HC-7366 (GCN2 activator; ISR/metabolic-stress agonism) + belzutifan (HIF-2α inhibitor) posts 37% BORR in post–PD-(L)1/VEGF-TKI ccRCC

HC-7366 is an oral, selective activator of GCN2 kinase designed to drive the integrated stress response and suppress HIF/cell-cycle programs; belzutifan is an oral HIF-2α inhibitor. In this Phase 1b open-label dose-escalation/expansion study in heavily pretreated advanced clear-cell RCC (≥1 prior anti–PD-(L)1 and ≥1 VEGF-TKI; data cutoff Dec 10, 2025), 69 patients were treated (HC-7366 mono n=16; combo n=53), with efficacy-evaluable cohorts including mono 60mg (n=13), combo 40mg/120mg (n=19) and combo 60mg/120mg (n=19): BORR/cORR were 36.8%/26.3% at 40mg and 31.6%/31.6% at 60mg with DCR 89.5% and 84.2%, versus monotherapy BORR 15.4% (DCR 61.5%). Grade 3 AEs were common (71%–73% in combo cohorts), led by anemia (21%–23%) and hypoxia (8%–9%); dose reductions occurred in 29%–50% and discontinuations in ~9%–13% (one DLT: Grade 3 nausea at 40mg), a toxicity mix that looks directionally more intense than belzutifan monotherapy benchmarks (e.g., LITESPARK-005 ORR 21.9% vs everolimus 3.5%; PFS HR 0.75) but with a higher response signal than belzutifan alone historically in the same post–IO/VEGF-TKI setting.