It is also a distinct pleasure of mine to introduce Dr. Stephanie Leroux. Dr. Leroux is going to present data about immunotherapy after immunotherapy, what are the opportunities for immune checkpoint inhibition rechallenge, and the role of pembrolizumab plus linvatinib in this patient population. So we understand that there has been a growth in the treatment landscape for the management of endometrial cancer. There's been the presentation and the publication of both the NRG-GY018, RUBY, and DUO-E clinical trials, but we also saw the ATTEND clinical trial data presented. All of these studies looking at chemotherapy with immunotherapy, or in the case of DUO-E immunotherapy plus PARP inhibitor. And we recognize that the frontline landscape may evolve such that patients are exposed to immunotherapy. The difficult question for us is, how do we manage immunotherapy after prior immunotherapy? I think it's important to set the landscape by stating that standard of care chemotherapy options are terribly ineffective in the recurrent setting for patients who've progressed on prior treatment. And that's critically important in highlighting the potential opportunity for immunotherapy after prior progression on immune checkpoint inhibition. I think it's critical to understand that there is data that suggests efficacy for immunotherapy after prior immunotherapy progression. This came from data that Stephanie LaRue, who you're going to hear from, shortly has published, cabozantinib and nivolumab. There was also the LIO clinical trial looking at lucitinib plus nivolumab. And then most recently, and really quite exciting for us to see, was a paper that was published by Peter Rosen, colleagues, that reported that linvatinib and pembrolizumab, after progression on immunotherapy in a DMMR patient population, should very provocative results and benefit. Small population of patients, but really highlighting the potential opportunity there and informing what options we may have in the future. So really an exciting topic. I am incredibly thrilled to have Dr. LaRue presenting this data. I'm eager to learn from her presentation, but of course, highlighting that immunotherapy may be an option for these patients, even after progression on prior treatment, but also discussing future clinical trial opportunities. I have the great topic of what we do after immune therapy. I think I just wanted to start saying that there's a lot of work in this area, actually, because as you saw, there's a lot of immunotherapy that now would be incorporated in our treatment for our patients. So what are the future opportunities? As was brilliantly presented, immunotherapy combination first line, these different trials that was conducted with doftalumab, pembrolizumab, azithelizumab, showing benefits for our patients in the first line. And I just wanted to highlight that these benefit in the subgroup, in all patients, but specifically, and that was now FDA approved for the MMRD. So I just want to pause about what is actually MMRD. Just want to recap what is MMRD. So MMR deficiency is actually characterized by two different mechanisms. So you can have MMR deficiency by either a germline or somatic mutation in one of the MMR protein. And to have a loss of expression of one MMR protein led to the MMR deficiency. That is actually a somatic or germline mutation is seen in 10% to 20% of our patients. The other mechanism is actually the epigenetic MLH1 promoter methylation. So because you have this promoter methylation, you do not have the transcription or the protein production of this methylated MMR gene, which also led to the MMR deficiency. And this methylation status is actually the most common mechanism of MMRD in our population. It's about 75% to 80% of our endometrial cancer. And when you look at these different mechanisms of MMRD, definitely the trials show that there's a benefit of IO in first-line treatment. These three trials really show and highlight the benefit of IO combination with chemotherapy, with the hazard ratio of 0.3, 0.2, 8, or 0.36. So definitely IO combination in this population is very important. And because we know now that there's two different mechanisms of MMR deficiency, does that have an impact? And if we look at, for example, what was presented in the GYO18 trial regarding the PFS and OS by the mechanism of MMR loss, it seems to have no difference. And this is, as you can see here, the mechanism of MMRD loss is what is expected. The promoter methylation is seen in 72% of the case, and the MMR protein loss secondary to mutation is 13% of the case. And when you can see, the median PFS by the mechanism of MMR loss is not impacting because it's not rich in both. But if you look at the 12-month PFS, it's 75% in the promoter hypermethylation and 85% in the MMR protein loss secondary. So it seems to not have an impact, but maybe further interesting studies need to be looked at that. But definitely what really highlights is the fact that IO is definitely beneficial