Hello, wherever you are, welcome to the IGCS 360 Education Platform. I'm here with my distinguished guest, Dr. Rob Coleman, who's going to introduce himself here in a moment. And today we're going to talk about mismatch repair, proficiency, recurrent endometrial cancer and some opportunities in this space and clinical trials and developments. I'm Flora Backus. I am the co-chair of the Advances and Updates for IGCS 360, and I do this together with Dr. Wendell Nauman, and I'll let Dr. Coleman introduce himself. Thanks so much, Flora. It's great to be with you. So, Rob Coleman, GEO oncologist, now residing in Georgetown, Texas, because we have international everything here in Texas, which is just north of Austin. I work at U.S. Oncology, and I am the immediate past president of IGCS, so it's great to be with you. I also serve as the PI for the U.S. on the X4DC trial, so I'm really happy to have this opportunity to speak with you today. Thanks for the invitation. And it's been quite a year for endometrial cancer. I can't believe that it was just a year ago that the data was presented for recurrent endometrial cancer with immunotherapy added to chemotherapy, and it's really changed our landscape. And we've talked about in these sessions, we've had a session on the mismatch repair deficient population and how the magnitude of benefits that just blows all our minds, but we've really adopted that as our new strategy. But for this PMMR, mismatch repair proficient population, we see a benefit there, but not as big. And I was wondering if you would be able to talk about some of the results that we've seen over the last year also developing in this PMMR space and potential other maintenance treatment options rather than the immunotherapy. Yeah, boy, hasn't it, it's really, it is kind of amazing. You know, I think for those of us who have been in this business for a long time have been always, you know, we almost have to pinch ourselves to see that there's so much development in a disease that really most people just kind of said, well, you got front, front playing chemo and that's really about it. Patients are too sick to get anything else. And you know, now we've come to this point where now the molecular annotation is becoming so important, just as you mentioned, obviously one of the biggest critical factors is this is this MSI, MMR status, because that's allowed us to differentiate really two cohorts. And I love the way you say how, you know, we were all mind boggled by the efficacy. I think one of the, one of the kind of the things that for me has been so transformative is to look at the PFS curves and the tails, those PFS curves that don't drop. So, you know, we, we, we'd love to see overall survival, but to see a patient who never recurs, that's transformative. So, so yeah. And, and again, you mentioned, you know, in the, in the, in the opposite, in essentially the cohort that it wasn't defined by that biomarker, the ones that are in the MMRP category, you know, we, we do see, seem to see at least somewhat of an effect in that group. We don't really have a great understanding as to why that is. And what that has done is to cause us to dig deeper into not only hypotheses that might explain why an immunotherapy would work in a, in a proficient MMR tumor, but also are there other potential opportunities based on that molecular annotation? And so now we've started to see this kind of like, you know, segmentation become even more segmented as we get further down into these, you know, molecular annotated cohorts. So, so I think that one of the things we should, you know, probably start the conversation with is that when we look at just the PMMR tumor cohort, you know, we do see across different studies, varying degrees, strongest in the, in GY018, weakest probably in INTEND. But we are seeing that these curves do kind of separate up for a little bit, and the magnitude of that effect is probably driven by many other factors that we haven't controlled for. And one of those, as we saw from Mansur last year, was to look at what, you know, P53 mutation status might, might, you know, inform us of that. And again, of course, we're talking about a subgroup now, P53 wild-type versus mutated of a subgroup, which is PMMR versus DMMR. So I don't want to get too, too, too eye-opening about that. Yes, we are definitely in subgroups and hypothesis generating, but that brings me to, I mean, we saw that difference there in the PMMR, sorry, in the PMMR group, but the P53 subsets that had a P53 mutation, and that was by whole exome sequencing, by NGS, not just by immunohistochemistry. But in that, that nonspecific molecular profile is really what we're looking for other opportunities. And when we first saw it, we were really getting to that, so sell an extra data. Tell us how you decided, because initially that was a negative trial, how did you start developing this? Yeah. So, you know, so this is, this is, you know, as people have heard me speak about subgroup analyses and what, how to interpret them, this is actually really applaud the company for trying to, to actually, you know, kind of stake, put a stake into what we, what is a match between a biomarker P53 wild type status and an, a mechanism of drug, which is to, to target the XPO1 export and nuclear export and protein, protein function, which would allow accumulation of wild type P53 protein in the nucleus to do what it's going to, what we, what we want it to do, which is to govern, you know, these aberrations in, in cellular mechanisms. So the whole idea here was to take a drug and again, selenixor is not a new drug. It is for us, but not in the, in the heme, heme malignancy space where it's also targeting the same kind of mechanism where it blocks this, this transfer from nucleus to cytoplasm of, of what would be considered normal protein. And this is a two, this is a tumor, you know, a, a, a, to, to allow this to happen is actually advantageous to the tumor. It takes out functional protein out of its control so that the tumor cells can continue to proliferate and with even damaged DNA on endlessly. So, so this is actually, it was a strategy for, for therapy. And so what we did is we designed a trial called Siendo that basically looked at the use of this drug as a maintenance strategy in patients who have had you know, who had responded to, to index therapy. And so the trial was done. It used a slightly higher dose of cell A that selenixor that we would have wanted to use. And actually, if