FDA to Decide on Dostarlimab Plus Chemo Approval in dMMR/MSI-H Advanced Endometrial Cancer in 4 Months

The FDA has accepted the supplemental new drug application (sNDA) for dostarlimab (Jemperli) in combination with chemotherapy for the treatment of patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) primary advanced or recurrent endometrial cancer. The application was also granted priority review.¹

“This has become another tool we have in our armamentarium because our big goal has been moving this to frontline therapy,” said Matthew Powell, MD, in an interview with Targeted Oncology™.

According to GSK plc, a future approval of dostarlimab for this indication would bring the first meaningful frontline treatment for this patient population in decades. The regulatory body will make its decision on the sNDA on the PDUFA target action date of September 23, 2023.

Supporting the sNDA are data from the phase 3 RUBY/ENGOT-EN6/GOG3031/NSGO study (NCT03981796) for which results were recently presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. Overall, the results showed that dostarlimab added to the standard chemotherapy combination of carboplatin and paclitaxel yielded better outcomes than placebo with carboplatin and paclitaxel, according to an assessment conducted by independent central review (BICR).²

“At ASCO, we provided further data on the RUBY trial. This study led to transformative results, especially in the defective mismatch repair population, and 2 months ago, led to a publication in New England Journal of Medicine, and now, the NCCN Compendium listed it as an option for our patients with advanced to recurrent endometrial cancer,” said Powell, professor, Obstetrics and Gynecology and chief, Division of Gynecologic Oncology, Siteman Cancer Center, Washington University School of Medicine.

First, the results for the co-primary end point of progression-free survival (PFS) favored the dostarlimab/chemotherapy arm. In the dMMR/MSI-H disease subgroup, PFS was longer with dostarlimab than with placebo (hazard ratio [HR], 0.29; 95% CI, 0.158-0.543; P <.0001), as was the case in the overall population (HR, 0.66; 95% CI, 0.517-0.853; P <.0006). Results also showed that the probability of PFS at 24 months with dostarlimab was 66.3% (95% CI, 50.8%-77.9%) and 42.5% (95% CI, 35.2%-49.6%) among the dMMR/MSI-H.

In terms of the secondary end points, overall response rate (ORR), disease control rate (DCR), and duration of response (DOR) data were presented as part of ASCO abstract 550. The ORR in the dMMR/MSI-H population by BICR was 77.1% (95% CI, 62.7%-88.0%) with dostarlimab vs 63.3% (95% CI, 49.9%-75.4%) with placebo. This ORR included a complete response (CR) rate of 22.9% in the dostarlimab-containing arm vs 13.3% in the placebo arm and partial response rates of 54.2% vs 50.0%, respectively.

The ORR for the dostarlimab/chemotherapy arm in the overall population was 68.2% (95% CI, 61.6%-74.2%) vs 59.4% (95% CI, 52.7%-65.8%) in the placebo arm. The CR rates were 20.6% vs 14.8%, respectively, and the PR rates were 47.5% vs 44.5%, respectively.

The DCR observed was 91.7% (95% CI, 80.0%-97.7%) in the dostarlimab arm vs 91.7% (95% CI, 81.6%-97.2%) in the placebo arm in the dMMR/MSI-H population. In the overall population, the DCR was 88.3% (95% CI, 83.4%-92.2%) vs 86.9% (95% CI, 81.8%-91.0%), respectively.

In the overall population, dostarlimab showed a median DOR of 12.9 months (95% CI, 8.2-not reached [NR]), compared with 6.7 months (95% CI, 5.7-8.3) in the placebo arm. The median in the dMMR/MSI-H population was not reached (95% CI, 13.1-NR) with dostarlimab vs 6.9 months (95% CI, 5.5-10.1) with placebo.

Image Credit: © Dr_Microbe - www.stock.adobe.com

Safety results showed that treatment-emergent adverse effects (TEAEs) occurred in 70.5% of patients treated in the dostarlimab arm vs 59.8% of those treated with placebo. Serious TEAEs were seen in 37.8% vs 27.6% of patients, respectively. TEAEs leading to discontinuation of dostarlimab compared with discontinuation of chemotherapy plus placebo occurred in 17.4% vs 9.3% of patients, respectively. TEAEs related to dostarlimab occurred in 2 patients (0.8%), and these events led to death.

The global, double-blind, multicenter RUBY study included 494 patients who were randomly assigned to receive dostarlimab plus chemotherapy (n = 245) or the placebo. Of the enrolled population, 47.8% had recurrent disease, 18.6% had primary stage III disease, and 33.9% had primary stage IV disease.

Dostarlimab was administered at a dose of 500 mg plus carboplatin at a dose of the area under the curve of 5 mg/mL/minute and paclitaxel at a dose of 175 mg/m² every 3 weeks for a total of 6 cycles. This combination treatment was followed by maintenance dostarlimab at a dose of 1000 mg every 6 weeks for up to 3 years. Patients in the control arm received the same regimen with a matched placebo instead of dostarlimab.

“We are excited about this initial filing for this potential new indication for dostarlimab in the patient population that demonstrated the strongest treatment effect in the phase 3 RUBY trial. Long-term outcomes for patients with primary advanced or recurrent endometrial cancer remain poor, and there is an urgent need to evolve the current standard of care, which is platinum-based chemotherapy. We look forward to working with the FDA and other health authorities as they review this application,” said Hesham Abdullah, senior vice president, global head of oncology development, GSK, in a press release.¹

_REFERENCES:

_{1. GSK receives US FDA file acceptance for Jemperli (dostarlimab) plus chemotherapy for the treatment of dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GSK plc. June 6, 2023. Accessed June 7, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-receives-us-fda-file-acceptance-for-jemperli/}

_{2. Powell MA, Hietanen S, Coleman RL, et al. Dostarlimab for primary advanced or recurrent (A/R) endometrial cancer (EC): outcomes by blinded independent central review (BICR) of the RUBY trial (ENGOT-EN6-NSGO/GOG-3031/RUBY). J Clin Oncol. 2023;41(suppl 16):5503. doi:10.1200/JCO.2023.41.16_suppl.550}