Hello, I'm Wendell Nauman. I'm the co-director of the IGCS 360 Learning Portal. And today I have Matt Powell joining me. Matt is the chair of the NRG Corpus Committee. He's also the president-elect of SGO and gave us an update on the overall survival for the Ruby trial at the SGO meeting last month. Matt, welcome and thank you for joining us. Hey, good morning and thanks for having me. I'm excited to talk about this exciting data. Yeah, so just give us a little overview of the Ruby trial and how this basically changed the landscape in endometrial cancer. Yeah, as you mentioned, we really haven't made much progress in nearly 20 years in the management of metastatic endometrial cancer. And the Ruby trial was designed to test the addition of immunotherapy in the form of distalimab added to our standard chemotherapy of carboplatin-paclitaxel. And we've reported last year the progression-free survival benefit, which was really quite staggering. And what we recently presented is the overall survival benefit now that it has become mature. Now, the patient population in Ruby, can you describe who this applies to and how you have selected patients in your practice? Yeah, so these are patients with newly diagnosed stage 3 and 4 disease or the first recurrence of their cancer. Really, all histology types are eligible except for pure sarcomas. So, we include carcinosarcoma, which was one of our most aggressive tumors. The patients were enrolled, received chemotherapy for six cycles with distalimab and then had distalimab maintenance for up to three years. Right, and so you included MMTs and the stage 3s had to be measurable, is that correct? That's correct. There were some fine points with some of the more aggressive histologies, but yes, that's the case. Yeah, so that's great. I guess, were you surprised by any of these results? And, you know, the crossover issue potentially would impact the OS. I know that about 40% of patients in both groups had crossover from the placebo to immunotherapy. Were you surprised that that didn't impact the overall survival? Definitely. I think a lot of us thought, you know, we knew immunotherapy worked especially for our defective mismatch repair tumors, but I think we were surprised by the magnitude of benefit even with that degree of crossover, as you mentioned. You know, the crossover really happened in all groups. And there was crossover to the combined immunotherapy regimen of pembrolizumab and lobatinib, you know, most commonly in our mismatch repair proficient population. So I think it's a real world evidence that combining immunotherapy with chemotherapy would be a very valid strategy. Yeah. So what about the MMR deficient patients? Yeah, there's some controversy about whether or not they need chemotherapy or just immunotherapy. What is your view on that? Yeah, I think, you know, when you see a hazard ratio of 0.32 and overall survival benefit with that two years, over 80% of the patients, 82.8% of the patients were alive if they had chemotherapy with immunotherapy versus 57% that just had chemotherapy. As you mentioned, almost 42% of those patients crossed over to immunotherapy later. I think there may be something to the addition of chemotherapy and immunotherapy to see such a dramatic difference in those populations. The, you know, we don't really know we'd like to test that immunotherapy alone versus immunotherapy and chemotherapy. That's a trial that there's a couple ongoing that that look that will provide some evidence of that. But that trial needs to be done. Yeah. So do you think the standard is, is absolutely chemotherapy with immunotherapy? What, what about the patients? I know the, the Ruby trial did allow patients with adjuvant chemotherapy in the trial. Yeah. If they had prior adjuvant chemotherapy and it's been greater than six months, those patients were eligible and that's slightly different than some of the other trials that required a 12 month chemo free interval. Right. What about some of the subgroups? I know there is obviously there's greater impact in the MMR deficient patient population but the MMR proficient patient population has some subgroups and we have the, the so-called NSMP or the endometrioid P53 wild type. And then we have the P53 mutated patients. And I know that Dr. Mirza presented some of these subgroups at the meeting last year, I guess at ESMO last year. What do you think about these subgroups and how should we approach those? Yeah. And again, this is exploratory. So we don't, you know, it the when these trials were designed, we didn't know as the impact of these molecular subgroups nearly as much as we do now. And we still have a lot to learn. We need to learn about HER2 status, but I think what you're pointing out is within the mismatch repair proficient population, you know, that overall survival benefit of adding distarlomab was a hazard ratio of 0.74 with, you know, the, again, exploratory endpoint. The but when we look specifically at the components that make up mismatch repair proficient, as you mentioned that P53 mutated groups seem to do the best with the magnitude of benefit nearly as strong as we see in the defective mismatch repair population. So I think as we learn more about molecularly personalizing care, we'll get a sense of what the degree of benefit, especially as the other trials that are out there, GYO18, DOE, et cetera, report their molecular data. If this is all confirmed, we really may need, you know, we may further refine how we care for these patients. Yeah. So you bring up a good point. What about the HER2 positive patients with serous cancer? How do you approach those now with the ruby data? I mean, we certainly have data with trastuzumab in that patient population. Do you still do chemo trastuzumab or do you go to chemo immunotherapy and reserve the HER2 therapy for the recurrent setting? Yeah. So great question. And ideally getting these patients on trial, we do have the trastuzumab, pertuzumab trial going on with GYO26. The off trial, it's tricky because we don't have HER2 data within the ruby trial at this point or within the ONA trial at this point to see, you know, how did those