Toxicity and efficacy of lenvatinib plus pembrolizumab in advanced endometrial cancer: a real-world retrospective analysis

Mali Barbi; Chung-Shien Lee; Husneara Rahman; Kit Ling Cheng; Veena S John

doi:10.3389/fonc.2025.1622253

Toxicity and efficacy of lenvatinib plus pembrolizumab in advanced endometrial cancer: a real-world retrospective analysis

Front Oncol. 2025 Sep 8:15:1622253. doi: 10.3389/fonc.2025.1622253. eCollection 2025.

Authors

Mali Barbi^{1

2}, Chung-Shien Lee^{1

3}, Husneara Rahman⁴, Kit Ling Cheng¹, Veena S John¹

Affiliations

¹ Division of Medical Oncology, Department of Medicine, Northwell Health Cancer Institute, New Hyde Park, NY, United States.
² Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States.
³ College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.
⁴ Biostatistics Unit, Office of Academic Affairs, Northwell Health, New Hyde Park, NY, United States.

Abstract

Background: The treatment landscape for advanced recurrent endometrial cancer (EC) has been transformed with the introduction of lenvatinib and pembrolizumab, supported by results from the KEYNOTE-775 trial. However, the recommended 20 mg daily lenvatinib dose often results in significant toxicity, limiting its use in clinical practice.

Objective: To evaluate the toxicity and efficacy of reduced (≤10 mg) versus higher (>10 mg) initial doses of lenvatinib combined with pembrolizumab in patients with advanced recurrent EC.

Methods: In this retrospective cohort study, patients with EC treated with lenvatinib and pembrolizumab were stratified by initial lenvatinib dose into reduced (≤10 mg) and higher (>10 mg) groups. Study endpoints included progression-free survival (PFS), overall survival (OS) and treatment-related toxicity.

Results: Of the 92 patients included, 62% initiated lenvatinib at ≤10 mg and only 14.1% received the recommended 20 mg dose. Baseline characteristics were comparable between groups, except for age (71.2 vs. 67.5 years; p = 0.003). Grade ≥2 adverse events occurred in 74% of patients, with half experiencing treatment interruptions, and 36% discontinuations, primarily due to fatigue, diarrhea, or thromboembolic events. While unadjusted PFS and OS did not differ significantly between groups (p = 0.074 and p = 0.148, respectively), age-adjusted analysis showed significantly higher hazard of progression or death in the reduced-dose group (HR: 2.92; 95% CI: 1.32-6.44; p = 0.008).

Conclusion: This is the largest real-world study to date evaluating initial lenvatinib dosing strategies in advanced EC. Our findings suggest that although reduced starting doses (≤10 mg) are commonly used to mitigate toxicity, they may compromise efficacy. These results challenge current prescribing patterns and emphasize the need for prospective studies to define optimal dosing strategies.

Keywords: KEYNOTE-775 trial; adverse events; dose optimization; endometrial cancer; lenvatinib; microsatellite-stable (MSS); pembrolizumab.