52: LITESPARK-011: a randomized, phase 3 study of belzutifan plus lenvatinib versus cabozantinib after anti–PD-1/PD-L1 therapy in patients with advanced renal cell carcinoma

Background: First-line anti–PD-1/PD-L1 immunotherapy is standard of care for renal cell carcinoma (RCC), but treatment options are limited once progression occurs. Hypoxia-inducible factor (HIF)-2α has been identified as a key oncogenic driver in clear cell RCC (ccRCC). The first-in-class HIF-2α inhibitor belzutifan showed antitumor activity in ccRCC both as monotherapy and with cabozantinib. The randomized phase 3 LITESPARK-011 trial (NCT04586231) will evaluate the efficacy and safety of belzutifan + lenvatinib versus cabozantinib in heavily pretreated patients with advanced ccRCC who experienced progression after anti–PD-1/PD-L1 therapy.

Methods: Approximately 708 patients will be enrolled. Adults aged ≥18 years with locally advanced/metastatic ccRCC, no more than 2 prior systemic therapies (only 1 prior anti–PD-1/PD-L1 agent), measurable disease per RECIST v1.1, progression on or after a first- or second-line anti–PD-1/PD-L1 agent (most recent therapy or adjuvant treatment with progression on or within 6 months of last dose), and KPS score of ≥70% will be eligible. Patients will be randomly assigned 1:1 to receive oral belzutifan 120 mg once daily (QD) + lenvatinib 20 mg QD or oral cabozantinib 60 mg QD, stratified by geographic region (Western Europe, North America, or rest of the world), IMDC score (1, 2, or 3-6), and number of prior therapies (1 or 2). CT/MRI assessments will occur every 8 weeks (Q8W) through week 80, then Q12W thereafter. AEs will be reported through 30 days after treatment cessation (90 days for serious AEs). Primary end points are PFS per RECIST v1.1 by blinded independent central review (BICR) and OS; secondary end points include ORR and DOR per RECIST v1.1 by BICR and safety and tolerability. LITESPARK-011 is recruiting patients in Asia, Australia, Europe, North America, and South America.