you don't mind, I can actually share that just to kind of highlight what that looks like. I'll just share my screen here real quick and I can show you what we have. So hopefully that can be seen. So this was the Siendo trial, 3055. And you can see there was 263 patients who had received chemotherapy and had responded to it by, you reached this criteria, then randomization of two to one of 80 milligrams of selenixor versus placebo. And the end point was to look at progression-free survival. And overall, what they saw was that in this intent to treat population, that there was a slight separation in those curves. You can see this slight difference between the blue and the red lines, and you can see what the hazard ratio was. And you can see, unfortunately, that there were some, there were some stratification variables that were misallocated, I guess is the best way to say this. And so when those, when those, and so the hazard ratio was in an unaudited population was 0.76 with the hazard, with the upper limit over 1.0. However, when it was audited, you can see that when those were correctly allocated by their strata, that it was a 0.71 with a hazard ratio of just under one. And so this was, this was thought to be potentially a signal, but it was because of this issue, there was actually a call to move this forward and to actually assess it. One of the, one in that, in this discussion, what we noted was that when we broke out the subgroup for p53 wild type, we saw this kind of efficacy. And so now you can see that the curves are quite a bit, quite a bit split. Now unfortunately, this is a subgroup. And so the question was, can we, can we reproduce this in a formal phase three study? And that really led to kind of the export EC trial. So I think that that's, you know, again, it's, it was hypothesis generating, which we're seeing here with a pretty profound effect. And so the hope is, is that this biomarker p53 wild type could actually indeed serve as a, as a surrogate that aligns with the, aligns with the mechanism of action and hopefully would drive the efficacy we might see in a phase three trial. Yeah, I think this is really great that we're taking it forward and trying to conform it also with a phase three trial. We certainly have seen sometimes that things change when we go from one to the next trial. But hopefully this will just see a stronger signal. In this current space though, like how, how do you think about this? Like how do you decide, and when do you decide to get a patient here? Because we now have, we don't have for the PMMR immunotherapy with chemotherapy FDA approved yet, but it is still listed on the NCCN and it's been pretty wildly adopted. Like how should people think about it and, and kind of make their strategy? It's good. Good question because you know, I think, I think many of us were influenced by, you know, what we saw and obviously we're waiting for a formal opinion, which should be coming soon with respect to the efficacy in the, in the PMMR cohort of patients. But as it is right now, we still don't have proof that, that in that therapy line that this is the most effective strategy. And so I would say that in, in certainly in patients where pfE3 wild type is seen, you know, by the, by the same kind of inference that we saw with the pfE3, excuse me, with the MMRP category, it may be way more nuanced than what we just looking at it from a high level. And, and so it may be that the PMMR pfE3 wild type patients should be potentially treated differently than the PMMR pf, you know, pfE3 mutated tumors. And, and, and so that would be a nuance that would maybe help divide this because we really don't have in that pfE3 wild type category, we really don't have a strong signal really of any of our adjuvant treatments that we might use such as bevacizumab or in immunotherapy immune checkpoint inhibitor. So this is kind of where that fits, it fits in that potential population that could benefit again with a biomarker pfE3 wild type with a drug that, that, that is looking for pfE3 normal protein. And so when you say pfE3 normal protein, also as in as far as the tumor mechanism, when we think about how we're going to strategize, we're going down the NCCN schema, the PROMIS schema, however you want to call it. But some people use NGS, whole exome sequencing, some people use immunohistochemistry. How should we be testing our tumors at this point and thinking about thinking ahead, like how we're going to treat our tumors based on those results? Yeah. I mean, this is again, an evolving story. Before we had evidence that MSI status was important for primary treatment, we never did check it till patients recurred. Right now we're doing kind of more holistic whole genome or whole exome sequencing along with immunohistochemistry for patients with recurrent disease. But I suspect that as time goes on, we will be doing comprehensive testing on all new patients just so that we have the data available and can make potential treatment decisions as time goes forward with the development of all of what's in clinical trial right now. So I think that, but one of the things that is done frequently in most pathology places that do pathology evaluation of tumors is a pfE3 assessment. It's kind of like, you'll see maybe ER being done as part of an evaluation, pfE3 may be checked in higher grade histologies to rule out a uterine serous type of tumor. So it can be used as a biomarker to assess that. So frequently we can get that done by IHC. Now, it doesn't necessarily mean that there's a mutation in pfE3 by sequencing, but at least the protein is either there or not. And then you'll hear pathologists often say that the pfE3 staining was done, but it had a wild type pattern. So again, that is, it's an estimate based on what they see and generally a non amplified or non high level of staining, like a three plus would help them to say that this is wild type pattern or nuclear distribution. But we found that that's not a great screening tool. So I think for this particular trial, one of the things that we have wanted to message is that we don't often see pfE3 wild type as a called out biomarker. We just know when it's abnormal. And so what we, and the relationship between pfE3 staining by pathology IHC and pfE3 mutation by next-gen sequencing is not, it's imperfect. I wouldn't say it's, some people are very good at it, but it's imperfect. And of course, loss of protein can be a function of mutation as well as too much protein. So I