番茄社区

The conversation at the Society of Gynecologic Oncology (SGO) annual meeting was dominated by the two randomized phase III trials that showed improved progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer treated with immunotherapy. But now the conversation turns to the practice. How do you select a frontline treatment for your patients?

番茄社区 brought together three expert leaders in the field. Moderator , chief of the division of gynecologic oncology at Dana-Farber Cancer Institute in Boston is joined by , a gynecologic oncologist at Stephenson Cancer Center at the University of Oklahoma in Oklahoma City, and , a gynecologic oncologist at the University of California Irvine, for a virtual roundtable discussion. This second of four exclusive episodes concludes a two-part discussion about the and trials.

Following is a transcript of their remarks:

Matulonis: Hello, everyone. My name is Ursula Matulonis. I'm a medical oncologist from Dana-Farber Cancer Institute in Boston, Massachusetts. And I have the privilege and honor of being here today with two of my wonderful colleagues, Dr. Kathleen Moore from the University of Oklahoma, and Dr. Krish Tewari from the University of California Irvine. And we're going to be talking about updates that were presented at the Society of Gynecologic Oncology 2023 annual meeting that just took place in Tampa, Florida.

I'm gonna start now with you, Krish, on this question. And really again, helping clinicians out there whose patient comes in with advanced endometrial serous cancer, maybe a uterine carcinosarcoma, clearly mismatched repair-proficient. IHC [immunohistochemistry] on the mismatch-repair proteins are all normal. When would you consider carboplatin-paclitaxel IO [immunotherapy]?

Tewari: Well, if they're mismatch repair [MMR]-proficient, it's really going to depend on the label at that point, what kind of label we get. But what's nice about RUBY was it did enroll carcinosarcomas. So we do have some guidance there, but now you're throwing in this thing that the patient's mismatch repair-proficient.

So I don't know what to do with that patient. Hopefully we'll get an all-comers label for this because otherwise we're kind of stuck in another situation where, like with Katie's SOLO-1 study -- phenomenal results, but only applies to a relatively small proportion of the patients, those that have BRCA-mutated tumors. So I'm just hoping the MMR proficient cohort in NRG-GY018 shows a sustained PFS benefit to be able to get those patients a label.

But yeah, I don't know when I would use chemo plus IO. I guess I'd do it according to the label if the label allows me to do that for the mismatch repair-proficient. But fortunately, like I said, RUBY did enroll carcinosarcoma of the uterus, which was good.

Matulonis: Yeah, thanks. And then Katie, I think the role of pembrolizumab [pembro; Keytruda], lenvatinib [len; Lenvima] versus [carboplatin/paclitaxel/IO], comment on how you would choose regimens now for patients? Again, I think the mismatch repair-deficient patients, I think the results there're pretty impressive. It's really the mismatch repair-proficient patients where I think there's going to be a question. And I think now we've got a choice potentially of [carboplatin/paclitaxel/IO] versus pembro/lenvatinib. So what are your thoughts about approaching those patients?

Moore: I think we're on the cusp. I'm actually writing a trial proposal right now for this, I'm excited. I think we're on the cusp of actually doing a lot better by these patients. So this is the first step. So mismatch repair-deficient, I agree with you, again, I'm gonna go back to SOLO-1. It's great, except for the 55% of patients who recurred. Why? 24% recurred on PARP [inhibition] with BRCA, why?

You see the same thing on both these studies in mismatch repair-deficient, you have a fraction that are progressing on IO. So I want to know who they are, first of all. It seems like they all got through chemo about the same, and then there was some that progressed. So I think that group may need [lenvatinib/paclitaxel] as one example, but I don't know, maybe they need something else. Maybe they need ipi/nivo [ipilimumab (Yervoy)/nivolumab (Opdivo)]. I don't know. They need something other than just pembro or just dostarlimab [Jemperli]. Because they're recurring. So that's my first question. I think we need to look at who they are and if there's some clinical or molecular signature that tells us who they are.

Mismatch repair-proficient is an even more exciting opportunity. You're going to have your serous. Well, I'm testing them all for HER2, as are you. We have a clinical trial running for that in the NRG-GY026, that's led by our colleague Dr. Britt Erickson testing addition of trastuzumab. That's a very important study.

There are other studies in the wings with the new ADCs [antibody-drug conjugates]. It is an exciting time for that group of patients. An incredibly aggressive poor prognostic biomarker that disproportionately affects women of color. And I think we're about to have some really killer regimens in trials for them.

Now, is it better than IO? I'm going to guess it is. I'm gonna tell you if you want me to guess I'm going to say it is. But we'll see. Those trials are going to run. That's exciting.

