EMA Validates Type II Variation Application for Dostarlimab/Chemo for dMMR/MSI-H Primary Advanced or Recurrent Endometrial Cancer

The European Medicines Agency (EMA) has validated a type II variation for potential approval of dostarlimab-gxly (Jemperli) in combination with carboplatin and paclitaxel for the treatment of patients with mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) primary advanced or recurrent endometrial cancer, allowing the EMA’s Committee for Medicinal Products for Human Use to begin discussions regarding the marketing authorization for the proposed indication.¹

The regulatory submission is based on interim data from the phase 3 RUBY/ENGOT-EN6/GOG3031/NSGO trial (NCT03981796). The trial met its primary end point of investigator-assessed progression-free survival (PFS), showing a statistically significant and clinically meaningful benefit with dostarlimab plus carboplatin/paclitaxel vs placebo plus chemotherapy in patients treated in the dMMR/MSI-H population.

In addition, the safety and tolerability profile of the combination was in line with the known safety profiles of dostarlimab, carboplatin, and paclitaxel alone.

The results were presented during the March ESMO Virtual Plenary and the 2023 SGO Annual Meeting, and were simultaneously published in The New England Journal of Medicine.^1-3

“New treatment options are urgently needed for patients with primary advanced or recurrent endometrial cancer. With this initial filing, we are accelerating the submission of a potential new indication for dostarlimab in the patient population that demonstrated the strongest treatment effect in the RUBY phase 3 trial. These patients currently face significant unmet medical needs, and this combination could change the treatment paradigm for this condition. The RUBY phase 3 trial continues to follow patients for the dual-primary end point of overall survival [OS] in the intent-to-treat population,” Hesham Abdullah, senior vice president and global head of oncology development at GSK, said in a news release.

The global, double-blind, randomized, placebo-controlled trial enrolled patients with primary advanced stage III or IV or first recurrent endometrial cancer. Eligible patients were randomly assigned 1:1 to receive 500 mg of dostarlimab or placebo, plus carboplatin at an area under the concentration–time curve of 5 mg/mL per minute and 175 mg/m² of body-surface area of paclitaxel every 3 weeks for 6 six cycles, followed by 1000 mg of dostarlimab or placebo every 6 weeks for up to 3 years.

In addition to investigator-assessed PFS, OS served as a coprimary end point. Safety was also assessed.

Baseline characteristics of the enrolled population were generally representative of patients with primary advanced or recurrent endometrial cancer. In the overall population, 18.6% of the patients had primary stage III disease, 33.6% had primary stage IV disease, and 47.8% had recurrent disease. Overall, 54.7%, 20.6%, and 8.9% of patients had received a diagnosis of endometrioid carcinoma, serous adenocarcinoma, and carcinosarcoma, respectively. Most patients (82.6%) had not been previously exposed to external pelvic radiation.

The median duration of follow-up was 24.8 months (range, 19.2-36.9) in the dMMR/MSI-H population and 25.4 months (range, 19.2-37.8) in the overall population.

Of the 494 patients who underwent randomization, 118 (23.9%) had dMMR/MSI-H tumors. In the dMMR/MSI-H population, the estimated 24-month PFS rate was 61.4% (95% CI, 46.3%-73.4%) with dostarlimab vs 15.7% (95% CI, 7.2%-27.0%) with placebo (HR, 0.28; 95% CI, 0.16-0.50; P < .001). In the overall population, the 24-month PFS rates were 36.1% (95% CI, 29.3%-42.9%) and 18.1% (95% CI, 13.0%-23.9%), respectively (HR, 0.64; 95% CI, 0.51-0.80; P < .001).

In the overall population, the 24-month OS rate was 71.3% (95% CI, 64.5%-77.1%) with dostarlimab and 56.0% (95% CI, 48.9%-62.5%) with placebo (HR, 0.64; 95% CI, 0.46-0.87; P = .0021), falling short of the prespecified P value for significance (P = .00177). In the dMMR/MSI-H population, the 24-month OS rate was 83.3% (95% CI, 66.8%-92.0%) with dostarlimab and 58.7% (95% CI, 43.4%-71.2%) with placebo (HR, 0.30; 95% CI, 0.13-0.70).

Objective response rate (ORR), a key secondary end point, also favored the use of dostarlimab. In the overall population, the ORR in the dostarlimab arm was 70.3% (95% CI, 63.6%-76.3%) vs 64.8% (95% CI, 58.1%-71.2%) in the placebo arm. In the dMMR/MSI-H population, the ORRs were 77.6% (95% CI, 63.4%-88.2%) and 69.0% (95% CI, 55.5%-80.5%) with dostarlimab and placebo, respectively.

Additionally, more patients in the overall population who received dostarlimab had a response lasting 12 months or more, at 40.3% vs 20.4% with placebo. Those rates were 57.9% vs 17.5% in the dMMR/MSI-H population. In the overall population, the probability of maintaining response for 2 years was 38.0% (95% CI, 29.4%-46.5%) with dostarlimab vs 13.0% (95% CI, 7.5%-20.2%) with placebo. In the dMMR/MSI-H population, these rates were 62.1% (95% CI, 44.4%-75.5%) and 13.2% (95% CI, 4.6%-26.3%), respectively.

Regarding safety, the most frequent adverse effects (AEs) that occurred or worsened during treatment with dostarlimab and placebo, respectively, were nausea (53.9% and 45.9%), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Rash and maculopapular rash occurred more often with dostarlimab compared with placebo, at 22.8% vs 13.8% and 14.1% vs 3.7%, respectively. The most common immune-related AEs were hypothyroidism (11.2% and 2.8%), rash (6.6% and 2.0%), arthralgia (5.8% and 6.5%), and increased alanine aminotransferase (5.8% and 0.8%).

Grade 3 or higher AEs and serious AEs that occurred or worsened during treatment were also higher with dostarlimab vs placebo, at 70.5% vs 59.8% and 37.8% vs 27.6%, respectively.

AEs leading to treatment discontinuation of dostarlimab or placebo occurred in 17.4% and 9.3% of patients, respectively.

References

1. European Medicines Agency validates marketing authorisation application for Jemperli (dostarlimab) plus chemotherapy for the treatment of dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GSK. April 25, 2023. Accessed April 25, 2023. https://www.gsk.com/en-gb/media/press-releases
2. Mirza MR, Chase DM, Slomovitz BM, 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). Presented at: 2023 SGO Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, FL.
3. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2216334