Dostarlimab Plus Chemo Provides OS Benefit in Primary Advanced or Recurrent Endometrial Cancer

The addition of dostarlimab-gxly (Jemperli) to carboplatin plus paclitaxel followed by dostarlimab monotherapy significantly improved overall survival (OS) compared with placebo plus chemotherapy followed by placebo in adult patients with primary advanced or recurrent endometrial cancer, meeting the primary end point of the phase 3 RUBY/ENGOT-EN6/GOG3031/NSGO trial (NCT03981796).¹

Data from part 1 of the trial showed that the dostarlimab regimen improved OS in the overall patient population and in both prespecified subpopulations: those with mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) and those with mismatch repair–proficient (pMMR) disease.

The safety and tolerability of the regimen proved to align with what has previously been reported for each agent. Full findings from the latest analysis will be shared at an upcoming conference and submitted for publication in a medical journal, according to GlaxoSmithKline.

“With today’s headline results from part 1 of the phase 3 RUBY trial, dostarlimab plus chemotherapy has become the only immunotherapy combination to show a survival benefit in this broader patient population in this treatment setting,” Hesham Abdullah, senior vice president of Global Head Oncology, R&D, at GlaxoSmithKline, stated in a press release. “We look forward to sharing detailed results of this analysis with regulatory authorities and the larger scientific community.”

The randomized, double-blind, phase 3 trial enrolled patients with a histologically or cytologically proven diagnosis of advanced or recurrent endometrial cancer who had stage III or IV disease or first recurrent disease with low potential for cure by radiation or surgery alone or in combination.² Patients could have carcinosarcoma, clear cell, serous, or mixed histology.

Other inclusion criteria included being naïve to systemic therapy or experienced disease recurrence or progression at least 6 months following the completion of systemic treatment, an ECOG performance status of 0 or 1, and acceptable organ function.

Study participants were randomly assigned 1:1 to receive placebo (n = 249) or dostarlimab (n = 245) intravenously (IV) at 500 mg paired with carboplatin at area under the curve (AUC) 5 mg/mL/min and paclitaxel at 175 mg/m² every 3 weeks for 6 cycles followed by IV placebo or dostarlimab at 1000 mg every 6 weeks for up to 3 years. Patients were stratified based on MMR/MSI status, whether they had prior exposure to external pelvic radiotherapy, and disease status.

The co-primary end points of the trial were investigator-assessed progression-free survival (PFS) by RECIST v1.1 criteria and OS. Important secondary end points included PFS by blinded independent central review by RECIST v1.1 criteria, second PFS, objective response rate, duration of response, disease control rate, health-related quality of life and patient-reported outcomes, as well as safety.

In July 2023, the FDA approved dostarlimab plus chemotherapy, followed by single-agent dostarlimab for adult patients with primary advanced or recurrent endometrial cancer that is dMMR, as determined by a FDA-approved test, or MSI-H based on findings from the interim analysis of the first part of RUBY.³

The dostarlimab combination (n = 53) reduced the risk of disease progression or death by 72% and 36% vs placebo (n = 65) in those with dMMR/MSI-H disease (HR, 0.28; 95% CI, 0.162-0.495; P < .0001) and the overall population (HR, 0.64; 95% CI, 0.507-0.800; P < .0001), respectively.²

At a median follow-up of 24.8 months (range, 19.2-36.9) in the dMMR/MSI-H population, the median PFS was not reached (NR; 95% CI, 11.8-NR) in the dostarlimab arm vs 7.7 months (95% CI, 5.6-9.7) in the placebo arm. The 12-month PFS rates were 63.5% and 24.4%, respectively; at 24 months, these rates were 61.4% and 15.7%, respectively. At a median follow-up of 25.4 months in the overall population, the median PFS with the dostarlimab combination was 11.8 months (95% CI, 9.6-17.1) vs 7.9 months (95% CI, 7.6-9.5) with chemotherapy alone. The 12-month PFS rates were 48.2% and 29.0%, respectively, and the 24-month rates were 36.1% and 18.1%, respectively.

The most common any-grade adverse effects (AEs) reported in more than 20% of patients in the investigative and control arms included fatigue (51.9% vs 54.5%, respectively), alopecia (53.5% vs 50.0%), nausea (53.9% vs 45.9%), peripheral neuropathy (44.0% vs 41.1%), anemia (37.8% vs 42.3%), arthralgia (35.7% vs 35.0%), constipation (34.4% vs 35.8%), diarrhea (31.1% vs 28.9%), myalgia (26.1% vs 27.6%), hypomagnesemia (21.6% vs 28.5%), peripheral sensory neuropathy (21.2% vs 19.1%), reduced appetite (21.6% vs 17.5%), dyspnea (18.3% vs 20.3%), and rash (22.8% vs 13.8%).⁴

Grade 3 or higher AEs experienced in the investigative and control arms, respectively, included anemia (14.9% vs 16.3%), neutropenia (9.5% vs 9.3%), decreased neutrophil count (8.3% vs 13.8%), decreased lymphocyte count (5.4% vs 7.3%), decreased white cell count (6.6% vs 5.3%), hypertension (7.1% vs 3.3%), pulmonary embolism (5.0% vs 4.9%), and hypokalemia (5.0% vs 3.7%).

References

1. Phase III RUBY trial of Jemperli (dostarlimab) plus chemotherapy meets endpoint of overall survival in patients with primary advanced or recurrent endometrial cancer. News release. GlaxoSmithKline. October 30, 2023. Accessed October 30, 2023. https://www.gsk.com/en-gb/media/press-releases/phase-iii-ruby-trial-of-jemperli-dostarlimab-plus-chemotherapy-meets-endpoint-of-overall-survival-in-patients-with-primary-advanced-or-recurrent-endometrial-cancer/
2. Mirza MR, Sharma S, Herrstedt J, et al. 740MO Dostarlimab + chemotherapy for the treatment of primary advanced or recurrent endometrial cancer (pA/rEC): analysis of progression free survival (PFS) and overall survival (OS) outcomes by molecular classification in the ENGOT-EN6-NSGO/GOG-3031 RUBY trial. Ann Oncol. 2023;34(suppl 2):S507. doi:10.1016/j.annonc.2023.09.1919
3. Jemperli (dostarlimab) plus chemotherapy approved in the US as the first new frontline treatment option in decades for dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GlaxoSmithKline. July 31, 2023. Accessed July 31, 2023. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/ 
4. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158. doi:10.1056/NEJMoa2216334