HC-7366/Belzutifan Exhibits Manageable Safety Profile in Advanced RCC

Treatment with HC-7366—a selective, potent inhibitor of general control nonderepressible 2 (GCN2) kinase—alone or in combination with belzutifan (Welireg) displayed manageable safety consistent with the known profile of each agent among patients with locally advanced or metastatic renal cell carcinoma (RCC), according to findings from a phase 1b trial (NCT06234605) presented in a poster at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.

What Were The Safety Findings With HC-7366 In This RCC Population?

Safety findings revealed that any-grade adverse effects (AEs) occurred in 100% of patients across all dose levels in the combination cohorts, including the 20-mg arm (n = 7), 40-mg arm (n = 22), and 60-mg arm (n = 24). In patients who received HC-7366 monotherapy (n = 16), the rate of any-grade AEs was 93.8%. Moreover, grade 3 or higher AEs were observed at a rate of 71.4%, 81.8%, and 75.0% in the 20-mg, 40-mg, and 60-mg combination arms; 62.5% of the monotherapy arm experienced grade 3 or higher AEs. Treatment-related AEs (TRAEs) occurred at a rate of 85.7%, 100%, and 95.8% in the combination arms, respectively, and at a rate of 93.8% of the monotherapy arm; grade 3 or higher TRAEs occurred in 42.9%, 68.2%, 54.2%, and 43.8% of each arm.

Serious AEs were reported at a rate of 57.1%, 27.3%, and 54.2% in the combination arms and 18.8% in the monotherapy arm. Serious TRAEs were reported at a rate of 14.3%, 4.5%, 20.8%, and 12.5%, respectively. In the combination arms, 0%, 9.1%, and 12.5% experienced TRAE-related discontinuations; 14.3%, 50.0%, and 29.2% experienced TRAE-related dose reductions; and only 1 patient in the 40-mg cohort died due to a TRAE. In the monotherapy arm, 12.5% experienced TRAE-related discontinuations, and 37.5% experienced TRAE-related dose reductions; no TRAE-related deaths were reported.

“The combination of HC-7366, at doses of 20 mg, 40 mg, and 60 mg with belzutifan [at] 120 mg, demonstrated a manageable toxicity profile consistent with the known profiles of the respective drugs,” Neil J. Shah, MBBS, assistant attending physician and genitourinary oncologist at Memorial Sloan Kettering Cancer Center, wrote in the presentation with study coinvestigators. “Preliminary efficacy analyses results indicate encouraging overall response and disease control rates, with a low [rate of] primary [disease progression].”

Trial Design

Patients in the trial were previously treated with at least 1 anti–PD/PD-L1 therapy and at least 1 VEGF-tyrosine kinase inhibitor (TKI). Those enrolled on the monotherapy cohort underwent between 1 and 4 prior lines of therapy and had an ECOG performance status of 0 to 1. In the belzutifan combination cohort, patients received up to 3 prior lines of therapy, excluding prior HIF-2α inhibition.

In the dose-escalation portion of the trial, patients received 60 mg of HC-7366 alone or escalating doses of HC-7366 starting at 20 mg up to 60 mg plus 120 mg of belzutifan. In dose expansion 1, patients received 40 mg or 60 mg of HC-7366 with 120 mg of belzutifan.

In the monotherapy cohort, the median age was 64.5 years (range, 36-76), 68.8% of patients were male, and 62.5% had an ECOG performance status of 1. The median number of prior lines of therapies was 3 (range, 1-5), with 4 patients having received prior belzutifan and 9 treated with 2 or more TKIs.

In the 20-mg, 40-mg, and 60-mg combination arms, the median age was 58 years (range, 45-75), 61 years (range, 46-81), and 67 years (range, 43-77), respectively. A total of 85.7%, 77.3%, and 83.3% were male; 57.1%, 54.5%, and 58.3% had an ECOG performance status of 0. The median number of prior therapy lines was 2 (range, 1-3), 2 (range, 1-4), and 2 (range, 1-4); 1, 9, and 8 patients in each arm, respectively, received at least 2 prior TKIs.

The primary end points of the study were safety, tolerability, and investigator-assessed objective response rate (ORR) per RECIST v1.1 criteria.

The study investigators noted that a second expansion phase is ongoing, with final results expected to further support the development of HC-7366 for patients with locally advanced or metastatic RCC.

What Were The Preliminary Efficacy Data?

In the 20-mg, 40-mg, and 60-mg combination arms, the biologic ORR was 0%, 37%, and 37%, respectively; the confirmed ORR was 0%, 26%, and 37%. Moreover, the disease control rate (DCR) was 71%, 89%, and 84%. The median time to response was not found in the 20-mg cohort but was 3.8 months in the 40-mg cohort and 3.7 months in the 60-mg cohort. The 6-month progression-free survival (PFS) rate was 43%, 58%, and 73% in the respective arms.

In the monotherapy arm, the biologic ORR was 15%, with no confirmed responders to treatment observed. The DCR was 62%, with a median time to response of 1.6 months. The 6-month PFS rate was 15%.

Reference

Shah NJ, Bupathi M, McKay R, et al. A phase 1b, open-label, safety, tolerability, and efficacy study of HC-7366 in combination with belzutifan in patients with locally advanced (inoperable) or metastatic renal cell carcinoma. J Clin Oncol. 2026;44(suppl 16):4534. doi:10.1200/JCO.2026.44.16_suppl.4534