Abstract 4615: HC-7366, a potent GCN2 activator, complements belzutifan, a HIF-2⍺ antagonist, by providing combination benefit in belzutifan-sensitive models and monotherapy activity in belzutifan-resistant models

Abstract Recent approval of the HIF-2α antagonist belzutifan (Welireg) for patients with VHL disease has enabled the clinical opportunity to target the HIF-2 axis in cancer. This is particularly important for patients with clear cell renal cell carcinoma (ccRCC), in which 90% of tumors are VHL deficient, and approximately one in four primary tumors express HIF-2α exclusively. Clinical studies to date suggest an overall response rate (ORR) of 20-25% for belzutifan monotherapy, highlighting the need for a rational combination strategy to improve patient outcomes. This has led to multiple clinical trials testing belzutifan in combination with diverse therapeutic agents, including immune-checkpoint inhibitors, VEGFR-TKIs, and CDK4/6 inhibitors. HiberCell is developing a first-in-class GCN2 activator currently undergoing Ph1 clinical evaluation in patients with solid tumors (NCT05121948). GCN2 activation by HC-7366 drives the Integrated Stress Response (ISR), resulting in translation inhibition and delayed cell cycle progression in cancer cells. In preclinical studies, HC-7366 demonstrated significant antitumor activity associated with HIF suppression across diverse tumor models, including ccRCC (70% TGI), head and neck (33% regression), sarcoma (84% TGI) and prostate (100% TGI). Analysis of tumor samples revealed that HC-7366 inhibited both HIF-1α and HIF-2α, as well as multiple cell cycle regulators. Given the mechanistic link between HIF-2 and cell cycle regulation, and the noted combination benefit reported when CDK inhibitors are combined with belzutifan, we hypothesized that HC-7366 would enhance the antitumor effects of belzutifan in RCC. Combination studies in HIF-2 dependent 786-O and A-498 RCC xenografts demonstrated that HC-7366 improved the antitumor effects of belzutifan at clinically relevant doses. The combination of HC-7366 and belzutifan in A-498 drove robust tumor inhibition (~90% TGI). In 786-O, HC-7366 increased the number of complete responses from 2 of 8 tumors in the belzutifan-treated animals to 6 of 8 in the combination group. When tested in two belzutifan-resistant PDX models, HC-7366 resulted in significant monotherapy activity, achieving 17% regression as a maximal response, and inhibiting both HIF and cell cycle markers. Belzutifan is currently being tested in indications beyond RCC, so we evaluated the combination in VHLwt endometrial cancer model, MFE-280. Consistent with RCC models, the combination of HC-7366 and belzutifan resulted in tumor stasis with activation of ISR, enhanced inhibition of HIF and cell cycle markers in the combination vs belzutifan monotherapy. Together, these findings suggest that HC-7366 enhances belzutifan activity and serves as a rationale supporting clinical evaluation of this therapeutic combination. Citation Format: Michael E. Stokes, Feven Tameire, Paulina Wojnarowicz, Sho Fujisawa, Crissy Dudgeon, Sharon Huang, Nick Collette, Ben Harrison, Ashley LaCayo, Xiaohong Qiu, Takashi Kangas, Weiyu Zhang, Jeremy Drees, David Surguladze, Eric S. Lightcap, Nandita Bose. HC-7366, a potent GCN2 activator, complements belzutifan, a HIF-2⍺ antagonist, by providing combination benefit in belzutifan-sensitive models and monotherapy activity in belzutifan-resistant models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4615.