A Phase 1b/2 Trial of Lenvatinib+Pembrolizumab in Patients With Renal Cell Carcinoma S1

Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor alpha, RET, and KIT. LEN was approved in combination with everolimus to treat advanced renal cell carcinoma (RCC) after 1 prior VEGF-targeted treatment. We report results for the RCC cohort of a phase 1b/2 trial of LEN+pembrolizumab (PEM) in patients with selected solid tumors (NCT02501096).

This was a multicenter open-label study. Patients had metastatic clear cell RCC, measurable disease according to immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status ≤1. LEN 20 mg/d plus PEM 200 mg intravenously every 3 weeks was assessed as the maximum tolerated dose and recommended phase 2 dose in phase 1b. Tumor assessments were performed by trial investigators using irRECIST. The primary phase 2 endpoint was objective response rate at 24 weeks. Secondary endpoints included objective response rate, progression-free survival, and duration of response.

30 Patients were enrolled in either the phase 1b (8 patients) or phase 2 cohort (22 patients). Data cutoff was March 1, 2017. 12 (40%) Patients had 0, 10 (33%) patients had 1, and 8 (27%) patients had ≥2 prior anti-cancer therapies. Of patients who received prior medication (n=18 [60%]), 16 (53%) received prior VEGF-targeted therapy. Efficacy outcomes are summarized in the table. At data cutoff, 17 (57%) patients were still receiving treatment, 8 (27%) completed treatment due to disease progression, and 5 (17%) discontinued treatment. The most common any-grade treatment-emergent adverse events were diarrhea (83%), fatigue (70%), hypothyroidism (67%), stomatitis (60%), hypertension (57%), and nausea (57%). Toxicities were manageable with dose interruption and/or modification and no new safety signals were found.

Combination treatment with LEN+PEM showed promising antitumor activity and an acceptable safety profile. A phase 3 trial of LEN+PEM and LEN+everolimus, vs sunitinib in first-line treatment for metastatic clear cell RCC is ongoing.