment response. And this was, again, a follow-up study after a phase two that showed an objective response rate over 30 percent when chemotherapy predicted responses are 10 to 15 percent. These were recurrent pretreated patients randomized, as I alluded to, one-to-one with the primary endpoint of PFS and OS. And as many of you are aware, the study met its primary endpoint, really showed us a benefit with progression-free survival, basically a doubling in the PMMR population, as you can see on the panel on the left. And then when you look at the overall survival in these cohorts, over a five-month improvement in overall survival. We don't usually see, you know, this was in the prior session in cervix, we talked about this. We are getting a bit spoiled because we have all these positive trials and we're looking at this data, but these are overall survival advantages for our patients. So it makes us pause for a minute to appreciate the movement we're seeing in oncologic outcomes in gynecologic cancers where historically we were stalled. And I think we have to pause, and it's a testament to all the efforts being done by everyone in this room from a clinical trial perspective. I do put this slide together for the sake of time. We can't talk about all of the data that we're looking at and examining in endometrial cancer given 25 minutes. But we're looking at opportunities to capitalize on p53. We talked about the rationale for antiangiogenesis therapy when they looked at a subset of 86p. There was a suggestion that Bevacizumab was beneficial, but that was a cross-trial comparison. But we also have nuclear export, the Selenexor opportunity. There was data presented in an ASCO virtual, but then a publication shortly thereafter in JCO, which suggested a benefit in the TP53 wild-type population based on the biologic mechanism of action of this drug. So there's opportunities here for us to continue to evolve the treatment landscape. Anti-HER2 therapy, a lot of excitement after the DestinyPanTumorO2 presentation at ASCO. Again, we had an update for that, and it appears that the IHC3 plus is really the provocative patient population. We will see. This will evolve further. This is NCCN compendium listed now in both cervix and endometrial cancer in the United States. NRG GY026 we discussed, and also the status trial, which looked at carcinosarcomas, which showed an objective response rate of 54 to 70% in pretreated carcinosarcoma, who historically do very poorly. DNA damage repair, we are eager to see if we can capitalize on this or not. We don't know. We've had difficulties with treatment-related adverse events, but there are active studies examining WE1 inhibition to drive replication stress in endometrial cancer. And then lastly, is there going to be a role for hormonal therapy? The paleo study, Dr. Constantinopoulos' combination, CDK46, and hormonal therapy, this is an unanswered question for us, and perhaps most provocatively, we need to do a trial comparing that to chemotherapy to make sure that the outcomes are similar, and that's an arm of the RAINBOW study. Just briefly, I want to highlight the TDX story, the Destiny pan-tumor O2. This was a multi-cohort clinical trial. For the sake of time, I want to focus here on the endometrial cancer cohort, 40 patients, and what we saw in these 40 patients was an objective response rate of 57.5%. But if we look a little bit closely, the median duration of response is not reached in a previously treated patient population, and if you look at the HER2 IHC3+, the objective response rate was nearly 85%. So it's important, it's provocative, it led to an NCCN compendium listing, but it will have to be validated in a larger patient population to make sure that the signal holds up. We discussed the carcinosarcoma, trastuzumab directs a TCAN signal here. Again, you can see small patient populations, but very important data suggesting efficacy, and many of us have already incorporated examining HER2 IHC and offering trastuzumab directs TCAN in the recurrent setting if we have access. And lastly, ADC-wise, there are multiple platforms. We'll talk about TROP2 here briefly, sasituzumab, which is used in breast cancer, but also the opportunity to expand this to the endometrial space where Dr. Centene showed a 33% objective response rate in a biomarker agnostic, so not selected by HITROP2 or LOPTRO2 expression. And we'll see whether or not there's a place for us to move TROP2 ADCs in the endometrial cancer arena. We're all excited to see this because we have a vacuum now, post-IO, and then we'll review that. And Dr. Puthuri presented STRO02FR-alpha targeting a small cohort of endometrial cancer patients at ESMO, again highlighting the fact that maybe FR-alpha will be a therapeutic target in endometrial cancer. So we've evolved also to incorporate a plethora of antibody drug conjugates to try to identify effective strategies and efficacy. Just briefly to touch base on hormonal therapy, I want to highlight that the two studies that showed the greatest benefit in hormonal therapy were in hormone-naive and chemotherapy-naive patient cohorts. And that's critical when we think about developing strategies in endometrial cancer, because if we use these in later line treatment, are we going to expect the same clinical outcome? And ER expression may be relevant, but there's no standardization in endometrial cancer for ER expression, so we have to figure that out if we're going to run an international trial about how are we going to communicate the same way about ER selection to augment response. And then combinations. Dr. Slomovitz, the letrozole plus everolimus, which was provocative, interesting information, particularly in the chemo-naive population, where it appeared to be similar to chemotherapy in a cross-trial comparison. And then I already discussed the paleo data and Dr. Constantinopoulos' data. But I want to highlight in Panos' paper, which was published looking at letrozole and abemacyclib, there were no responses in P53-mutated endometrioid histology. So that's key as we think about development. And that's it.

endometrial cancer

treatment options

immunotherapy

molecular classification

clinical trials

improve outcomes