Dostarlimab Plus Chemo Granted EU Approval for dMMR/MSI-H Endometrial Cancer

The European Commission (EC) has granted marketing authorization to dostarlimab (Jemperli) paired with carboplatin and paclitaxel in adults with mismatch repair­–deficient (dMMR)/microsatellite instability–high (MSI-H) primary advanced or recurrent endometrial cancer who are eligible to receive systemic treatment.¹

With this authorization, the conditional approval for the use of single-agent dostarlimab in adult patients with dMMR/MSI-H recurrent or advanced endometrial cancer that has progressed on or after a platinum-containing regimen has been converted into a full approval.

The regulatory decision is supported by data from an interim analysis of the dMMR/MSI-H population of the first part of the phase 3 RUBY/ENGOT-EN6/GOG3031/NSGO trial (NCT03981796). In this group, those who received the dostarlimab/chemotherapy regimen (n = 53) experienced a significant improvement in investigator-assessed progression-free survival (PFS) vs placebo plus chemotherapy (n = 65; HR, 0.28; 95% CI, 0.16-0.50; P < .001).² The estimated Kaplan-Meier 24-month PFS rates were 61.4% (95% CI, 46.3%-73.4%) and 15.7% (95% CI, 7.2%-27.0%) in the dostarlimab and placebo arms, respectively.

“Today’s EC approval is welcomed news as I believe it will define a new standard of care for certain patients with advanced or recurrent endometrial cancer in the European Union,” Mansoor Raza Mirza, MD, chief oncologist at Copenhagen University Hospital in Denmark and principal investigator of the trial, stated in a press release.¹ “The results from the RUBY trial, which led to this approval, underscore the practice-changing potential for dostarlimab for these patients.”

The double-blind, multicenter, randomized, phase 3 RUBY trial enrolled patients who were at least 18 years of age and had cytologically or histologically confirmed primary advanced or recurrent endometrial cancer who were not candidates for curative therapy.²

They needed to meet 1 of the following criteria: primary advanced stage IIIA, IIIB, or IIIC1 disease that is evaluable or measurable by RECIST v1.1 criteria; primary advanced stage IIIC1 disease with carcinosarcoma, clear-cell, serous, or mixed histologic characteristics; primary advanced stage IIIC2 or stage IV disease; disease that was in first recurrence and who had not received systemic treatment or who had received neoadjuvant or adjuvant systemic treatment and experienced recurrence or progression at least 6 months after treatment was completed.

Study participants were randomized in a 1:1 fashion to dostarlimab at 500 mg or placebo plus carboplatin at area under the curve of 5 mg/mL/min and paclitaxel at 175 mg/m² every 3 weeks for 6 cycles, followed by dostarlimab at 1000 mg or placebo every 6 weeks. Treatment continued until disease progression, discontinuation due to toxicity, patient withdrawal, investigator decision to withdraw, treatment completion of up to 3 years, or death.

Patients were stratified based on MMR/MSI status (dMMR/MSI-H vs pMMR/MSS), receipt of prior external pelvic radiation (yes vs no), and disease status (recurrent vs primary stage III vs primary stage IV).

The trial’s primary end points included investigator-assessed PFS by RECIST v1.1 criteria in the dMMR/MSI-H population and the overall population, as well as overall survival (OS) in the overall population. Secondary end points comprised PFS by blinded independent central review, objective response rate, disease control rate, duration of response, time to second disease progression, patient-reported outcomes, and pharmacokinetics. Safety was also examined.

In the dMMR/MSI-H population, the median patient age was 61 years (range, 45-81) in the dostarlimab arm and 66 years (range, 39-85) in the placebo arm. Most patients were White (83% vs 86%), had an ECOG performance status of 0 (54% vs 60%), FIGO stage I disease at diagnosis (34% vs 34%), recurrent disease (51% vs 49%), and endometrioid histology (83% vs 86%). The majority of patients (85% vs 80%) did not receive prior external pelvic radiotherapy.

Additional data showed that in the overall population, the 24-month PFS rates in the dostarlimab and placebo arms 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). At 25.4 months of follow-up in this population, the median OS was numerically longer in the dostarlimab arm vs the placebo arm; however, the difference was not statistically significant (HR, 0.64; 95% CI, 0.46-0.87; P = .0021). The Kaplan-Meier estimated 24-month survival rates were 71.3% (95% CI, 64.5%-77.1%) and 56.0% (95% CI, 48.9%-62.5%), respectively.

In the dMMR/MSI-H group, the 24-month OS rate with the dostarlimab regimen was 83.3% (95% CI, 66.8%-92.0%) vs 58.7% (95% CI, 43.4%-71.2%) with the placebo regimen (HR, 0.30; 95% CI, 0.13-0.70).

The safety of the dostarlimab combination was generally consistent with what has previously been reported with each agent.¹ The most frequently reported adverse effects included rash, hypothyroidism, alanine aminotransferase increase, aspartate aminotransferase increase, pyrexia, and rash.

In July 2023, the FDA approved dostarlimab plus carboplatin/paclitaxel, followed by single-agent dostarlimab, for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is dMMR per an FDA-approved test and MSI-H.³ The approval was based on the RUBY data.

References

1. GSK/s Jemperli (dostarlimab) plus chemotherapy approved as the first and only frontline immuno-oncology treatment in the European Union for dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GlaxoSmithKline. December 11, 2023. Accessed December 13, 2023. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-as-the-first-and-only-frontline-immuno-oncology-treatment-in-the-european-union/
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
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 December 13, 2023. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/