in this MMRD subgroup. So the next question for our patient is, do we need chemo for this patient of MMRD? And these two trials that will look at the specific question in the MMRD population, you have a trial really comparing IO versus chemotherapy. And another trial as well that has been conducted, and we await the result, is actually looking at the combination of lenvativity with pembrolizumab, given the data we had in the recurrence setting, versus chemotherapy alone. And given the data in the recurrence setting here, this trial do not focus on the MMRD, but also include the MMRP. But definitely the next question for our patient is, do we need chemotherapy in first line? Why is it important? It's important because when you look at the first line trial, it seems that the main toxicity actually appeared during the chemotherapy regimen. The alopecia, the fatigue, the nausea, the peripheral neuropathy is really significant side effect that impact our patient quality of life, and is also really seen during the chemotherapy. So definitely an important question that we need to define for population. So as you can see, IO is coming first line, already FDA approved for MMRD. But can we go beyond the MMR deficient? So all the trial was positive in all commas. But as presented, maybe the biomarker is important. I want to reiterate that it was only hypothesis generated because it's a subgroup analysis, but is intriguing. And we talk here about evolving the treatment and what will be the next step. And the next step is definitely in the molecular characterization. Because if we look at the ruby, chemo plus dorsalima versus chemo alone, definitely in the MMRD now, we know it's a no-brainer. There's a benefit of the IO. But what was really unexpected in this hypothesis generated study is the fact that you have a benefit in DTP53 mutation. Why surprising? It's because we didn't see that in the high-grade serosuvarian cancer. So that is really surprising. We need to dig dive. We need to understand why. And it's true that in the NSMP, the benefits was not as high. But further study is also needed in this subgroup population. And why is also important to understand? Because if we look at the immune therapy, there's very different pattern of response. And IO have a very different pattern of response compared to our chemotherapy. We know that there is some hyper-progressing on IO. There's some patients that have this pseudo-progression. I must admit that in gyne cancer, I didn't see a lot of pseudo-progression. But definitely what we see, we have primary resistance. We have some patients that have acute resistance. But also what we have seen that when we compare to chemotherapy with the different trial that was presented, we have really this durable response with immune therapy. So this pattern of IO response is important to understand to actually select appropriately our patient. So now if we want to focus on the primary resistance, the primary resistance is well described. It's actually seen in heart tumor because we also talk about immune therapy being beneficial in the heart tumor. And even in the heart tumor, we have some primary resistance. And here's the list of the heart tumor. And if you look at the MMRD here, you can see that approximately 40% will have a primary resistance. So this group of patient is important to understand to be able to act on them and offer them a different type of treatment. And this primary resistance has been seen in our trial. Because if we look at the curve of the trial, because when we look at clinical trial, we often talk about PFS, OS. But the curve is very important. What is the curve looking like? And you can see here we have a gap. You have a portion of patient, despite being MMR deficient, do not respond to the IO. It's true for the PFS. And you have the same curve for the OS. So definitely you have primary resistance in the MMRD subgroup. And we need to understand why. If we want to summarize the factor related to the response to resistance to IO, so that here is a kind of a big circle where there's still a lot of information that needs to be incorporated. It's just a kind of a summary. But you have different intrasect factor. You can have, for example, new mutation. You can have, as has been described, some mutation in JAK1 and JAK2. You can have some oncogene activation. You can have alteration on the antigen presentation pathway. You can have, for example, some genetic alteration in the interferon gamma pathway. You can have all these intrasect factors that lead to the primary resistance to the IO. You can have also some acute resistance with the treatment evolution under pressure. You can have intrasect factor and constitutive resistance. But if we are able to actually identify this mechanism of resistance, you can have some specific strategy. Because if you identify the different mechanism of resistance, you can act on them and offer combination treatment that will be beneficial for our patient. So, for