Combination IO Strategies in Advanced Endometrial Cancer: RUBY and GY018


Expert perspectives on the RUBY and GY018 trials, which tested dostarlimab and pembrolizumab, respectively, in combination with chemotherapy in patients with advanced or recurrent endometrial cancer.


Ritu Salani, MD, MBA: Hello, and welcome to this Targeted Oncology™ program on recent updates in gynecologic cancers. I’m Ritu Salani, a gynecologic oncologist from UCLA in Los Angeles, California. I’m looking forward to discussing recent updates in endometrial cancer. Let’s get started.

This has been an exciting time [for] the treatment [of] endometrial cancer. Endometrial cancer incidence and mortality have both been increasing. This is due to multiple factors, such as the population living longer and also…a higher rate of high-risk histologies. This is the first time we’ve had multiple studies that have been positive, targeting endometrial cancer, and [they] are going to change the landscape. This year at SGO [Society of Gynecologic Oncology], ASCO [American Society of Clinical Oncology], and ESMO [European Society for Medical Oncology], we heard a lot of practice-changing abstracts, and I’m excited to discuss them with you today.

The first study I’m going to talk about is [the phase 3 RUBY trial (NCT03981796) investigating] dostarlimab for primary advanced or recurrent endometrial cancer. This was presented first at ESMO, then SGO, and published in The New England Journal of Medicinesimultaneously. This study was looking at the role of chemotherapy with carboplatin and paclitaxel, with or without the addition of dostarlimab, followed by dostarlimab maintenance. Dostarlimab maintenance was given for up to 3 years in these patients. The patient population for the study was predominantly patients with measurable stage III disease, stage IV disease, or recurrent endometrial cancer, who could have received prior chemotherapy, but there had to be at least a 6-month interval [of] disease. The study also allowed for different histologies, including high-risk histologies with about 10% of carcinosarcoma cases, and then additional serous/clear cell cases as well as classic endometrioid histologies. The study looked at patients with mismatch repair deficiency first, and then the intention-to-treat group, which also included the mismatch repair deficient population.

This study noted a significant benefit in those patients with mismatch repair deficiency, as well as a significant benefit in progression-free survival in those with mismatch repair proficient tumors. Although the overall survival [rate] was not positive for the patients with mismatch repair proficient, it still made a significant impact. The study was exciting, and we’re looking forward to the FDA’s approval, at least in the mismatch repair deficient population. We’ll see how the mismatch repair proficient population plays out. At ASCO this year, we saw 2 additional presentations on this trial… These 2 studies looked at the BICR or blind independent central review outcomes of the RUBY trial. This is important because we know there can be subjective bias when evaluating patients, [such as] wanting to keep patients on trial longer when they’re getting, potentially, the study drug. Doing an independent review can add to the confirmatory data or results. It’s also important to recognize there may be some differences because physicians or clinicians may see clinical progression, which may not be apparent on radiographic review. This is a nice complement to the study. The BICR study on dostarlimab was presented by Dr Matthew Powell and showed that the BICR and the physician-[assessed] progression were consistent, so there was a good concordance rate between the two. This highlights the impact of dostarlimab’s addition to chemotherapy and maintenance in the setting. The other study that was really important highlighted some additional outcomes in the RUBY trial, where the patients reported outcomes. This was presented by Dr Mansoor Mirza, and it looked at patients’ reported outcomes in both populations. The highlight is that patients who [were in] the dostarlimab arm actually had better outcomes and did well. This is important and highlights data that we had seen before with other chemotherapy regimens and immunotherapy. It really shows that not only is this treatment better in survival outcomes, but [it] also has improved in patient-reported outcomes, which are both important metrics. In my opinion, these 2 studies will continue to impact the approval for dostarlimab in the setting, and I look forward to using this regimen as soon as possible in my patients who meet these criteria.

The next study that is changing the landscape is a similar study. It’s pembrolizumab versus placebo in addition to carboplatin and paclitaxel for measurable stage III, stage IVa, stage IVb or recurrent endometrial cancer. This is a phase 3 NRG-GY018 [NCT03914612] study that was presented by Dr Ramez Eskander at SGO this past year.

This study looked at the addition of pembrolizumab to chemotherapy followed by maintenance for 2 years. This is a bit different than the RUBY study, which looked at dostarlimab maintenance for 3 years. The study also looked at 2 different cohorts. They looked at mismatch repair proficient cohort and a mismatch repair deficient cohort. Both were powered for PFS [progression-free survival] as the primary end point. When this study was presented and published in The New England Journal of Medicine, there was a lot of excitement. Once again, it highlighted the same findings of the dostarlimab study. But, because it was a bit different, we see that PFS benefit in both the mismatch repair deficient population, which is impressive, and then a better statistical benefit in the mismatch repair proficient population as well. The follow-up on the study has not been as long as we kind of wait for this [data] to continue to mature, but it did meet its primary end point and is a positive study. Both the RUBY trial and the GY018 trial are going to inform practice and change the landscape, moving immunotherapy into that frontline systemic therapy place.

Transcript edited for clarity.

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