Abstract

Background: Patients with recurrent glioblastoma (GBM) have a poor prognosis and limited treatment options. The authors report the efficacy and safety of lenvatinib plus pembrolizumab in participants with recurrent GBM enrolled in the phase 2, multicohort LEAP-005 study (NCT03797326). Methods: Eligible participants had histologically confirmed GBM (World Health Organization grade IV) with disease progression since previous treatment, and one or more prior lines of therapy. Participants were enrolled regardless of tumor programmed cell death ligand 1 (PD-L1) status and received oral lenvatinib 20 mg per day plus intravenous pembrolizumab 200 mg every 3 weeks. The dual primary end points were objective response rate (ORR; per Response Assessment in Neuro-Oncology by blinded independent central review) and safety. Results: A total of 101 participants were enrolled, with median (range) follow-up of 23.7 (16.4?46.6) months. The median (range) duration of treatment with lenvatinib plus pembrolizumab was 3.4 (0.3?32.2) months. The ORR (95% confidence interval [CI]) was 20% (13%?29%), with 20 participants achieving a partial response, and the median (range) duration of response was 3.7 (1.4+ to 27.6) months. Median (95% CI) progression-free survival was 3.0 (2.7?4.0) months and median (95% CI) overall survival was 8.6 (7.4?10.8) months. Responses were observed regardless of PD-L1 status. Treatment-related adverse events occurred in 93 participants (92%; grade 3?5, n = 41 [41%]). Two participants died due to treatment-related adverse events (intestinal perforation and pneumonitis). Conclusions: The combination of lenvatinib plus pembrolizumab demonstrated antitumor activity in a small subpopulation of participants with recurrent GBM as second-line or later treatment. The safety profile was manageable. © 2025 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.