patients do? I think the one caveat now being we have the antibody drug conjugate trastuzumab directocan to where a very active HER2 targeting strategy to be used later lines as well. And so I think that whole HER2 story is really evolving. Yeah. So any thoughts in combining trastuzumab and immunotherapy? I don't know if there are any trials out there that have looked at that. Yeah, certainly. I think there's been looked at in breast cancer. I think they're, you know, obviously ripe for more options now, especially if we have more active HER2 director, you'll see combinations with immunotherapy. That's a trial already proposed in that same strategy that you just mentioned. Yeah. Yeah. You know, one of the things that comes up for us is the patient who's at high risk has got an MMR deficient tumor and has multiple positive nodes. How are you treating those patients now? Obviously they were not included in the ruby trial, but that's a high risk patient population. And when you see that, as you mentioned, the overall survival of over 80%, in the ruby trial, in that patient population, what are you doing with those patients now? Yeah, I think that's still a dilemma. And I get that question all the time. What about those patients that weren't quite eligible? And one of the things we know this patient wasn't measurable. They didn't have measurable Zs on the trial. Again, that's a pretty small portion, less than 10%. Those patients, at least, you know, in the forest plot analysis did not seem to have the degree of benefit. So I think we need to wait on the additional trials that are out there evaluating immunotherapy in this population before fully endorsing those patients at combined chemo immunotherapy. I think the good news is, you know, watching those patients closely, treating them with standard of care chemotherapy at this point and adding in immunotherapy, you know, when they're eligible, you know, makes sense. And I, you know, I think that's, it's an area of unmet need at this point that the question that we, you know, all are eager to see the answer, we should have the answer the next few years about what's the most appropriate thing for that population. So that would be the B21 trial. And I think that's actually fairly soon, but I suspect that, that many of those, the results are going to be delayed because the outcomes are so favorable in the trial. So that obviously makes the maturation of the trial delayed. So anything, you know, I, the other issue I think with the LEAP 00, LEAP 01 trial is the, is the immunotherapy was not as successful upfront as we would have thought without chemotherapy. So any comments on that in terms of why that was? I mean, and there were obviously subgroups in that patient population that received chemo before immunotherapy actually benefited more. Is that a lesson that we, we, we take to future trial designs? Yeah, the LEAP 01 was interesting. I think the, it'll also be helpful to learn how the different molecular subgroups performed within that trial, you know, is there going to be a P53 story there as well, that maybe libatinib pembolizumab is, has some improvement there. There's a lot yet to be learned. I think the, it's clear that we, we can't give up on chemotherapy yet. It still has a major role in the, in managing of these patients. Yeah. So I think that's really sort of in terms of future design, you know, where are we going to go in, in terms of where is the NRG, GOG partners going to do their next trial and upfront treatment or in terms of recurrent treatment? And what is your, your view on immunotherapy with linbatinib and pembolizumab after treatment in the upfront setting? Yeah. I mean, sequencing, I think is important. But as we learn from, from Ruby and we may learn from further from 018 as it matures more that that combination immunotherapy, chemotherapy seems to be critical. You know, could you just sequence it with chemotherapy followed by limbatinib pembolizumab? I don't know the answer to that at this point. What's the future? I think probably better immunotherapy agents trying to overcome the T cell exhaustion that we see adding in combination immunotherapies. You know, I think we're still behind our colleagues within melanoma and other areas of, of, of immunobiology to understand how best to treat these patients long-term. We're still, you know, we, we, we still have starting to see this cure word coming up for endometrial cancer. So it's very exciting. But I think that's still few and far between, and we need to capitalize on this, these good data and hopefully make it better and more sustainable to really lead to more cures. Yeah. It has been remarkable in terms of the change, any further testing or, or molecular markers that might be good indicators as to who would respond and who wouldn't respond. And obviously there's some differences, regional differences in terms of response to immunotherapy. Do you want to comment on that? Yeah. I don't think we know the whole story. I think there may, diabetes may play a role. Western diet may play a role. We, we see less efficacy in our Asian patients for some reason, or patients treated in Asia, I should say. So we're, you know, I think again, more, more unanswered questions that have come out of all the data that's come out recently. And as you point out, really a role for biomarkers and hopefully we'll learn who best to target these new therapies. And thankfully the toxicity is quite manageable. So, you know, I think the you know, other than financial toxicity, which is certainly a problem in general, I think we patients tolerate this new therapy quite well. Well, thanks Matt. It's been great chatting with you. Any, any other issues that you want to talk about? No, I think, you know, the importance of clinical trials is always needs to be highlighted. I think we don't make progress without patients and their families committing to clinical trials. And thanks to all the investigators around the world that made this happen. Well, thanks Matt. That was very helpful. Have a great day.

Matt Powell

NRG Corpus Committee

Ruby trial

metastatic endometrial cancer treatment

immunotherapy