Global Phase 3 Study Explores Belzutifan/Lenvatinib Doublet in Advanced RCC

The novel combination of belzutifan and lenvatinib will be tested against cabozantinib in a phase 3 clinical trial of patients with advanced renal cell carcinoma.

Enrollment has begun in the phase 3 study of belzutifan (Welireg) in combination with lenvatinib (Lenvima) versus cabozantinib (Cabometyx) in patients with advanced renal cell carcinoma (RCC) after anti-PD-1/PD-L1 therapy, according to a poster presented during the 2021 International Kidney Cancer Symposium: North America.

For patients with advanced clear cell RCC (ccRCC), there is no standard of care therapy for those who progress after treatment with PD-1/PD-L1 inhibitors or VEGF targeted therapies. With consideration of the 90% of patients with ccRCC who have lost function of the

von Hippel-Lindau (VHL) tumor suppressor gene and experience promoted tumor growth, the HIF-2a inhibitor is hypothesized to be helpful in combination with lenvatinib, which has demonstrated activity against ccRCC.

The phase 3 study (NCT04586231) will follow an open-label, multicenter, randomized, active-controlled design. The coprimary end points to be explored are progression-free survival (PFS) per RECISTs v1.1 by blinded independent central review, and overall survival (OS). Secondary end points will also be explored in the study including, objective response rate, duration of response, safety, and tolerability.

The approximate enrollment in the study will be 708 patients with advanced ccRCC whose immediate preceding treatment was anti-PD-1/PD-L1 therapy. Patients cannot have more than 2 prior systemic regimens and can only have received 1 prior anti-PD-1/PD-L1 therapy for locally advanced or metastatic disease. Patients are also required to have measurable disease per RECIST v1.1, and Karnofsky performance score of 70% or higher.

Those deemed eligible for enrollment will be randomized 1:1: to receive belzutifan 120 mg once daily combined with lenvatinib 20 mg once daily in an experimental am of 354 patients or cabozantinib 60 mg once daily in a control rm of 354 patients. Following treatment in the study patients will undergo a 30-day safety follow-up, an imaging follow-up every 8 weeks through week 80 followed by every 12 weeks thereafter, and a survival follow-up every 12 weeks for patients with documented progression.

Assessment of the coprimary endpoints will be performed with a stratified log-rank test with a hazard ratio estimated using a stratified Cox proportional hazard model. PFS and OS events observed during the study will be evaluated using the Kaplan-Meier method. Further, the stratified Miettinen and Nurminen method will be utilized to determine the ORR result.

For the safety analysis, investigators will grade adverse events per the Common Terminology Criteria for Adverse Events version 5.0. All patients who received at least 1 dose of belzutifan /lenvatinib or cabozantinib will be evaluated for safety and results will be analyzed through a tiered approach.

More than 80 locations worldwide are actively recruiting patients with advanced ccRCC to receive the experimental belzutifan plus lenvatinib combination or cabozantinib in the study.


Motzer R, Liu Y,Perini R, et al. Randomized, open-label, phase 3 study of belzutifan plus

lenvatinib versus cabozantinib in patients with advanced renal cell carcinoma after anti–pd-1/pd-l1 therapy. Presented at: 2021 International Kidney Cancer Symposium. November 5-6, 2021; Austin, TX.