FDA Approves Dostarlimab Combination for Primary Advanced or Recurrent Endometrial Cancer

The FDA has granted approval to dostarlimab-gxly (Jemperli) combined with carboplatin and paclitaxel, followed by dostarlimab as a monotherapy, for the treatment of adults with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) as determined by an FDA-approved test, or microsatellite instability high (MSI-H).¹

The approval was based on findings from an interim analysis of part 1 of the RUBY/ENGOT-EN6/GOG3031/NSGO phase 3 trial (NCT03981796).² The FDA previously approved dostarlimab as a single agent in adults with dMMR recurrent or advanced endometrial cancer that has progressed on or after prior treatment with a platinum-containing regimen in any setting and who are not candidates for curative surgery or radiation.¹

“As a clinician, I celebrate the practice-changing potential of adding [dostarlimab] to chemotherapy for patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer who have had limited treatment options," trial principal investigator Matthew Powell, MD, chief of the Division of Gynecologic Oncology at Washington University School of Medicine, said in a press release.¹ "Based on the results from the RUBY clinical trial, I look forward to the addition of [dostarlimab] to chemotherapy becoming a new standard of care for patients.”

Dostarlimab-gxly is a programmed death receptor-1 (PD-1)-blocking antibody that binds to the PD-1 receptor and blocks its interaction with the PD-1 ligands PD-L1 and PD-L2. It has shown potential both as a monotherapy and in combination with standard of care and future novel cancer therapies, particularly in patients with currently limited treatment options.

At a median follow-up of 24.8 months (range, 19.2-36.9) in the RUBY/ENGOT-EN6/GOG3031/NSGO trial, the addition of dostarlimab to chemotherapy produced a 72% decline in the risk of disease progression or death compared with 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%) compared with 15.7% (95% CI, 7.2%-27.0%) with placebo.

Further, the 24-month overall survival (OS) rate with the dostarlimab combination was 83.3% (95% CI, 66.8%-92.0%) compared with 58.7% (95% CI, 43.4%-71.2%) with placebo or chemotherapy (HR, 0.30; 95% CI, 0.13-0.70). The 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

Enrollment eligibility included having 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 therapy or neoadjuvant or adjuvant systemic therapy and recurred or progressed within 6 months of the completion of treatment.

Patients were randomized 1:1 to receive 500 mg of dostarlimab or placebo combined with carboplatin at an area under the curve of 5 mg/mL/min and paclitaxel at 175 mg/m² every 3 weeks for the first 6 cycles, followed by single agent dostarlimab at 1000 mg or placebo every 6 weeks. Patients were treated for up to 3 years or until disease progression, intolerable toxicity, withdrawal, or death.

The trial’s primary endpoints were investigator-assessed PFS and RECIST v1.1 criteria in patients with dMMR/MSI-H disease and in the overall patient population and OS in the overall patient population. Secondary endpoints 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.

There were 494 patients randomized, with 245 administered dostarlimab plus chemotherapy and 249 administered placebo plus chemotherapy. Among those enrolled, 118 patients had dMMR/MSI-H disease, with 53 in the investigative arm and 65 in the control arm.

There were no significant differences reported in the demographic and clinical characteristics of patients in either cohort, which were noted as “generally representative of patients with primary advanced or recurrent endometrial cancer.”

The dostarlimab combination produced a 36% reduction in the risk of disease progression or death compared with chemotherapy alone (HR, 0.64; 95% CI, 0.51-0.80; P < .001). 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.

At the first interim analysis of OS in the overall population at a median follow-up of 25.4 months, the hazard ratio for OS was 0.64 (95% CI, 0.46-0.87; P = .0021) in favor of the dostarlimab combination; however, the difference between cohorts was not deemed statistically significant. The estimated 24-month OS rates in the dostarlimab cohort was 71.3% (95% CI, 64.5%-77.1%) compared with 56.0% (95% CI, 48.9%-62.5%) in the placebo cohort.

Further, among patients 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 these cohorts 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).

In terms of safety, grade 3 or higher adverse effects (AEs) were reported in 70.5% of patients administered dostarlimab (n = 241) and in 59.8% of patients in the placebo (n = 246) cohort. Serious toxicities were reported in 37.8% and 27.6% of patients, respectively.

The most common any-grade AEs experienced by more than 20% of patients in the investigative and control cohorts were 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%), reduced appetite (21.6% vs 17.5%), dyspnea (18.3% vs 20.3%), and rash (22.8% vs 13.8%)

Grade 3 or higher AEs reported in the investigative and control cohorts 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%), respectively.

References

1. 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 July 31, 2023. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/
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