example, you can have some combination strategy when you increase the release of cancer antigen. For example, is the idea with a combination with chemotherapy or radiation therapy. You can also improve your cancer antigen presentation, for example, with a vaccine. You can also improve your priming of an activation. So it's all the idea of the combination with all the type of immunotherapy, such as the anti-CDL-4. You can also improve the trafficking of the T-cell to the tumor. It's all the promise on the anti-angiogenic, trying to improve the trafficking of the T-cell and the infiltration of the T-cell into the tumor. And you can also act on the recognition of the killing of the cancer cell with the anti-PDL-1, but beyond the anti-PDL-1, for example, the IDO inhibitor. So all of this mechanism of resistance actually can be an opportunity for further treatment. So what will be our potential strategy after IDO? As we discussed and as we know from the recurrence setting, there is potentially interest of combining with anti-angiogenic pathway. So let's start with that. We know there's a rationale of combining TKI with anti-PDL-1 or PDL-1. So if we take from the lenvatinib-pembrolizumab trial, we know that we increase with anti-angiogenic the CD8 T-cell function, we increase the cytotoxic of the EK cell, and we decrease the expression of PD-1 with a combination. And this idea is really to have the synergy mechanism of the microenvironment to increase the response of the IDO alone. And if we look here, that was already presented, the trial at the time of recurrence with a combination of pembrolizumab and lenvatinib definitely you have a benefit compared to chemo in the MMRD. That is expected because we know that IDO in MMRD will be beneficial. But also you have an improvement in the MMRP. So the combination seems to be synergistic and have benefit in the MMRP population. So really again, really highlight the question of how much lenvatinib add to pembrolizumab in the DMMR, but more importantly, this trial was done at the time of IO-naive. So we don't know what to do after IO. And I really want to highlight that currently there is no standard of care, and IO after IO in endometrial cancer, there is definitely a need for clinical trial. And because there is not a lot of data in endometrial cancer, I had to look at what the other disease type did. And another disease type that actually use a lot immune therapy is in renal cell carcinoma. And this trial actually was published in Lancet Ecology in 2011, and it's actually very interesting. This trial actually look at the renal cell carcinoma and three group of patient. The patient here who are treatment naive and receive the combination Pembrolizumab-Lenvatinib. Here in orange, the patient who previously received all the treatment but not I.O. And here, patient who received prior I.O. And what is interesting is that you can see here, the patient with renal cell carcinoma who previously received I.O. seems to have benefit of the combination of Pembrolizumab and Lenvatinib. So the question is, is the rechallenge of I.O. combined with an antiandrogenic maybe beneficial in this population? So very interesting data that we can maybe use for endometrial cancer patient that now they will receive I.O. in first line. So then, continue with the renal cell carcinoma. They conducted another trial because the question was, do you need to rechallenge with the I.O. and antiandrogenic, or is the I.O. not necessarily, if you were previously treated with the I.O.? So they conducted the trial here, again, in renal cell carcinoma. So the population was patient with metastatic clear cell or non-clear cell renal cell carcinoma who all received prior I.O. And the patient were randomized to having atezolizumab with cabozantinib or cabozantinib alone. The primary endpoint was the PFS and DOS. And here, the result. Actually, looking at the primary analysis of the PFS and DOS, it seemed to have no difference between the cabozantinib alone versus a combination. So really, the question is, after I.O., do we need the combination, or the antiandrogenic alone is sufficient? Still, hypothesis generated, and we need to conduct specific study to answer this specific question. I want to highlight another study looking at I.O. after I.O. in endometrial cancer with cabozantinib that we discussed. And why cabozantinib is important that we discussed? Because actually, cabozantinib is an antiandrogenic. It also have a MEK inhibition as well. But here in this trial, it was patient who have advanced endometrial cancer, and they were randomized to cabozantinib plus nivolumab or nivolumab alone. So that was the main study. But this study actually built a specific exploratory cohort, allowing patient who previously received I.O. So this patient were here in this exploratory cohort, received prior I.O. as part of the standard of care of previous trial, or they were crossover from this arm. And this patient post I.O. received cabozantinib