The addition of a checkpoint inhibitor to standard chemotherapy as first-line treatment of advanced or recurrent endometrial cancer not only reduced the risk of disease progression but improved overall survival, particularly for the mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) population, according to late-breaking abstracts presented at the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer.
A statistically significant and clinically relevant overall survival benefit emerged in the ENGOT-EN6-NSGO/GOG-3031/RUBY trial. The addition of the PD-1 blocker dostarlimab-gxly to carboplatin/paclitaxel yielded a 31% reduction in the risk of death in the overall population and an “unprecedented” 68% reduction in the risk of death in patients with dMMR/MSI-H disease, RUBY investigators reported.1
Matthew A. Powell, MD
“These data confirm dostarlimab plus carboplatin/paclitaxel as a new standard of care for patients with primary advanced or recurrent endometrial cancer, regardless of mismatch repair status,” said Matthew A. Powell, MD, Professor of Obstetrics and Gynecology and Chief, Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis. The regimen was approved by the U.S. Food and Drug Administration in July 2023 for advanced or recurrent dMMR/MSI-H endometrial cancer, based upon the benefit shown in the first interim analysis.2 Dr. Powell presented updated overall survival data, with 51.2% data maturity.
RUBY: Overall Survival Benefit
RUBY Part 1 included 494 patients with advanced or recurrent endometrial cancer, approximately one-quarter of whom had dMMR/MSI-H disease. Patients were randomly assigned to receive dostarlimab at 500 mg plus chemotherapy or placebo plus chemotherapy for six cycles followed by dostarlimab at 1,000 mg or placebo every 6 weeks for up to 3 years.
At nearly 37 months’ median follow-up, in the overall intent-to-treat population, dostarlimab plus chemotherapy resulted in a 31% reduced risk for death compared with chemotherapy (hazard ratio [HR] = 0.69; P = .002). Median overall survival was 44.6 months with dostarlimab compared with 28.2 months without, representing a 16.4-month improvement; the 3-year overall survival rates were 54.9% vs 42.9%, respectively.
“The improvement in overall survival was seen despite the fact that 38% of patients in the control arm went on to receive immunotherapy,” Dr. Powell noted.
In the dMMR/MSI-H population (with 39.8% maturity), median overall survival was not reached with dostarlimab plus chemotherapy and was 31.4 months with chemotherapy alone; the 3-year overall survival rate was 78% vs 46%, respectively (HR = 0.32; P = .0002). Patients with MMR-proficient/microsatellite-stable (pMMR/MSS) disease also experienced a “clinically meaningful” 7-month improvement in median overall survival, based on medians of 34 and 27 months, respectively (HR = 0.79; P = .0493), Dr. Powell reported. “Consistent overall survival benefit was seen across most exploratory subgroups,” he added.
No new safety signals were noted, and there were no new deaths related to therapy with the additional follow-up.
ENGOT-EN6-NSGO/GOG-3031/RUBY Part 2
In a separate presentation,3 Mansoor Raza Mirza, MD, Chief Oncologist at Rigshospitalet, Copenhagen University Hospital, Denmark, reported that RUBY Part 2 also met its primary endpoint. There was a significant and clinically meaningful improvement in progression-free survival with dostarlimab plus chemotherapy followed by dostarlimab and niraparib as maintenance, compared to placebo plus chemotherapy followed by placebo, particularly for pMMR/MSS disease.
Mansoor Raza Mirza, MD
At 19 months’ median follow-up, median progression-free survival in the overall population was 14.5 months on the experimental arm and 8.3 months on the control arm; at 12 months, 57.0% and 33.7% were progression-free, respectively (HR = 0.60; P = .00007). In the pMMR/MSS population, medians were 14.3 months and 8.3 months, with 54.7% and 31.1%, respectively, progression-free (HR = 0.63; P = .0060).
In exploratory analyses, the investigators also found a “clinically relevant” benefit in patients with dMMR/MSI-H disease (HR = 0.48; P = .0174) and a positive impact in virtually all molecular subgroups. “These outcomes demonstrate a potential role for PARP inhibitor maintenance in patients receiving dostarlimab plus chemotherapy, in particular for pMMR/MSS disease,” Dr. Mirza said.
