A Deep Dive Into Two Randomized Trials in Endometrial Cancer

Immunotherapy combined with standard chemotherapy significantly improved progression-free survival in patients with advanced or recurrent endometrial cancer, according to results from two randomized phase III trials presented at the Society of Gynecologic Oncology (SGO) annual meeting.

MedPage Today brought together three expert leaders in the field: moderator Ursula A. Matulonis, MD, chief of the division of gynecologic oncology at Dana-Farber Cancer Institute in Boston is joined by Kathleen Moore, MD, a gynecologic oncologist at Stephenson Cancer Center at the University of Oklahoma in Oklahoma City, and Krishnansu S. Tewari, MD, a gynecologic oncologist at the University of California Irvine, for a virtual roundtable discussion. This first of four exclusive episodes begins a discussion about the NRG-GY018 and RUBY 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. And a lot of really great abstracts were presented, and certainly practice-changing data was presented.

So I’m going to start right into really the truly very exciting set of abstracts that were presented, GY018 and the RUBY study, and I’m going to start with Dr. Moore and ask you, Dr. Moore, what were your impressions of the data? And I think it would just be good to hear your concise feelings. And then I’m going to turn it over to Dr. Tewari.

Moore: Well, thanks, and it’s my pleasure to be here. I think impressions of the data were outstanding. This is one of the trials, there’s three studies in the frontline, metastatic, or recurrent space incorporating immunotherapy. So we heard two of them at this meeting. RUBY being the one that reported out first. And really outstanding, it heralds a new era for how we approach the treatment of women with recurrent or metastatic disease.

I think the day after the meeting, the new standard of care for mismatch repair-deficient [disease] is inclusive of IO [immuno-oncology]. And I know I went home and was adding it in. It reminds me of SOLO-1, where you’re trying to catch people up. Because it does look to me — and I think we’ll talk about 018 as well — it does look to me like we probably cured some patients in that population, or at least with 2 years of follow-up in RUBY, which is a pretty good amount of time in that high-risk population. At least we have markedly prolonged disease-free survival.

And so I think that’s impressive and really should be the standard of care starting yesterday. I think the data in the all-comer group was mostly driven by that. I’m just going to be honest, the subset analysis from RUBY, and this is where it differs from 018, was the mismatch repair-proficient, so it wasn’t fully analytic. But it did have a clinically significant benefit that I think warrants consideration of use of IO in this population.

But I think it also throws the gauntlet down for what we’re going to do next and how we’re going to improve upon that, because that population benefited. But clearly I think we can agree not as much. So that group for me was a win, but not a home run, and we need to do better.

Matulonis: Yeah. Krish, thoughts?

Tewari: Yeah, I agree with everything. You know, the presentation of both of those papers was stunning. They’re different studies and I thought RUBY was a little more fleshed out. We had some OS [overall survival] analysis, we had quality of life, we even had the objective response rates. We didn’t have any of that with the GY018 study. But I think that they’re both very compelling papers.

The follow-up for GY018, specifically for the nested cohort for the mismatch repair-proficient patients, is pretty short, relatively short. So I think we need some more follow-up on that to see if that signal that they demonstrated is real. But definitely for the mismatch repair-deficient populations, I think both studies are a home run.

I think they’re complementary studies also, with NRG-018, we could potentially answer the mismatch repair-proficient question, with RUBY we can answer the OS question, because that’s one of the dual endpoints, primary endpoints for that study. So I hope they go together and change practice for all patients.

Matulonis: Yeah, no, I don’t disagree either. I think the mismatch repair-deficient results were really quite impressive. So I think, for the clinician, so the meeting happens, the data get presented and for those patients who are mismatch repair-deficient, sounds like we’re all going to use this. And I think we can talk more about the proficient patients, and I think Katie kind of alluded to, you said something, but maybe 2 years of IO?

So I think the question’s going to be in the real world as we’re incorporating this now into our practice, the two questions come up are 2 years versus 3 years, and then are pembrolizumab [Keytruda] and dostarlimab [Jemperli] interchangeable? Katie, do you want to start?

Moore: Sure. Sorry, I have a little friendly tussle underneath my desk with these dogs. It’s about to storm here in Oklahoma City, so I had to bring them all in. So they’re kind of like, ah!

