As reported in The New England Journal of Medicine by Vicky Makker, MD, of Memorial Sloan Kettering Cancer Center, 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.¹

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 are not candidates for curative surgery or radiation.

Vicky Makker, MD

In the open-label trial, 827 patients from sites in 21 countries who had previously received at least one platinum-based chemotherapy regimen 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 in 28-day cycles. Patients could receive up to 35 doses of pembrolizumab. Treatment was continued until disease progression or unacceptable toxicity. Randomization in the total population was stratified by mismatch repair (MMR) status. The pMMR population consisted of 697 patients, including 346 in the lenvatinib/pembrolizumab group (84.2% of the group) and 351 in the chemotherapy group (84.4% of the 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 assessed 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 (95% confidence interval [CI] = 5.6–7.4 months) in the lenvatinib/pembrolizumab group vs 3.8 months (95% CI = 3.6–5.0 months) in the chemotherapy group in the pMMR population (hazard ratio [HR] = 0.60, 95% CI = 0.50–0.72, P < .001) and 7.2 months (95% CI = 5.7–7.6 months) vs 3.8 months (95% CI = 3.6–4.2 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.

Median overall survival was 17.4 months (95% CI = 14.2–19.9 months) in the lenvatinib/pembrolizumab group vs 12.0 months (95% CI = 10.8–13.3 months) in the chemotherapy group in the pMMR population (HR = 0.68, 95% CI = 0.56–0.84, P < .001) and 18.3 months (95% CI = 15.2–20.5 months) vs 11.4 months (95% CI = 10.5–12.9 months) in the total population (HR = 0.62, 95% CI = 0.51–0.75, P < .001).

Among patients with MMR-deficient status, hazard ratios were 0.36 (95% CI = 0.23–0.57) for progression-free survival and 0.37 (95% CI = 0.22–0.62) for overall survival. In other subgroup analyses, hazard ratios for progression-free survival were 0.58 (95% CI = 0.43–0.77) among patients with and 0.60 (95% CI = 0.48–0.76) among those without prior pelvic irradiation in the pMMR population and 0.53 (95% CI = 0.41–0.69) and 0.55 (95% CI = 0.44–0.68), respectively, in the total population. Hazard ratios were 0.59 (95% CI = 0.46–0.76) among those with and 0.56 (95% CI = 0.43–0.73) among those without endometrioid histology in the pMMR population and 0.52 (95% CI = 0.41–0.65) and 0.56 (95% CI = 0.43–0.73), respectively, in the total population.

Hazard ratios for overall survival were 0.78 (95% CI = 0.56–1.08) among those with and 0.62 (95% CI = 0.47–0.80) among those without prior pelvic radiation in the pMMR population and 0.69 (95% CI = 0.51–0.93) and 0.56 (95% CI = 0.44–0.72), respectively, in the total population. Hazard ratios were 0.78 (95% CI = 0.57–1.05) among those with and 0.56 (95% CI = 0.42–0.74) among those without endometrioid histology in the pMMR population and 0.65 (95% CI = 0.49–0.84) and 0.55 (95% CI = 0.42–0.72), respectively, in the total population.

An 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. Among responders, median response durations were 9.2 months (range = 1.6–23.7 months) vs 5.7 months (range = 0.0–24.2 months) in the pMMR population and 14.4 months (range = 1.6–23.7 months) vs 5.7 months (95% CI = 0.0–24.2 months) in the total population.

Adverse Events

The most common adverse events of any grade with lenvatinib/pembrolizumab were hypertension (64.0%), hypothyroidism (57.4%), diarrhea (54.2%), nausea (49.5%), decreased appetite (44.8%), and vomiting (36.7%). Grade ≥ 3 adverse events occurred in 88.9% of the lenvatinib/pembrolizumab group vs 72.7% of the chemotherapy group; the most common events in the lenvatinib/pembrolizumab group were hypertension (37.9%) and decreased weight (10.3%) and in the chemotherapy group, 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. The most common immune-mediated adverse events of any grade in the lenvatinib/pembrolizumab group were hypothyroidism (57.6%), hyperthyroidism (11.6%), and colitis (4.7%). 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. Dr. Makker has received institutional research support from or has served as a consultant/advisor to AstraZeneca, Clovis Oncology, Eisai, Faeth, ­Genentech, GlaxoSmithKline, iTEOS Therapeutics, Karyopharm Therapeutics, Moreo, MSD, Novartis, Takeda Oncology, and Zymeworks.

REFERENCE

1. Makker V, Colombo N, Herraez AC, et al: Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med 386:437-448, 2022.