HC-7366 Plus Belzutifan Shows Favorable PK/PD Profile in Advanced ccRCC

The addition of selective GCN2 kinase activator HC-7366 to belzutifan (Welireg) demonstrated early activity and favorable systemic and tumor microenvironment (TME) changes to overcome HIF2α resistance among patients with advanced clear cell renal cell carcinoma (ccRCC), according to findings from a phase 1b study (NCT06234605) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Findings from a pharmacokinetic analysis revealed that steady state free exposure of HC-7366 at 40- to 60-mg doses were clinically consistent with exposures maximizing combinatorial benefit with belzutifan. Additionally, on-treatment biopsies at week 4 showed ATF4 pathway biomarker asparagine synthetase induction.

Moreover, HIF1α was decreased in cycle 2, day 1 biopsies compared with screening in 7 of 8 samples across all treatment cohorts, with HIF2α expression decreasing in the 40-mg and 60-mg cohorts of the combination regimen in 3 of 4 paired tumor biopsies. Regarding modulation of the TME, 3 of 3 biopsy pairs from the 40-mg and 60-mg cohorts displayed non-terminally exhausted CD8 T cells, all of which were associated with response to immune checkpoint inhibition.

Among patients with HIF1α and HIF2α co-expression who received 40 mg to 60 mg of HC-7366 as part of the combinatorial regimen, 58% experienced partial responses (PR). In contrast, 17% of patients with HIF1α expression only, 17% of those with low HIF expression, and 8% of those with HIF2α expression experienced PRs. Of note, 75% of PRs were observed among patients with more than 2% of tumor cells expressing HIF1α.

“HC-7366 [plus] belzutifan demonstrated several favorable changes systemically as well as in the TME that address potential mechanisms of resistance to HIF2a inhibition,” Benjamin Garmezy, MD, associate director of genitourinary research for Sarah Cannon Research Institute (SCRI), a medical oncologist at SCRI Oncology Partners, and executive cochair of the Genitourinary Cancer Research Executive Committee at SCRI specializing in genitourinary cancers, wrote in the presentation with study coinvestigators.¹ “Notably, modulation of angiogenic and immune-related pathways in ccRCC provides additional rationale for the combination with [immune checkpoint inhibitors] and/or VEGFR-TKIs.”

Patients in the trial were previously treated with at least 1 anti–PD/PD-L1 therapy and at least 1 VEGF-TKI. Those enrolled on the monotherapy cohort with 60 mg of HC-7366 (n = 16) underwent between 1 and 4 prior lines of therapy and had an ECOG performance status of 0 to 1. In the belzutifan combination cohorts, patients received up to 3 prior lines of therapy, excluding prior HIF-2α inhibition.

In the dose-escalation phase of the trial, patients received escalating doses of HC-7366 at 20 mg (n = 7), 40 mg (n = 6), or 60 mg (n = 5) plus 120 mg of belzutifan. In the dose-expansion portion of the trial, HC-7366 was given at 40 mg (n = 16) or 60 mg (n = 19) plus 120 mg of belzutifan.

In the translational plan, plasma and serum samples were gathered on days 1, 8, 15, 21, and 28 of cycles 1, 2, 3, and 6, as well as day 1 of every 4 cycles thereafter. Tumor biopsies were gathered at screening as well as cycle 2, day 1 ± 7 days.

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.² 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.

Plasma and serum tissue were collected to evaluate pharmacodynamics and soluble pharmacodynamic biomarkers such as angiogenesis and metabolism. Tumor biopsies were collected to assess GCN2 pathway activation, baseline/on treatment effects on HIF, cell cycle effects, and immune modulation.

The investigators noted that the biology of ccRCC was characterized by HIF stabilization leading to core oncogenic features such as hypoxia signaling, metabolic reprogramming, cell-cycle dysregulation, and immune suppression. They purported that through GCN2-dependent integrated stress response induction, HC-7366 may be able to target several vulnerabilities. Furthermore, through the combination with belzutifan, a simultaneous deepening of HIF pathway suppression and blocking of resistance mechanisms through broad, coordination of integrated stress response activation could optimize outcomes for these patients.

References

1. Garmezy B, Emamekhoo H, Gelmann EP, et al. Combining HC-7366 with belzutifan in patients with renal cell carcinoma alters tumor and microenvironment: pharmacokinetic and pharmacodynamic (PK/PD) analysis of a phase 1b study. J Clin Oncol. 2026;44(suppl 16):4535. doi:10.1200/JCO.2026.44.16_suppl.4535
2. 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