and nivolumab. It was the cohort of the arm C of this trial. What did we see? We see that definitely, it seems that some patient benefit of the re-challenge with a nivol and cabozantinib in this trial. As you can see here, if you look at the six months PFS, definitely the combination provide some benefit of patient who previously received I.O. So definitely, there's a population that seem to benefit of this combination. And you can see here, in the red, it was patient who were identified as MMRD. So definitely, the combination may be beneficial for some patient. Again, hypothesis driven. But we need to see what are this patient? What is a characteristic of this patient? As part of this trial, we had some baseline biopsy. And we were able to look with a mass cytometry to see what is the immune system at the time of the re-challenge of the combination and at the time of I.O. progression. And when we look at the baseline biopsy by CyTOF, we use a 37 marker immune profiling panel to try to identify what is the immune population at that time. And we look at the UMAP clustering of Paul CD45 plus cell, which resulted in, actually, when you can see here, 35 unique immune cell population, defining by the lineage and the phenotypic marker. So this is actually very interesting. When you look at the baseline biopsy of this patient post I.O., there's definitely a variety of immune cells that are different. Can we see which patient may benefit of the re-challenge of the I.O. with antiandrogenic, here the cabozantinib? And we see that, actually, the non-progressor have a higher proportion here of the activated tissue resident gamma T cell than the progressor. So definitely, the patient who have benefit of this combination have higher gamma T cell activated cell compared to the other one. So definitely, having a biomarker driven may be important to distinguish patient that may benefit from this re-challenge. And we begin to know that biomarker in endometrial cancer is key. And if we go back to a trial that was done by GOG86, which was the regular chemo plus bevacizumab, they look at the biomarker TP53. So if you look at the patient who have TP53 wild type, the benefit of adding bevacizumab was not there. But actually, if you look at the subgroup of patient with TP53 mutation, definitely adding bevacizumab to the standard chemotherapy drive benefit of the patient. So definitely, subgroup analysis of patient is very important for selecting the patient for treatment. So what else can we do post-IO? So as we remember, we can have potential other immune therapies that we can assess. Because if you look at this schema as well, if you look at the immunity cycle, already we know at baseline there's different population. But you can act at a different level. And if you can, example here, you can look at the PD-1, the PD-L1, which was a lot assessing this different first-line trial. But you have different option with TG that we heard this morning, for example, in cervix. But you have LAG-3 as well. You can also act on the microenvironment with the VGF pathway, as we were just discussing. But there's a lot of opportunity to actually improve the immune therapy going beyond PD-1 and PD-L1. So what is currently ongoing? So we know that the role of CTL4 and Treg in MMRD is crucial in endometrial cancer. And the rationale was maybe a dual immune checkpoint would be better than PD-1, PD-L1 alone blockade. And in DMMRD, for example, when we're talking about the primary resistant in DMMRD, it's a percentage of population. What could be the cause of it? And we know that one of the immune mechanism is actually the upregulation of CTL4 and other exertion marker LAG-3. And this trial is currently ongoing in the MMRD to really assess to see if a dual inhibition may be better than the single inhibition by PD-1 and PD-L1. So this trial is looking at the MMR deficient endometrial cancer. And the patient will be randomized with a combination nivol plus low dose epilimumab or nivolumab alone to really see if the dual inhibition is better. And when we look at the next generation of IOs, there's a lot going on in the IO space. And when we look at the dual checkpoint inhibitor, you have the PD-L1 CDL4 dual checkpoint. But you can also have the PD-1 and the TG checkpoint as well. And I just want to focus here on another example. And again, I have to go outside of endometrial cancer. But we learn a lot from the other disease as well. And I talk about the LAG-3 that could be also a target. And there's a lot of interest actually to combine L3 and PD-1 as a distinct inhibitory immune checkpoint. Because they both contribute to the T cell exhaustion. So some drugs that actually are developing to simultaneously block LAG-3 and PD-1 to actually restore the T cell activation and enhance the anti-tumor activity. So this trial actually was presented in pre-treated melanoma. So you can see here, the dual inhibition was assessed in melanoma previously treated with IO. And as you can see