As reported in The New England Journal of Medicine by Vicky Makker, MD, and colleagues, the phase III Study 309-KEYNOTE-775 trial has shown prolonged progression-free and overall survival with lenvatinib plus pembrolizumab vs physician’s choice of chemotherapy among previously treated patients with advanced endometrial cancer, including those with mismatch repair–proficient (pMMR) disease.
The trial supported the July 2021 regular approval of the combination for treatment of patients with advanced endometrial carcinoma that is not microsatellite instability–high or mismatch repair–deficient who have disease progression following prior systemic therapy in any setting, and who are not candidates for curative surgery or radiation.
Vicky Makker, MD
Study Details
The open-label trial included 827 patients from sites in 21 countries who had previously received at least one platinum-based chemotherapy regimen. They were randomly assigned between June 2018 and February 2020 to receive lenvatinib at 20 mg once daily plus pembrolizumab at 200 mg every 3 weeks (n = 411) or physician’s choice of chemotherapy (n = 416); chemotherapy options consisted of doxorubicin at 60 mg/m2 every 3 weeks or paclitaxel at 80 mg/m2 weekly for 3 weeks on/1 week off.
The pMMR population consisted of 697 patients, including 346 in the lenvatinib/pembrolizumab group and 351 in the chemotherapy group. The primary endpoints were progression-free survival on blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1, and overall survival among the pMMR population and the total population.
Survival Outcomes
At data cutoff (in October 2020) for the final analysis of progression-free survival and first interim analysis of overall survival, median follow-up was 12.2 months in the lenvatinib/pembrolizumab group and 10.7 months in the chemotherapy group.
Median progression-free survival was 6.6 months in the lenvatinib/pembrolizumab group vs 3.8 months in the chemotherapy group in the pMMR population (hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.50–0.72, P < .001) and 7.2 months vs 3.8 months in the total population (HR = 0.56, 95% CI = 0.47–0.66, P < .001).
Among all patients, 28.0% of the lenvatinib/pembrolizumab group and 48.1% of the chemotherapy group received subsequent anticancer systemic therapy. In the chemotherapy group pMMR population, 9.1% received lenvatinib/pembrolizumab and 16.9% received PD-1 pathway–targeting monotherapy.
Median overall survival was 17.4 months in the lenvatinib/pembrolizumab group vs 12.0 months in the chemotherapy group in the pMMR population (HR = 0.68, 95% CI = 0.56–0.84, P < .001) and 18.3 months vs 11.4 months in the total population (HR = 0.62, 95% CI = 0.51–0.75, P < .001).
Objective response was observed in 30.3% vs 15.1% of patients in the pMMR population and in 31.9% vs 14.7% in the total population.
KEY POINTS
- Lenvatinib/pembrolizumab significantly improved progression-free and overall survival vs chemotherapy among all patients and among those with pMMR disease.
- Among all patients, median progression-free and overall survival were 7.2 vs 3.8 months and 18.3 vs 11.4 months.
Adverse Events
The most common adverse events of any grade with lenvatinib/pembrolizumab were hypertension (64.0%), hypothyroidism (57.4%), and diarrhea (54.2%). Grade ≥ 3 adverse events occurred in 88.9% of patients in the lenvatinib/pembrolizumab group vs 72.7% of the chemotherapy group; the most common in the combination group were hypertension (37.9%) and decreased weight (10.3%), and the most common in the chemotherapy group were neutropenia (25.8%) and anemia (14.7%).
The most common serious adverse events were hypertension (4.2%) in the lenvatinib/pembrolizumab group and febrile neutropenia (4.1%) in the chemotherapy group. Adverse events led to study drug discontinuation in 33.0% of patients (lenvatinib in 30.8%, pembrolizumab in 18.7%, both in 14.0%) vs 8.0% of patients. Adverse events led to death in 5.7% vs 4.9% of patients.
The investigators concluded, “Lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer.”
Disclosure: The study was funded by Eisai and Merck Sharp and Dohme, a subsidiary of Merck. For full disclosures of the study authors, visit nejm.org.
