An open-label phase 1 trial of lenvatinib plus pembrolizumab in patients with advanced selected solid tumors

Abstract

Background: Lenvatinib mesilate (lenvatinib) is an oral multiple RTK inhibitor that selectively inhibits the kinase activities of VEGFR1-3, in addition to other proangiogenic and oncogenic pathway-related RTKs including FGFR1-4, PDGFR α, KIT, and RET. Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Method: This phase 1 study was initiated to confirm the tolerability and safety for combination of lenvatinib plus pembrolizumab in patients with selected solid tumors; NSCLC, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma (excluding uveal melanoma) in Japan. Lenvatinib was administered orally (QD) and pembrolizumab was administered intravenously (Q3W) in subjects on a 21-day treatment cycle. DLT was evaluated during the first cycle (21 days). Results: As of 2 November 2017, all the 6 pts (3 Urothelial, 3 NSCLC) received lenvatinib 20 mg QD in combination with fixed dose of pembrolizumab 200 mg Q3W and completed Cycle 1 without DLT. The most common TEAEs (all grade, ≥ 3 of pts) were AST increased (6 pts), hypertension (6 pts), ALT increased (5 pts), fatigue (5 pts), hypothyroidism (5 pts), decreased appetite (4 pts), nausea (4 pts), proteinuria (3 pts), lipase increased (3 pts), thrombocytopenia (3 pts), and WBC decreased (3 pts). Grade 3 TEAEs (≥ 2 of pts) were AST increased, ALT increased, and γ -GTP increased (each 2 pts). No Grade 4 or 5 TEAEs were observed. Grade 5 AE was pneumonitis (1 pt). One complete and 1 partial response were observed in pts with urothelial carcinoma. Pharmacokinetic evaluation is ongoing and will be presented. Conclusions: Safety profile of lenvatinib in combination with pembrolizumab was tolerable and manageable with preliminary antitumor activities in Japanese pts with solid tumors, especially urothelial carcinoma.