NRG GY018: Update on Pembrolizumab
Ramez N. Eskander, MD, Assistant Professor of Obstetrics, Gynecology and Reproductive Sciences at the University of California San Diego Moore Cancer Center, presented an update of the phase III NRG GY018 trial of 816 patients with advanced or recurrent endometrial cancer.4 Patients were randomly assigned to receive paclitaxel plus carboplatin every 3 weeks plus either pembrolizumab at 200 mg or placebo for six cycles; this was followed by pembrolizumab at 500 mg or placebo every 6 weeks for up to 14 additional cycles.
Ramez N. Eskander, MD
At the 2023 SGO Annual Meeting, Dr. Eskander reported significant improvements in progression-free survival in both dMMR (HR = 0.30; P < .001) and pMMR (HR = 0.54; P < .001) subsets, with improvements in response and response duration.5 For the current overall survival analysis, with data still not mature, Dr. Eskander reported a “favorable trend” (HR = 0.79), despite subsequent receipt of pembrolizumab by 45% of the placebo arm. This was true for both the dMMR/MSI-H and pMMR/MSS cohorts and regardless of PD-L1 status in either of those groups.
“These findings support the addition of pembrolizumab to chemotherapy as a first-line treatment of patients with advanced or recurrent endometrial cancer, regardless of MMR status,” he said.
DISCLOSURE: Dr. Powell has received honoraria or consultation fees from AstraZeneca, Clovis Oncology, Eisai, GlaxoSmithKline, ImmunoGen, and Merck. Dr. Mirza has had an advisory role and/or has served as a speaker for AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, GlaxoSmithKline, ImmunoGen/AbbVie, Incyte, Karyopharm, Merck, Regeneron, Ultimovacs, and Zai Lab; has received institutional research funding from Apexigen, AstraZeneca, Deciphera, GlaxoSmithKline, and Ultimovacs; is a member of the Board of Directors and owns stock in Karyopharm; and is a member of the Prix Galien Foundation Awards Committee. Dr. Eskander reported personal relationships with AstraZeneca, Cardiff Oncology, Clovis Oncology, Eisai, Elevar Therapeutics, GSK/Tesaro, ImmunoGen, Seagen, Mersana Therapeutics, Myriad Genetics, Daiichi Sankyo, and Gilead Sciences.
REFERENCES
1. Powell MA, Auranen A, Willmott LJ, et al: Overall survival among patients with primary advanced or recurrent endometrial cancer treated with dostarlimab plus chemotherapy in the ENGOT-EN6-NSGO/GOG-3031/RUBY trial. Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer. Presented March 16, 2024.
2. Mirza MR, Chase D, Slomovitz B, et al: Dostarlimab in combination with chemotherapy for the treatment of primary advanced or recurrent endometrial cancer: A placebo-controlled randomized phase 3 trial (ENGOT-EN6-NSGO/GOG-3031/RUBY). Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Abstract 265. Presented March 27, 2023.
3. Mirza MR, Ghamande S, Hanker L, et al: Dostarlimab plus chemotherapy followed by dostarlimab plus niraparib maintenance therapy in patients with primary advanced or recurrent endometrial cancer in Part 2 of the ENGOT-EN6-NSGO/GOG-3031/RUBY trial. Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer. Late-Breaking Abstract. Presented March 16, 2024.
4. Eskander RN, Sill M, Miller A, et al: Overall survival, progression-free survival by PD-L1 status, and blinded independent central review results with pembrolizumab plus carboplatin/paclitaxel versus placebo plus CP in patients with endometrial cancer: Results from the NRG GY018 trial. Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer. Late-Breaking Abstract. Presented March 16, 2024.
5. Eskander RM, Sill MW, Beffa L, et al: Pembrolizumab versus placebo in addition to carboplatin and paclitaxel for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer: The phase 3 NRG GY018 study. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Abstract 264. Presented March 27, 2023.