UPSC [uterine papillary serous carcinoma] or grade three, HER2 zero -- well I guess negative for now, but zero once the ADCs are in play -- are you TP53? And then the role of BEV [bevacizumab (Avastin)]? BEV versus IO versus BEV+IO? I mean, I think there's a real role there for these patients. We're not curing these patients with pembro. We're doing a little better. So can we notch that up?

And then there's a group of patients who are mismatch repair-proficient who are non-significant mutation profile. And there I think it's wide open. There's endocrine therapies, there's a lot of things that have some preclinical work with IO, some not. We gotta do some work there.

So I think it's gonna get real niche here. Where we're very much individualizing, the four TCGA [The Cancer Genome Atlas] groups and are going to become however many. A lot. And it's going to be a real niche based on biomarkers or lack thereof. And I think patients are gonna do better. So that's why I'm already thinking about it. I'm kind of just real excited to get some new studies open to test these ideas and other people's good ideas. So this is the new foundation for us. This is the new foundation to do better.

Matulonis: Yeah, totally agree. It's really quite exciting. Alright, so I'm going to wrap up the discussion on GY018 and RUBY. Krish, do you have any final thoughts about these two trials? Anything else you want to mention?

Tewari: Yeah, I think in relation to the lenvatinib/pembrolizumab question, if we get an all-comers label for chemo plus IO, including the mismatch repair-proficient patients, I think ultimately lenvatinib is gonna go away unless LEAP001 is positive. There's no head-to-head of the LEAP001 investigational regimen versus chemo plus IO. But if it is positive, it would potentially provide a non-chemo alternative in the first line advanced disease. That's if chemo plus IO gets an all-comers label. If it doesn't, then pembrolizumab plus lenvatinib will survive.

But like Katie, I'm very excited about the future. I think the new ADCs that are specific for endometrial cancer are very interesting. And I also think we need to revisit the whole PI3k AKT mTOR pathway because we had several studies with the mTOR class inhibitors several years ago, but we never went anywhere with them. And now that we have PI3k inhibitors I think that's a potential area where we can make some inroads in certain populations. So I'm also excited about the future.

Matulonis: Yeah, I agree. Katie, any last thoughts about these two trials?

Moore: No, I mean, I'm really proud of Drs. Mirza and Eskander and all the trial sites and pharma for caring about endometrial cancer. It was a great day. It harkens back to '18 and '19, when we actually finally did something in ovary for the first time in decades. So I think this is really gonna launch really smart trial designs moving forward for endometrial. So it was a great day.

They're different studies. We didn't get to talk about one of your questions around, I think Krish brought it up, how broadly do you apply this? Like, is it gonna creep into the node positive? And there are studies running, but they're not going to result for a long time. People are going to want to extrapolate early. So it's hard to deny your patients something that could be lifesaving.

Matulonis: Exactly. I mean, one of my thoughts was about, and this has come up already about patients who are stage three but fully resected, have no disease on CT or PET. And I think I would, especially if they're mismatched repaired-deficient, add an IO to those patients. But I don't know, would you guys think about doing that?

Moore: Yeah. You know, you even brought that up. We're going to keep talking about endometrial. Because I mean, really we should just be talking about endometrial for an hour.

Do you know what I've been thinking about? And again, just all goes back to PARP, but it just does. So Michael Friedlander, who's our good friend, made this point at ESMO [European Society for Medical Oncology] last year and it just stuck in my brain, that he's worried about neoadjuvant chemo and BRCA-mutated ovary. That maybe in some mutations by starting with all that disease and giving chemo, you're inducing resistance mechanisms a lot earlier because you have this strong driver. And he said that, and I was like, damn that's possibly true. And that makes me maybe want to debulk those patients even in places that don't debulk anymore. But how do you know it quick enough? How do you get the bracket quick enough? We heard that from Shannon's talk.

Same thing here. Now in stage four, recurrence is a little harder, but in stage four de novo, there's a lot of equipoise around side reduction. Some places do it, some people say, well chemotherapy doesn't work that well, your PFS is really less than a year, and so the risk-benefit, you know, they're not doing it.

But these results, if I knew someone was mismatch repair-deficient, which I should know on the individual biopsy, does that change my behavior surgically for that patient? Like, are you really gonna try and tee that patient up to have the longest disease-free survival possible by doing a cyber reduction, even in the setting of positive lung mets [metastasis] let's just say. I'm just making stuff up, but it does change how I'm thinking about these patients now that I've seen the potential in an otherwise incurable patient, in that biomarker selected group to really try and push the envelope.

So it comes to fully resected nodes to fully resected stage four, I mean, I'm just really rethinking the endometrial paradigm and a lot of it will be hard to prove with data, but that hasn't stopped us doing stuff before.

But I'm just really excited to be rethinking about long-term, let's talk about long-term survival. Let's talk about cure in these patients. We need to rethink the whole paradigm for them, I think.

Matulonis: Yeah. Really cool stuff. I agree.

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