Phase 3 belzutifan HIF-2α inhibitor + zanzalintinib MET/VEGFR TKI vs cabozantinib

Merck Sharp & Dohme (MSD) is running LITESPARK-033 (MK-6482-033), a Phase 3, randomized, open-label, multicenter study in recurrent advanced clear cell RCC after prior adjuvant anti–PD-1/PD-L1 therapy. Participants are randomized 1:1 to belzutifan (MK-6482), an oral HIF-2α inhibitor, plus zanzalintinib, an oral multikinase TKI targeting MET (c-Met) and VEGF receptors, versus Exelixis’s cabozantinib, an oral multikinase inhibitor (including MET, AXL/RET, and VEGFR2 pathways). Co-primary endpoints are progression-free survival by blinded independent central review (RECIST 1.1) and overall survival; key secondaries include objective response rate and duration of response. The scientific/commercial angle is “post-adjuvant IO recurrence” as a distinct and growing segment (especially after pembrolizumab adjuvant use), testing whether dual hypoxia signaling blockade (HIF-2α) plus angiogenesis/MET inhibition can outperform a widely used VEGFR/MET TKI. Today’s care after recurrence following adjuvant anti–PD-(L)1 often shifts to VEGFR TKIs (cabozantinib, axitinib, lenvatinib combinations) and selected IO/TKI regimens depending on prior IO exposure, timing, and risk group, so this trial directly challenges a common TKI standard in that setting.