Background:
Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT. LEN is approved in combination with everolimus (EVE) for treatment of metastatic RCC following 1 prior VEGF-targeted therapy. A phase 1b/2 study of LEN in combination with pembrolizumab (PEM) in patients with RCC LEN is also underway. We report the design of a multicenter, open-label, phase 3 trial of LEN plus EVE or PEM vs sunitinib (SUN; a standard therapy for RCC) as first-line treatment for advanced RCC.
Methods:
Patients aged ≥18 years with confirmed advanced RCC diagnosis, ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Karnofsky Performance Status ≥70, controlled blood pressure, and adequate organ function are eligible. Patients will be randomized 1:1:1 to receive LEN 18 mg/day + EVE 5 mg/day, LEN 20 mg/day + PEM 200 mg every 3 weeks, or SUN 50 mg/day (4 weeks on treatment followed by 2 weeks off) until disease progression, unacceptable toxicity, withdrawal of consent, or study end. The primary endpoint is to show superiority of LEN+EVE or LEN+PEM over single-agent SUN as first-line treatment for advanced RCC in improving progression-free survival (PFS). Secondary endpoints include comparison of objective response rate, overall survival, PFS on next-line therapy, health-related quality of life, and safety and tolerability in patients receiving LEN+EVE or LEN+PEM vs SUN. Exploratory endpoints include PFS in the LEN+PEM arm using immune-related RECIST, comparison of duration of response, disease control rate, and clinical benefit rate in patients treated with LEN+EVE or LEN+PEM vs SUN, and analysis of the relationship between blood biomarkers and outcome. No interim analysis is planned for efficacy or futility. Enrollment of 735 patients is planned to achieve 90% power at 2-sided α=0.05 to detect a difference in ≥1 of the primary comparisons.