FDA Grants Priority Review to Dostarlimab Plus Chemo for dMMR/MSI-H Endometrial Cancer

FDA

The FDA has accepted and granted priority review to a supplemental biologics license application (sBLA) seeking the approval of dostarlimab (Jemperli) plus chemotherapy for use in adult patients with mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) primary advanced or recurrent endometrial cancer.¹

The application is supported by findings from a prespecified interim analysis of part 1 of the RUBY/ENGOT-ENG/GOG3031/NSGO phase 3 trial, which were published in The New England Journal of Medicine.² At a median follow-up of 24.8 months (range, 19.2-36.9) for this population, the addition of dostarlimab to carboplatin and paclitaxel reduced the risk of disease progression or death by 72% vs placebo plus chemotherapy (HR, 0.28; 95% CI, 0.16-0.50; P < .001). The estimated 24-month progression-free survival (PFS) rate with dostarlimab was 61.4% (95% CI, 46.3%-73.4%) vs 15.7% (95% CI, 7.2%-27.0%) with placebo.

Moreover, the 24-month overall survival (OS) rate with the dostarlimab regimen in this group was 83.3% (95% CI, 66.8%-92.0%) vs 58.7% (95% CI, 43.4%-71.2%) with placebo/chemotherapy (HR, 0.30; 95% CI, 0.13-0.70).

Under the Prescription Drug User Fee Act, the regulatory agency will decide on the sBLA by September 23, 2023.¹

“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,” Hesham Abdullah, senior vice president and global head of oncology development at GlaxoSmithKline, stated in a press release. “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.”

The randomized, double-blind, multicenter trial enrolled patients who were at least 18 years of age and had histologically or cytologically confirmed primary advanced or recurrent endometrial cancer that was not amenable to curative treatment.²

Specifically, patients needed to have stage IIIA, IIIB, or IIIC1 disease that was 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 had not received systemic treatment or had received neoadjuvant or adjuvant systemic therapy and recurred or progressed within 6 months of treatment completion.

Study participants were randomly assigned 1:1 to receive dostarlimab at 500 mg or placebo in combination with chemotherapy comprised of carboplatin at an area under the curve of 5 mg/mL/min plus paclitaxel at 175 mg/m2 every 3 weeks for the first 6 cycles, followed by 1000 mg of dostarlimab or placebo every 6 weeks. Treatment continued for up to 3 years or until progressive disease, intolerable toxicity, withdrawal by investigator or patient decision, or death.

The primary end points of the trial were investigator-assessed PFS and RECIST v1.1 criteria in those with dMMR/MSI-H disease and in the overall population, as well as OS in the overall population. Key secondary end points included PFS by blinded independent central review, objective response rate, disease control rate, duration of response, time to second progression, safety, and patient-reported outcomes. Investigators are also performing pharmacokinetic and immunogenicity analyses.

A total of 494 patients were randomized on the trial; 245 received the dostarlimab plus chemotherapy and 249 received placebo plus chemotherapy. Of those who underwent randomization, 118 had dMMR/MSI-H disease; 53 of these patients were in the dostarlimab arm and 65 were in the placebo arm.

No significant between-arm differences were observed in the demographic and clinical characteristics of patients in the dMMR/MSI-H population or the overall population, according to the study investigators. In fact, the demographic characteristics were noted to be “generally representative of patients with primary advanced or recurrent endometrial cancer.”

Additional data showed that in the overall population, dostarlimab plus chemotherapy reduced the risk of disease progression or death by 36% vs chemotherapy alone (HR, 0.64; 95% CI, 0.51-0.80; P < .001). The 24-month PFS rates in the investigative and control arms were 36.1% (95% CI, 29.3%-42.9%) and 18.1% (95% CI, 13.0%-23.9%), respectively.

At the time of the first interim analysis of OS in the overall population, there was a median follow-up of 25.4 months, and the hazard ratio for OS was 0.64 (95% CI, 0.46-0.87; P = .0021), favoring the dostarlimab combination. However, this difference between arms did not reach statistical significance. The estimated 24-month OS rates in the investigative and control arms were 71.3% (95% CI, 64.5%-77.1%) and 56.0% (95% CI, 48.9%-62.5%), respectively.

In those with mismatch repair–proficient/microsatellite stable tumors, the 24-month PFS rates with dostarlimab and placebo were 28.4% (95% CI, 21.2%-36.0%) and 18.8% (95% CI, 12.8%-25.7%), respectively (HR, 0.76; 95% CI, 0.59-0.98). The 24-month OS rates in this group were 67.7% (95% CI, 59.8%-74.4%) and 55.1% (95% CI, 46.8%-62.5%), respectively (HR, 0.73; 95% CI, 0.52-1.02).

All patients experienced adverse effects (AEs) on the trial. Grade 3 or higher AEs were reported in 70.5% of those who received dostarlimab (n = 241) and in 59.8% of those who received placebo (n = 246). Serious toxicities occurred in 37.8% and 27.6% of patients, respectively.

The most common any-grade AEs that occurred in more than 20% of patients in the dostarlimab or placebo 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%), decreased appetite (21.6% vs 17.5%), dyspnea (18.3% vs 20.3%), and rash (22.8% vs 13.8%)

Grade 3 or higher toxicities reported 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. 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. June 6, 2023. Accessed June 6, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-receives-us-fda-file-acceptance-for-jemperli/
2. 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