do think what we're doing, at least with these kinds of trials, is we are noting with our biomarker testing pfE3 wild type status and the patient who qualifies for this trial, the Export EC trial, you know, we would want to use that as a way to screen almost as a way of prescreening that group of patients who then we can send for next-gen sequencing. But I wouldn't leave it exclusively to that because of the disconnect between protein staining patterns and mutation status. So patients are eligible though, if they have, by immunohistochemistry? So they have to be, they need to have formal next-gen sequencing testing so that they can go on to the trial. But a way to identify patients while you're thinking about this is you can actually use that IHC screen as a way to kind of like start to put them on your kind of your list of what you want to, who you might want to evaluate. So as you, as we're thinking about this trial as another great option in our exploding armamentarium for endometrial cancer and maintenance strategies, also this is going to be potential third maintenance strategy here in our armamentarium, what should we think about as far as side effects and which patients are particularly, should we think about this for this or should we not enroll? Oh no. Anybody can? Please enroll. Please enroll. Yeah. No, I think, I think that, you know, so first of all, the, one of the things that we want to, you know, kind of emphasize in a trial like this is, is that, is that this particular trial is actually looking for patients that have demonstrated a response to chemotherapy. Now, this is, this has been a tough one because many times we might have a patient who had advanced disease and has nothing measurable to follow. But one of the kind of biological biomarkers of an intact P53 mechanism is this response to platinum-based therapy would make sense. So we've required this trial that in patients who have, you know, state either primary stage four or recurrent disease, that they have evidence of response to platinum. So that, so that is kind of a, kind of a first, a first insight into that this is a group of patients for which P53 may be functionally normal. It's almost, almost like what we did in, with the PARP store where we use platinum as a surrogate for potential for PARP, for PARP sensitivity. So kind of a similar type of idea. And so, so that's kind of the first thing. And then the second thing is that if we find a patient like that, that we talk to them, that we talk to these patients early so that they understand what maintenance therapy is. Because those, as you were, as you, I'm sure you're well aware too, because you've counseled these patients like me, that, you know, once a patient kind of feels like they just finished their chemo, then they're kind of done and they don't want anything more. So we want to talk to them and talk to these patients early on and say, hey, listen, your treatment program, you know, potentially could involve a maintenance strategy and this is why we want to do it. So try to get ahead of that question as well. I think, you know, in counseling patients, we have had some experience, there's been a lot of experience with respect to adverse events that we've seen in our, in our previous exposure, treatment exposure from, from Siendo. But actually for people who have had experience with, with Selenexor for non-GYN indications, they're going to be very well versed with, with what to expect. And the most dominant one that we need to deal with is that of gastrointestinal side effects. And so what we did in between the Siendo trial and X4DC was to actually mandate that there be a dual antiemetic prophylaxis for the first two cycles. So a lot of this is expectation, just like we do with regular chemotherapy, but talk about that this GI side effect could happen. And then we, for the first two cycles have used a mitigation strategy that would involve an F5HT3 and an NK1 type drug to be used for the first, for the first two cycles, and then go back to kind of, you know, kind of a standard approach. And we think that that will help mitigate some of that, that adverse, adverse events. Yeah, that's great. And really, if we think about how we got to the PARP inhibitors too, yes, that's how we started and we're a little worried about the nausea and we see that improving too with time. And it sounds like we may, with good, good strategy and preventative things, we'll be able to manage this. This is great. It's, it's wonderful to hear all these options developing and really narrowing it down and very much getting to this personalized treatment of endometrial cancer and hopefully going against our rising death rates that we've seen in endometrial cancer and really starting to make some improvement for all these specific populations. And hopefully to a magnitude as we're seeing in the mismatch repair deficient population with a great incentive as well. Yeah. One thing I might want to mention too, just because I know people get nervous about adverse events, particularly in a maintenance setting against placebo. In this trial, we, we went back and actually looked at the Siendo trial for the dosing that was found there. We found that although it started at 80 milligrams, most patients basically ended up at 60, which is where this trial, Export EC is actually starting. So we're, we're fairly confident that we're with the mitigation strategy and the dosing adjustment that we should be able to get through treatment as, as we hope. Excellent. Well, I think this is another great, exciting option, and I really hope that we'll be able to complete or you'll be able to complete this trial and get the results. Hopefully as exciting and confirmatory to what we saw initially, but at least get the right answers and get it, find it out in the right ways. So congratulations on leading this and thank you so much for taking the time to talk to this today about mismatch repair, proficient endometrial cancer, and some new developments in this maintenance space. Thank you. And I really appreciate taking the time out to, to walk through it and help, help understand what the value of this kind of trial might bring to, to our patients. Really appreciate the invitation. Excellent. With that, we'll conclude our webinar or podcast, however you are listening to this. And we look forward to having you join for our next series.

endometrial cancer

recurrent

mismatch repair proficient

maintenance treatment

biomarkers

clinical trials