here, some patients definitely had benefits of this dual combination after relapse on the PD-1 or PD-L1 inhibition. And here again, maybe the expression of LAG-3 may impact the response to the combination. And based on this result, they actually moved to the first line setting in melanoma. And in melanoma is actually assessed in the IO naive, the nivolumab alone versus a combination. And definitely, the dual inhibition seems to improve the outcome for this patient. So definitely something that would be of interest for a patient with endometrial cancer. So what else? What other strategy we can look after IO? So we can look at the PARP inhibitor and the ADC. And we heard a lot about the ADC. So I will not talk about the ADC. But I will focus on the PARP inhibitor treatment. And on the PARP inhibitor treatment, we heard about the DOE. And the DOE was presented at ESMO by Shannon, showing that the chemotherapy alone here, the combination with duovalumab and PARP inhibitor treatment was actually better here. You can see here. And as was really highlighted this morning as well, is that the primary endpoint was comparing chemo versus the combination with the PARP and immunotherapy. And this trial was positive in the ITT population. Again, we can look at the subgroup analysis. And if we look at the DMMR population, it seems that we are not sure that we need to have the PARP inhibitor treatment for this patient. Again, going back to the fact that subgroup analysis is very important when we look at after IO option for our patient. Another example showing the importance of looking at the subgroup analysis when we talk about endometrial cancer after IO. This is another trial that was presented by Florence Jolie at ESMO. It's the EUTOLA trial. The EUTOLA trial was assessing PARP inhibitor maintenance after chemotherapy. In the overall population, PARP inhibitor maintenance was not beneficial. But then they look at the subgroup analysis, and we're going back to our TP53. And here, if you look at the P53 mutation, it seems that the patient who have the PARP maintenance did a little bit better than the one who are not P53. So again, hypothesis generated. Maybe the TP53 mutated patient are the one who may benefit of the PARP maintenance. Another question will be, maybe HRD testing also may be important for this population and need further work. And why is it important in the after IO area? Again, we go back to our melanoma cases. And if we look at the melanoma, they assess a phase 2 study assessing the SAD6738, which is ATR inhibitor, which is a DDR agent, in combination with duovalumab. And all these patients receive prior IO. So all, again, in this melanoma patient, they receive prior IO, and they assess the combination of ATR and duovalumab. And interestingly, you can see that they have seen some response of 31%. So again, we can overcome resistance to IO with, potentially, combination with PARP. But again, which patient will have this benefit? And we need to see if there's a specific biomarker. As part of this trial, they see that the immune enriched microenvironment, or the alteration of DDR pathway, may be a biomarker for response. So in conclusion, I think, definitely, there is a lot of opportunity post IO. It's just a new area that is coming, a lot of work that is in front of us. And I think a few things that we need to consider when we will design our next study post IO. I think we need to consider the time of progression. Because as we discussed, we have this durable response with immune therapy. And specific trial have a specific duration of immune therapy. So some patient may be post IO, and some patient may progress on IO. And maybe that is different. Maybe the mechanism of resistance would be different between these two situations and need to be considered. As we just highlighted, I think it would be very important to look at combination strategy and new potentially duoval inhibition or different pathway for combination. And as really showed by the different trial that was presented recently on endometrial cancer, endometrial cancer is not one box. It's a multiple box. And the biomarker and the subgroup analysis is very important. So when we look at IO post IO, we need to really specify how we'll select our patient for this specific study. And really, we have exciting new drug coming. We have seen the drug delivery improvement with all the ADCs that show promising activity. But we have also new drug looking at the dual targeting that are very promising as well and very interesting to assess. But really, when we will design our next trial, we need to have this biomarker assessment to really show which of the patient that benefits the most of our treatment strategy. So with that, I want to thank all our patient, our community here that make a big difference in how we manage our patient with endometrial cancer. Thank you.

immunotherapy

endometrial cancer

immune checkpoint inhibitors

biomarkers

PD-1 inhibitors

resistance mechanisms