A Phase 2 Trial of Lenvatinib 18 mg vs 14 mg Once Daily (QD) in Combination With Everolimus (5 mg QD) in Renal Cell Carcinoma

Based on findings from a phase 2 study, lenvatinib (LEN) plus everolimus (EVE) was approved in the United States and European Union for patients with advanced renal cell carcinoma (RCC) following 1 prior anti-angiogenic therapy. In that study, LEN 18 mg QD plus EVE 5 mg QD significantly prolonged progression-free survival (PFS) compared with either monotherapy. In the LEN+EVE cohort, grades 3 and 4 treatment-emergent adverse events (TEAEs) occurred in 71% of patients. We report the design of a multicenter, randomized, double-blind, phase 2 study to evaluate if a lower LEN starting dosage regimen provides similar efficacy with a better safety profile than LEN 18 mg plus EVE 5 mg (NCT03173560).

Eligible patients are aged ≥ 18 years with histologic or cytologic confirmation of predominantly clear cell RCC, advanced RCC, 1 prior anti-vascular endothelial growth factor therapy for advanced RCC, ≥ 1 measurable target lesion according to RECIST 1.1, and a Karnofsky Performance Status score of ≥ 70. Patients will receive LEN 18 mg or 14 mg QD plus EVE 5 mg QD in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The LEN 14-mg dose will be escalated to 18 mg if no intolerable grade 2, or any grade ≥ 3, TEAEs requiring dose reduction occur in cycle 1. The primary endpoints are objective response rate (ORR) at week 24 (ORR_24W) and the proportion of patients with intolerable grade 2, and any grade ≥ 3, TEAEs within 24 weeks after randomization. Secondary endpoints include PFS and ORR. An estimated 306 patients will be randomized. Sample size is based on detecting noninferiority of ORR_24W and superiority of the primary safety endpoint. Two interim analyses will be performed when 150 and 200 patients have completed 24 weeks of follow-up or discontinue earlier. Each analysis will test noninferiority and futility of the LEN 14-mg arm ORR_24W versus the 18-mg arm ORR_24W. An O’Brien-Fleming boundary will be used for noninferiority. If the 1-sided P-value is ≤ 0.005 at the first interim analysis, ≤ 0.014 at the second interim analysis, or ≤ 0.045 at the final analysis, then noninferiority in ORR_24W will be claimed. If the futility boundary is crossed (ie, 1-sided P-value is ≥ 0.776 at the first interim analysis or ≥ 0.207 at the second interim analysis), then futility will be claimed.