So, 2 years versus 3. Isn’t this the same conversation we had with PARP inhibitors? It’s like I’m reliving SOLO-1 when everything came out — 2 years or 3 years, right? BRCA, 100%. Everyone else, well there’s still equipoise. I mean, it’s like a same discussion, just a substitute checkpoint inhibitor.

So I don’t know the answer at this point, you know? As you know better than I do, as a medical oncologist, that checkpoint inhibitors have been used in biomarker-positive colorectal cancer and predominantly in others for many, many years. And when they did those studies where they had patients treating forever, then they said, you know what, 2 years, we’re going to stop, and you saw who was cured. And so I think that sort of led to this idea that you could get to 2 years. Now, where did that come from? It’s kinda like SOLO-1, where did 2 years come from, we kind of made it up.

But, I’m really interested. I never thought I’d say this cause I’ve always been all for kind of throwing everything at patients, because I want to keep them alive as we all do for as long as possible and not compromise cure. But going back to PARP, I really believe you stop in the frontline, because I think you could harm people with continuing on.

Checkpoint inhibitors, we just don’t know yet because the patients that have benefited from checkpoint inhibitors for endometrial cancer, even for cervical cancer thus far, have been largely in the recurrent setting where there is no chance of cure. We just have to be honest. And so you’re just so happy that they have a partial response and you hold that for as long as you can. There’s really not been this consideration of like, oh, I’m gonna stop this therapy in you.

Frontline, I think it’s a different game here. Two versus three is going to be tough for me though, in a stage IV mismatch repair-deficient woman who’s got a complete response, 2 versus 3 years. I think I’m going to just have to make decisions as we go. Fortunately, we have a little time to learn. I think we’ll start to get some more data from these studies in follow-up, longer follow-up. Krish alluded to the follow-up in 018 is only 7 months in the proficient group.

So I’m hopeful we’ll get some more, but I don’t have an answer for you today. If you asked me today, I’m probably going to go 3 [years] because I’m nervous, but I said that about PARP initially and I’ve backed, I pivoted, because I’ve learned, so right now I’m going say three, but I may pivot later.

Matulonis: Okay. And then, Katie, pembrolizumab or dostarlimab?

Moore: I’ve used both. As have you. And I don’t have a sense that they are different in efficacy or safety in my personal opinion. And so I think it’s going to come down to institutional formularies and cost. And I’ve already seen some circulating pathways just recently where the institution has made the decision for them, it’s been made. What they’re going to use within the last week. So I think that’s what it’s going to come down to, but I don’t think there’s a difference in my opinion in terms of efficacy or quality of the agent.

Matulonis: Gotcha. And Krish, what do you think?

Tewari: Yeah, so first taking that question 2 versus 3 years, I agree with Katie. If I have a stage IV patient that’s had a complete response, I’m going to be very concerned about turning the checkpoint off because historically those patients are just not curable. Now, if it’s a stage III patient by virtue of positive nodes, I’ve had those patients cured before, either with chemo alone or chemo plus radiotherapy. And if such a patient has a complete response and their scans are negative and they’re asymptomatic, I may actually consider stopping checkpoint after 2 years. But not for the stage IV [patients]. And then certainly anyone who’s had a response, but they have stable disease where you can still see it, I’ll never turn the checkpoint off as long as they’re tolerating it.

I mean, I have a perfect example. I have a patient that is on pembrolizumab and she’s been on it for 4 years. She wasn’t on a study or anything, it was just used as a second-line agent for her as a monotherapy. And every time I scan her, I can see her disease. It’s small, it’s not bothering her, but the checkpoint isn’t bothering her either, so I’m not stopping it because she’s got stable measurable disease that’s persistent. And so I don’t want to stop that. But I think for the stage IV’s, I’d be very concerned with stopping it.

As far as are they the same? I think so. The studies, whether we’re looking at GARNET or RUBY versus the pembrolizumab KEYNOTE studies or the NRG-GY018, they seem to behave similarly. I mean we haven’t had the equivalent study done in localized rectal cancer that we had with dostarlimab last year that was presented at ASCO [American Society of Clinical Oncology], which was just unbelievable and apparently longer-term follow-up on those patients and more patients accrued or the results have been sustained. But I still think the two drugs are pretty interchangeable. Maybe not interchangeable, but I think one’s not better than the other.

Matulonis: Yeah. Thanks.