On June 17, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) in combination with carboplatin and paclitaxel followed by single-agent pembrolizumab for adult patients with primary advanced or recurrent endometrial carcinoma; on June 14, the agency approved durvalumab (Imfinzi) in combination with carboplatin plus paclitaxel followed by single-agent durvalumab for adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair–deficient (dMMR).
KEYNOTE-868/NRG-GY018
Efficacy of the pembrolizumab/carboplatin/paclitaxel regimen was evaluated in KEYNOTE-868/NRG-GY018 (ClinicalTrials.gov identifier NCT03914612), a multicenter, randomized, double-blind, placebo-controlled trial which enrolled 810 patients with advanced or recurrent endometrial carcinoma. The trial included two separate cohorts based on mismatch repair (MMR) status: 222 patients in the dMMR cohort, and 588 patients in the mismatch repair–proficient (pMMR) cohort.
Patients were randomly assigned 1:1 to one of the following treatment arms:
- Pembrolizumab at 200 mg every 3 weeks, paclitaxel at 175 mg/m2, and carboplatin at area under the curve (AUC) = 5 mg/mL/min for 6 cycles, followed by pembrolizumab at 400 mg every 6 weeks for up to 14 cycles.
- Placebo every 3 weeks, paclitaxel at 175 mg/m2, and carboplatin at AUC = 5 mg/mL/min for 6 cycles, followed by placebo every 6 weeks for up to 14 cycles.
Random assignment was stratified according to MMR status, Eastern Cooperative Oncology Group performance status (0 or 1 vs 2), and receipt of prior adjuvant chemotherapy.
The major efficacy outcome measure was progression-free survival, assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In the dMMR cohort, median progression-free survival was not reached (95% CI = 30.7 months to not reached) in the pembrolizumab and chemotherapy arm and 6.5 months (95% CI = 6.4–8.7 months) in the placebo and chemotherapy arm (hazard ratio [HR] = 0.30, 95% CI = 0.19–0.48, P < .0001). In the pMMR cohort, median progression-free survival was 11.1 months (95% CI = 8.7–13.5 months) in the pembrolizumab and chemotherapy arm and 8.5 months (95% CI = 7.2–8.8 months) in the placebo and chemotherapy arm (HR = 0.60, 95% CI = 0.46–0.78, P < .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 which provides a framework for the concurrent submission and review of oncology drugs among international partners. For this review, the 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.
DUO-E
Efficacy of the durvalumab/carboplatin/paclitaxel regimen was evaluated in DUO-E (NCT04269200), a randomized, multicenter, double-blind, placebo-controlled trial in patients with primary advanced or recurrent endometrial cancer. Tumor MMR status was a stratification factor and was assessed using an immunohistochemistry tumor tissue test.
Patients were randomly assigned 1:1:1 to one of the following treatment arms:
- Durvalumab at 1,120 mg with carboplatin plus paclitaxel every 3 weeks for a maximum of six cycles. Following completion of chemotherapy, patients received durvalumab at 1,500 mg every 4 weeks as maintenance therapy until disease progression.
- Placebo with carboplatin and paclitaxel every 3 weeks for a maximum of six cycles. Following completion of chemotherapy, patients received placebo every 4 weeks until disease progression.
- An additional investigational combination regimen.
The major efficacy outcome measure was progression-free survival, determined by investigator assessment using RECIST version 1.1.
While a statistically significant improvement in progression-free survival was observed in the overall population for durvalumab with carboplatin plus paclitaxel compared to carboplatin and paclitaxel alone, the improvement in the overall population was primarily attributed to patients with dMMR tumors based on an exploratory analysis by tumor MMR status. In 95 patients with dMMR tumors, median progression-free survival was not reached (95% CI = not reached to not reached) in the durvalumab arm and was 7 months (95% CI = 6.7–14.8 months) in the placebo arm (HR = 0.42, 95% CI = 0.22–0.80). Overall survival, an additional efficacy outcome measure, was immature at the time of the progression-free survival analysis.
The most common adverse reactions occurring in > 25% of patients who received durvalumab in combination with carboplatin and paclitaxel were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, diarrhea, vomiting, and cough. The prescribing information provides the complete adverse reactions.
The recommended durvalumab dose for patients with a body weight ≥ 30 kg is 1,120 mg with carboplatin plus paclitaxel every 3 weeks for six cycles, followed by single- agent durvalumab at 1,500 mg every 4 weeks. The recommended durvalumab dose for patients with a body weight < 30 kg is 15 mg/kg with carboplatin and paclitaxel every 3 weeks for six cycles, followed by durvalumab at 20 mg/kg every 4 weeks.
This review used the Assessment Aid.
