FDA Approves Pembrolizumab With Chemotherapy for Primary Advanced or Recurrent Endometrial Carcinoma

Efficacy was evaluated in KEYNOTE-868/NRG-GY018 (NCT03914612), a multicenter, randomized, double-blind, placebo-controlled trial enrolling 810 patients with advanced or recurrent endometrial carcinoma. The trial 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 (pMMR) proficient cohort. Patients were randomized 1:1 to one of the following treatment arms:

• Pembrolizumab 200 mg every three weeks, paclitaxel 175 mg/m² and carboplatin AUC 5 mg/ml per minute for six cycles, followed by pembrolizumab 400 mg every six weeks for up to 14 cycles
• Placebo every three weeks, paclitaxel 175 mg/m² and carboplatin AUC 5 mg/ml per minute for six cycles, followed by placebo every six weeks for up to 14 cycles

Randomization 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 1.1. In the dMMR cohort, median PFS was not reached (NR) (95% 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 (HR = 0.30; 95% CI = 0.19, 0.48; p  < 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 < 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. See the prescribing information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125514s155lbl.pdf) for a complete list of adverse reactions.

The recommended pembrolizumab dose is 200 mg every three weeks or 400 mg every six weeks for up to 24 months or until patients experience disease progression or unacceptable toxicity. See the full prescribing information for pembrolizumab (https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125514s155lbl.pdf).

The review was conducted under Project Orbis (https://www.fda.gov/about-fda/oncology-center-excellence/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. FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, and Israel’s Ministry of Health for the review. The application reviews are ongoing at the other regulatory agencies. It also used the Assessment Aid (https://www.fda.gov/about-fda/oncology-center-excellence/assessment-aid), a voluntary submission from the applicant to facilitate the FDA’s assessment.

FDA granted the application priority review. FDA’s expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics).

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 (https://www.accessdata.fda.gov/scripts/medwatch/index.cfm) or by calling 800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate (https://www.fda.gov/about-fda/oncology-center-excellence/project-facilitate) at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov (mailto:OncProjectFacilitate@fda.hhs.gov).