Clinical Trials of Immunotherapies in Endometrial Cancer

Christian Marth, MD, PhD, and Bradley J. Monk, MD, FACS, FACOG, discuss data from the NRG GY018 and RUBY trials regarding the use of immunotherapies for the treatment of endometrial cancer.


Christian Marth, MD, PhD: We are really moving forward now. It’s a fascinating time because remember in earlier days, we had only, as you said, a little bit of chemotherapy and a little bit of progestins. Now we are in the era of immunotherapy. When we go back to the last meeting of the Society of Gynecologic Oncology there are really game-changing trials being presented. I would like to mention first NRG-GYO18 [NCT03914612].

Bradley J. Monk, MD, FACS, FACOG: Thank you.

Christian Marth, MD, PhD: I’d like to ask the question, could we improve the outcome of chemotherapy by adding immune-agent pembrolizumab [Keytruda]? And to answer this question, a patient with stage III or stage IVa immeasurable disease, stage IVb, or patients with recurrent disease have been enrolled. They had to be chemotherapy-naive. Only adjuvant therapy has been acceptable. However, the recurrence had to be at least 12 months or later. [And] 816 patients have been enrolled in this trial. It’s really fantastic and randomized. And in this study, 26% of the patients were mismatch repair deficient as we expected. It was surprising to me that 80% of the patients had endometrioid histology. And this clearly indicates that not only the bad histologists recurring but also suggested good ones. That’s the majority in this trial. And the patients have been randomized to standard chemotherapy, carboplatin-Taxol [paclitaxel] 6 cycles, or the addition of pembrolizumab. And after completion of chemotherapy, additional 14 maintenance cycles of pembrolizumab was given. So, in total, approximately 2 years of treatment. The results were really fantastic. The design of the trial allowed mismatch repair efficiency as a stratification factor. So it was really 2 trials that can be analyzed and that makes it very powerful. And in the mismatch repair deficient group, a hazard ratio of 0.3 has been observed. I don’t remember something else in endometrial carcinoma.

Bradley J. Monk, MD, FACS, FACOG: Ever?

Christian Marth, MD, PhD: Ever. Yes. The median progression-free survival has increased from 7.6 to not reached. And when we look at the curves, in the mismatch repair deficient, pembrolizumab, it’s really flattening. It’s not going down. No events in the later phase. So this really let us dream that we might also cure some patients in the recurrent situation. That’s a really new, new situation for us. But also in the mismatch repair proficient patients, the analysis was positive with a hazard ratio of 0.57. Here, the median progression-free survival was increased from 8.7 to 11.7 months. So still meaningful.

Bradley J. Monk, MD, FACS, FACOG: I think so.

Christian Marth, MD, PhD: It’s a meaningful increase. We can say nowadays, it’s obvious that for the mismatch repair deficient patients, this is a new standard chemotherapy plus checkpoint inhibitor that has to be given to all patients. For the mismatch repair proficient patient, I think we need some more data. Maybe we should look also at the molecular analysis to understand who are the patients who have benefited and who might not have benefited from the treatment. But still, a hazard ratio of 0.57 is meaningful, and I think we should consider also for those patients the combination with pembrolizumab. But I think there was another trial.

Bradley J. Monk, MD, FACS, FACOG: You think? He knows. So that’s great. That was a wonderful summary by the way. Very articulate. I have the pleasure of being the Vice President of the GOG [Gynecologic Oncology Group] Foundation and on the board. What the GOG Foundation does as a nonprofit is they do trials funded by the National Institutes of Health, NCI, and that’s what [NRG-]GY018 was, funded by the government. We also, and I’m the codirector of GOG Partners, still part of the foundation, which does pharma trials. So we did a complementary study, and the beauty of these is that they have very similar results, and because they have similar results it sort of adds confidence to just what you said. It was not a fluke because we have 2 complementary studies, but there are subtle differences. The pharma-sponsored trial is called RUBY [NCT03981796]. The medication used is dostarlimab [Jemperli]. There are some other subtle differences. This trial included carcinoma sarcomas, and [NRG-]GY018 did not. Although the duration of immunotherapy in RUBY was 3 years, 2 years is enough, or is probably enough.

Christian Marth, MD, PhD: Yes.

Bradley J. Monk, MD, FACS, FACOG: The other thing that’s interesting about [NRG-]GY018 is crossover was allowed. Crossover was allowed because it was mostly a US study. And I told you that when patients recur, there are immune therapies available either in the dMMR [deficient mismatch repair], dostarlimab, pembrolizumab; or pMMR [proficient mismatch repair], pembrolizumab, lenvatinib. So we sort of had to unblind the patients. But in RUBY there was not, because the European Network contributed substantially to this. It was a GOG and ENGOT [the European Network of Gynaecological Oncological Trial] collaboration. So they’re very different trials. The follow-up is also longer in RUBY, almost 2 years, and there will be a very analytic, appropriately powered survival assessment of RUBY. Now both of these papers were presented at the Society of Gynecologic Oncology on March 27th, 2023, and simultaneously published in the New England Journal of Medicine. Ramez Eskander [MD, University of California, San Diego] is [NRG-]GY018. Mansoor Mirza [MD, Copenhagen University Hospital] is RUBY. I encourage you to read those. They’re very well-written papers and they’re practice changing. The last comment about RUBY is, although [NRG-]GY018 was 2 separate studies in one, RUBY was fewer patients, it was 494. [NRG-]GY018 had over 800. So, what we did was, is we did the dMMR as an analytic cohort and, if that was positive, pivoted to the intent-to-treat analysis. So the pMMR subset, although very relevant, and you talked about it, is not technically analytic, but it is informative, and the results of RUBY are very similar. So, you said, I think, 0.30 in the dMMR, it was 0.28. It’s the same.

Christian Marth, MD, PhD: It’s the same.

Bradley J. Monk, MD, FACS, FACOG: And you said in the control arm it was 7.6 months, in RUBY it was 7.7. So the control arms are the same. They were about the same types of patients with advanced and recurrent endometrial cancer. The pMMR, the hazard ratio was higher at 0.76, but it’s a more mature result. Confidence intervals overlap. Again, it’s 2 studies that confirm that even in the non-dMMR patient that is the pMMR, there’s a benefit of what I call triplet therapy. Now RUBY has been filed as I look at the CHMP [Committee for Medicinal Products for Human Use] website for approval initially in the dMMR, is that true?

Christian Marth, MD, PhD: That’s true. Yes.

Bradley J. Monk, MD, FACS, FACOG: Exciting. [Is there] any timeline for getting this available in Europe?

Christian Marth, MD, PhD: They hope at the end of the year it could be available. Yes.

Bradley J. Monk, MD, FACS, FACOG: That’s great.

Christian Marth, MD, PhD: Yes, it’s great.

Bradley J. Monk, MD, FACS, FACOG: Then I think what we’re waiting for in the pMMR subset for RUBY is we’re waiting for the maturity of the survival. The survival data preliminarily are looking very good. In the pMMR subset, the survival hazard ratio, again preliminarily, was 0.73. So it was going and tracking in the right direction not quite mature, but the New England Journal of Medicine required they say what it is. They’re also for [NRG-]GY018. There is a look at overall survival, but it wasn’t analytic but it will continue to be followed.

Transcript edited for clarity.

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