番茄社区

Results from two phase III trials -- NRG-GY018 and RUBY -- presented earlier this year at the Society of Gynecologic Oncology (SGO) annual meeting demonstrated that immunotherapy combined with standard chemotherapy significantly improved progression-free survival (PFS) in patients with advanced or recurrent endometrial cancer.

Some poster updates on the findings were presented at the recent International Gynecologic Cancer Society (IGCS) annual meeting, and attendees are still buzzing about how these results will change the future of treatment for their patients, along with the implications for second-line care.

番茄社区 brought together three expert leaders in the field -- moderator Susana Campos, MD, from the Dana-Farber Cancer Institute in Boston, is joined by Richard Penson, MBBS, of Mass General Cancer Center at Massachusetts General Hospital in Boston, and Elizabeth K. Lee, MD, also from the Dana-Farber Cancer Institute -- for a virtual roundtable discussion. This first of four exclusive episodes focuses on the clinical implications of both of these studies.

Following is a transcript of their remarks:

Campos: Hi, good evening. My name is Dr. Susana Campos. I'm a medical oncologist at Dana-Farber Cancer Institute, and I'm joined today by colleagues Richard Penson and Elizabeth Lee. And we are going to take a walk through memory lane on what happened in the last year in terms of SGO, ASCO [the American Society of Clinical Oncology annual meeting], ESMO [the European Society for Medical Oncology annual meeting], and the IGCS. So I'll allow my colleagues to introduce themselves. Dr. Penson?

Penson: Hi, Richard Penson. I'm like Sue, a medical oncologist over at Mass General in Boston, and it is fabulous to be with you today.

Campos: Dr. Lee?

Lee: Hi everyone, I'm Dr. Lee. I'm another one of the medical oncologists, I work at Dana-Farber Cancer Institute.

Campos: Thank you so much for joining us. And I thought today we'd go and start with uterine cancer because 2023 really has been the year of endometrial cancer, with some specific trials like the NRG-018, the RUBY-1, the DUO-E study. So I thought perhaps we talk a little bit about just a synopsis of the NRG and the RUBY-1 data. Richard, would you like to review that with us very briefly?

Penson: Sure. These were essentially two very similar studies and they were almost identical in construct. There are a few differences. For example, the RUBY trial included a cohort of patients with carcinosarcoma, which is fabulous, but standard treatment for advanced or recurrent endometrial cancer. Subsequently being able to look at the subsets, which really has come out as useful data and taking standard treatment with paclitaxel/carboplatin and adding to it immunotherapy. G018 was the pembrolizumab [Keytruda] study and the RUBY study they used dostarlimab [Jemperli]. And so they reported really fabulous things presented at SGO. The paper's being published at the same time in the New England Journal of Medicine.

There's an Ingelfinger rule, if these are practice changing, when they pass the editor of the New England Journal of Medicine, they should come straight out in publication and they did, with an overall survival advantage reported for dostarlimab.

And the exciting thing was that that group, the deficient mismatch repair group, got approval for the concurrent immunotherapy with chemotherapy later in the year. So, really exciting times.

Campos: More recent data presented at ESMO and IGCS were some very interesting data on the NRG-018. And we've speculated on this, and I don't know if there is a correct answer or a concrete answer, but that trial looked to see whether or not there were any differences between patients with a deficiency in MMR, either they were methylated or not methylated. And what is your take on that? What did you think about some of that data?

Penson: So essentially the mechanism, whether it was direct mutation or epigenetic, did not seem to be prognostically or predictively important. There were some curious things. So for example, no methylation did seem to look better in the pembrolizumab/chemotherapy group, which is a bit sort of curious. But it was really interesting and it sort of speaks to our broader understanding of things and the complexity.

So whether or not you have microsatellite instability, whether or not you have a high copy number or a p53 mutation, it's not as simple as for groups -- POLE, microsatellite instability-high, p53-mutation driven, and hormonally responsive or copy number low. It's going to get more complicated than that.

Campos: But it's interesting just the same because in the RUBY data, when that was updated and they looked at molecular subgroups, it was very interesting to see what the p53 did. And then the POLE data, basically it was only 1.25%. Of course, they all did very well with the use of the IO [immunotherapy] therapy. So did of course MSI [microsatellite instability]-high or deficient, but the p53 was actually quite striking. And take a moment on that. What are your thoughts on the p53 subgroup analysis?

Penson: Yeah, so the curves are just amazing. So that first group, POLE, most patients, it's a relatively big group in patients who present but rarely with a recurrence because your immune system sees all this hypermutated tumor and it can eradicate it without any therapy. And so that line was flat, the PFS, they did not have recurrences, which is just amazing with immunotherapy, with either groups.

The p53 was a standout because the hazard ratio for the group you expect to do well, the deficient mismatch repair, 0.31, but 0.55, a really impressive hazard ratio in the p53-mutant.

What was also interesting was that with the hazard ratio of 0.77, the hormonally driven, the normal copy number group, that PFS was 50% better, went up from 20% to 31%. That's pretty impressive change. And so there's this intention-to-treat benefit that we are excited about, but a differential benefit in the subgroups.

Campos: Definitely.

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