On 17 June 2024, the Food and Drug Administration (FDA) approved pembrolizumab (Keytruda, Merck) with carboplatin and paclitaxel, followed by single-agent pembrolizumab, for adult patients with primary advanced or recurrent endometrial carcinoma.
Efficacy was evaluated in KEYNOTE-868/NRG-GY018 (NCT03914612), a multicentre, randomised, double-blind, placebo-controlled study enrolling 810 patients with advanced or recurrent endometrial carcinoma. The study included two separate cohorts based on mismatch repair (MMR) status: 222 patients in the mismatch repair deficient (dMMR) cohort, and 588 patients in the mismatch repair proficient (pMMR) cohort. Patients were randomised (1:1) to one of the following treatment arms:
- pembrolizumab 200 mg every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for 6 cycles, followed by pembrolizumab 400 mg every 6 weeks for up to 14 cycles.
- placebo every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for 6 cycles, followed by placebo every 6 weeks for up to 14 cycles.
Randomisation was stratified according to MMR status, ECOG performance status (0 or 1 versus 2), and prior adjuvant chemotherapy.
The major efficacy outcome measure was progression-free survival (PFS), assessed by the investigator according to RECIST v1.1. In the dMMR cohort, median PFS was not reached (NR) (95% confidence interval [CI] 30.7, NR) in the pembrolizumab and chemotherapy arm and 6.5 months (95% CI 6.4, 8.7) in the placebo and chemotherapy arm (hazard ratio [HR] 0.30, 95% CI 0.19, 0.48; p-value < 0.0001). In the pMMR cohort, median PFS was 11.1 months (95% CI 8.7, 13.5) in the pembrolizumab and chemotherapy arm and 8.5 months (95% CI 7.2, 8.8) for those receiving placebo and chemotherapy arm (HR 0.60, 95% CI 0.46, 0.78; p-value < 0.0001).
Adverse reactions associated with pembrolizumab and chemotherapy were generally similar to those previously reported for pembrolizumab or chemotherapy with the exception of a higher incidence of rash.
The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE). Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, and Israel’s Ministry of Health. The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted priority review.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.
For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate.