Combining HC-7366 with belzutifan in patients with renal cell carcinoma to alter tumor and microenvironment: Pharmacokinetic and pharmacodynamic (PK/PD) analysis of a phase 1b study.

4535 Background: Clear cell renal cell carcinoma (ccRCC), characterized by loss of von Hippel-Lindau (VHL) tumor suppressor function, and constitutive stabilization of hypoxia-inducible factor (HIF) proteins results in activation of genes promoting angiogenesis, metabolic reprogramming including altered lipid metabolism and glycolysis, cell proliferation, and immunosuppressive remodeling of the tumor microenvironment. HC-7366 is a novel, selective GCN2 kinase activator that regulates metabolic stress via the ATF4–driven integrated stress response. Preclinically, GCN2 hyperactivation with HC-7366 enhances belzutifan (BEL) activity, broadly impairing stress adaptation, disrupting tumor metabolism, decreasing HIF expression, inhibiting the cell cycle, and remodeling the tumor immune microenvironment. Methods: In this phase 1b study (NCT06234605), 69 patients with advanced ccRCC received HC-7366 monotherapy (60 mg QD; n=16) or HC-7366 (20 mg, n=7; 40 mg, n=22; 60 mg, n=24) plus BEL (120 mg QD). Blood samples for soluble biomarkers and paired biopsies for IHC were collected per IRB-approved guidelines. Results: Overall, PK analysis (N=69) demonstrated steady state free exposure of HC-7366 at 40-60 mg doses (Cmax = 5.8 ng/mL, AUC = 75 h*ng/mL) that were consistent with exposures providing maximal BEL combination benefit preclinically. Compared with screening biopsies, all on-treatment biopsies at week 3 (8/8) showed induction of the ATF4 pathway biomarker ASNS (asparagine synthetase). Baseline HIF expression analysis by IHC from 52 patients demonstrated that 33 patients (63%) express mid to high levels of HIF1 and HIF2. HIF1α, but not HIF2α, was reduced consistently with treatment across all cohorts (7/8, 66-98% reduction). Reduced cell cycle biomarkers, including pRB and Ki67 (4/4), and increased frequency of CD8 + PD1 + TCF1 + Lag3 - Tim3 - T-cells (3/3), suggesting ICI responsiveness, were observed in the 40-60 mg combination cohorts. Systemic changes were also observed in serum, including deep and sustained inhibition of EPO, decreases in proangiogenic cytokines like VEGF-A and PDGF-BB, and changes in adipokines that counter RCC progression (Table 1). Low baseline serum levels of KIM-1 predicted response to the combination (p=0.005). Conclusions: Early clinical findings suggest HC-7366 + BEL is associated with modulation of angiogenic and immune-related pathways in ccRCC, providing a rationale for the combination with ICIs and/or VEGFR-TKIs. Clinical trial information: NCT06234605 . Avg max change with treatment. Biomarker 60 mg mono 20 mg combo 40 mg combo 60 mg combo EPO (week 2) -43% -82% -81% -84% Chemerin (week 2) -34% -16% -36% -28% Adiponectin (week 5) +64% +35% +46% +36% VEGF-A (week 9) -53% -42% -28% -37% PDGF-BB (week 9) -30% -20% -54% -63%