Abstract B004: Belzutifan and lenvatinib mutually reshape renal cell carcinoma tumor microenvironment through the HIF-2A axis

Abstract Belzutifan (MK-6482) provides a critical late line treatment option for advanced renal cell carcinoma (RCC) by selectively inhibiting HIF-2A. In the heavily pretreated RCC population, overall response rates to belzutifan are limited, suggesting rational combination strategies are needed to maximize therapeutic benefit. VEGF tyrosine kinase inhibitors (TKIs) such as lenvatinib are an attractive partner to additionally target the HIF-2A axis and orthogonal biology while maintaining a manageable safety profile. To provide preclinical proof of concept data to this strategy, we examined the efficacy of combining belzutifan and lenvatinib in multiple VHL-deficient RCC models. Lenvatinib monotherapy exhibited robust anti-tumor efficacy and reduced tumor vessel density across models tested, but induced hypoxia genes, consistent with previous literature implicating HIF-2A as a resistance factor in VEGF targeted therapies. The addition of belzutifan in a combo setting was able to reverse tumor expression of HIF-2A as well as downstream target genes such as VEGFA, CCND1, and CXCR4. To explore clinically relevant scenarios, we treated RCC tumors growing through either belzutifan or lenvatinib monotherapy with combo treatment and confirmed their sensitivity to the switch. Together these studies have provided evidence that combining belzutifan and lenvatinib, such as in the ongoing LITESPARK-011 trial, each favorably modify the RCC tumor microenvironment which can translate into added therapeutic benefit and efficacy. Citation Format: Douglas Linn, Long Cui, Gustave Hebert, Eric Muise, Rodolfo Perini, Brian J. Long. Belzutifan and lenvatinib mutually reshape renal cell carcinoma tumor microenvironment through the HIF-2A axis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr B004.