First-Line Lenvatinib Plus Pembrolizumab Versus Chemotherapy for Advanced Endometrial Cancer: A Randomized, Open-Label, Phase III Trial

Abstract

Purpose: Lenvatinib plus pembrolizumab (len + pembro) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in previously treated advanced or recurrent endometrial cancer (aEC) in the phase III Study 309/KEYNOTE-775. We report results from the phase III, randomized, open-label European Network of Gynaecological Oncological Trial-en9/LEAP-001 study (ClinicalTrials.gov identifier: NCT03884101) that evaluated len + pembro versus chemotherapy in first-line aEC.

Methods: Patients with stage III to IV or recurrent, radiographically apparent EC and no previous chemotherapy or disease progression ≥6 months after neo/adjuvant platinum-based chemotherapy were randomly assigned 1:1 to lenvatinib 20 mg once daily plus pembrolizumab 200 mg once every 3 weeks or paclitaxel 175 mg/m² plus carboplatin AUC 6 mg/mL/min once every 3 weeks. Primary end points were PFS and OS, evaluated in the mismatch repair-proficient (pMMR) and all-comers populations. Noninferiority was assessed for OS at final analysis (FA) for len + pembro versus chemotherapy (multiplicity-adjusted, one-sided nominal alpha, .0159; null hypothesis-tested hazard ratio [HR], 1.1).

Results: Eight hundred forty-two patients were randomly assigned (len + pembro, n = 420 [pMMR population, n = 320]; chemotherapy, n = 422 [pMMR population, n = 322]). At FA (data cutoff, October 2, 2023), median PFS (95% CI) in the pMMR population was 9.6 (8.2 to 11.9) versus 10.2 (8.4 to 10.5) months with len + pembro versus chemotherapy (hazard ratio [HR], 0.99 [95% CI, 0.82 to 1.21]) and among all-comers was 12.5 (10.3 to 15.1) versus 10.2 (8.4 to 10.4) months (HR, 0.91 [95% CI, 0.76 to 1.09]; descriptive analyses). Median OS (95% CI) in the pMMR population was 30.9 (25.4 to 37.7) versus 29.4 (26.2 to 35.4) months with len + pembro versus chemotherapy (HR, 1.02 [95% CI, 0.83 to 1.26]; noninferiority P = .246, not statistically significant per multiplicity control strategy) and among all-comers was 37.7 (32.2 to 43.6) versus 32.1 (27.2 to 35.7) months (HR, 0.93 [95% CI, 0.77 to 1.12]). Grade ≥3 treatment-related adverse events occurred in 331/420 (79%) versus 274/411 (67%) treated patients.

Conclusion: First-line len + pembro did not meet prespecified statistical criteria for PFS or OS versus chemotherapy in pMMR aEC.

FIG 1.

LEAP-001 trial profile. ^aCompleted 35 infusions of pembrolizumab in cases where lenvatinib was discontinued before 35 infusions of pembrolizumab. ^bReceived seven or more cycles of paclitaxel plus carboplatin, or per local standard. ^cIncludes patients with clinical progression or progressive disease. ITT, intention-to-treat; pMMR, mismatch repair-proficient.

FIG 2.

Descriptive analysis of PFS at the time of the final overall survival analysis. Kaplan-Meier estimates of PFS (A) in the pMMR population and among all-comers; (B) in key patient subgroups in the pMMR population and among all-comers; (C) in the dMMR subgroup; and (D) in the subgroup of patients in the pMMR and all-comers populations who had received previous neoadjuvant or adjuvant chemotherapy. Tick marks indicate censored data. ^aIncludes nonendometrioid, adenocarcinoma with no further information (17 patients in the pMMR population; 22 patients among all-comers), and other histologies (two patients in the pMMR population; three patients among all-comers). dMMR, mismatch repair-deficient; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; MMR, mismatch repair; NR, not reached; PFS, progression-free survival; pMMR, mismatch repair-proficient.

FIG 3.

Kaplan-Meier estimates of OS (A) in the pMMR population and among all-comers; (B) in key patient subgroups in the pMMR population and among all-comers; (C) in the dMMR subgroup; and (D) in the subgroup of patients in the pMMR and all-comers populations who had received previous neoadjuvant or adjuvant chemotherapy. Tick marks indicate censored data. ^aIncludes nonendometrioid, adenocarcinoma with no further information (17 patients in the pMMR population; 22 patients among all-comers), and other histologies (two patients in the pMMR population; three patients among all-comers). dMMR, mismatch repair-deficient; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; MMR, mismatch repair; NR, not reached; OS, overall survival; PFS, progression-free survival; pMMR, mismatch repair-proficient.

FIG 4.

Confirmed tumor responses. Objective response rates and duration of response among patients with a complete or partial response (A) in the pMMR population and among all-comers; (B) in the dMMR subgroup; and (C) in the subgroup of patients who had received previous neoadjuvant or adjuvant chemotherapy. ^aPostbaseline assessment(s) available, but not evaluable. ^bNo postbaseline assessment available for response evaluation. dMMR, mismatch repair-deficient; DOR, duration of response; ORR, objective response rate; pMMR, mismatch repair-proficient.