CHMP Recommends Dostarlimab Plus Chemotherapy in dMMR/MSI-H Advanced/Recurrent Endometrial Cancer

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended the approval of dostarlimab-gxly (Jemperli) plus chemotherapy for the treatment of adult patients with mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) primary advanced or recurrent endometrial cancer who are candidates for systemic therapy.¹

The opinion was based on findings from the phase 3 RUBY trial (NCT03981796) that were presented during the ESMO Virtual Plenary and SGO Annual Meeting and simultaneously published in The New England Journal of Medicine in March 2023. Data from the interim analysis of part 1 of the study demonstrated that patients with dMMR/MSI-H endometrial cancer (n = 53) achieved a 24-month progression-free survival (PFS) rate of 61.4% (95% CI, 46.3%-73.4%) with dostarlimab plus chemotherapy compared with 15.7% (95% CI, 7.2%-27.0%) among patients who received chemotherapy plus placebo (n = 65; HR, 0.28; 95% CI, 0.16-0.50; P < .001). Part 1 met its primary end point of investigator-assessed PFS in the dMMR/MSI-H population.^1,2

"We are pleased with this positive CHMP opinion and the potential for dostarlimab with chemotherapy to treat patients with this very challenging form of endometrial cancer,” Hesham A. Abdullah, MD, MSc, senior vice president, Global Head Oncology, Research & Development, of GSK, the manufacturer of dostarlimab, said in a news release. “If approved, dostarlimab plus chemotherapy will be the first new treatment option in decades for these patients in the European Union [EU], offering long-awaited new hope for improved long-term outcomes. This opinion further reinforces our confidence in dostarlimab’s important role in the immuno-oncology treatment landscape."¹

RUBY was a global, double-blind trial that enrolled patients with primary advanced stage III or IV or first recurrent endometrial cancer. Eligible patients were randomly assigned in a 1:1 manner to receive intravenous (IV) dostarlimab 500 mg or placebo plus IV carboplatin at an area under the curve of 5 mg/mL per minute and paclitaxel 175 mg/m² of body-surface area every 3 weeks for the first six cycles, followed by IV dostarlimab 1000 mg or placebo every 6 weeks for up to 3 years. Treatment continued until disease progression, unacceptable toxicity, patient withdrawal, or death.²

The coprimary end points were PFS in the dMMR/MSI-H population and in the overall population, as well as overall survival (OS) in the overall population. Secondary end points included objective response rate, disease control rate, duration of response, and safety.

In the dMMR/MSI-H population, the baseline patient characteristics were well balanced between the 2 arms; the median age was 61 years (range, 45-81) compared with 66 years (range, 39-85) in the dostarlimab and placebo arms, respectively. Most patients in both arms were White (83% vs 86%), had an ECOG performance status of 0 (54% vs 60%), had endometroid histology (83% vs 86%), and had not received prior external pelvic radiotherapy (85% vs 80%).

Additional findings from RUBY showed that the 24-month PFS rates in the overall population were 36.1% (95% CI, 29.3%-42.9%) vs 18.1% (95% CI, 13.0%-23.9%) in the dostarlimab (n = 245) and placebo arms (n = 249; HR, 0.64; 95% CI, 0.51-0.80; P < .001). The 24-month OS rates were 71.3% (95% CI, 64.5%-77.1%) vs 56.0% (95% CI, 48.9%-62.5%), respectively (HR, 0.64; 95% CI, 0.46-0.87; P = .0021). In the dMMR/MSI-H population, the 24-month OS rates were 83.3% (95% CI, 66.8%-92.0%) vs 58.7% (95% CI, 43.4%-71.2%), respectively (HR, 0.30; 95% CI, 0.13-0.70).

Investigators noted that the safety profile of the combination was mostly consistent with that of the individual agents. In the overall population, all patients who received dostarlimab (n = 241) or placebo (n = 246) experienced an any-grade adverse effect (AE). Most patients in both arms experienced a treatment-related AE (97.9% vs 98.8%, respectively) and a grade 3 or higher AE (70.5% vs 59.8%). The most common any-grade AEs in the dostarlimab arm included nausea (53.9%), alopecia (53.5%), and fatigue (51.9%). Five deaths due to AEs were reported in the dostarlimab arm; no patients in the placebo arm died.

Dostarlimab monotherapy currently holds a conditional approval in the EU for the treatment of adult patients with dMMR/MSI-H recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen. In the event the agent in combination with chemotherapy receives approval for the frontline indication, the conditional approval is anticipated to be converted to a full approval at the same time. A decision on the authorization application is expected by the end of 2023.¹

References

1. GSK receives positive CHMP opinion recommending approval of Jemperli (dostarlimab) plus chemotherapy as a new frontline treatment for dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GSK. October 16, 2023. Accessed October 16, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-receives-positive-chmp-opinion-recommending-approval-of-jemperli-dostarlimab-plus-chemotherapy/
2. 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