Abstract 6370: Farnesyl transferase inhibitor KO-2806 enhances the antitumor activity of cabozantinib in ccRCC tumors that progress on anti-VEGFR agents

Abstract Anti-angiogenic tyrosine kinase inhibitors (TKIs) targeting VEGFR remain the backbone of therapy in advanced renal cell carcinoma (RCC). However, durability of responses is limited, and resistance typically arises. The TKI cabozantinib demonstrated modest activity in patients with prior anti-VEGFR exposure, with a 21% overall response rate and 7.4 months median progression-free survival (NCT01865747). Thus, there is an urgent need for therapeutic agents that enhance responses to cabozantinib. We have previously shown that farnesyl transferase inhibitors (FTIs) improve upfront responses of preclinical clear cell RCC (ccRCC) models to anti-VEGFR therapies. However, given that most ccRCC patients are likely to receive anti-VEGFR agents prior to cabozantinib, we modeled tumor progression on TKIs in ccRCC xenograft models and asked whether KO-2806, a next-generation FTI, could enhance cabozantinib activity. To probe the mechanism of action, we assessed changes in angiogenic and cell signaling proteins in vitro and in vivo. The combination of KO-2806 and cabozantinib led to deeper and more consistent tumor growth inhibition than cabozantinib alone in tumor models that had progressed on axitinib or lenvatinib, two TKIs used to treat RCC. Addition of KO-2806 to tumors progressing on cabozantinib also resulted in tumor regression. Assessment of the vascular markers CD31 and NG2 revealed significantly reduced expression in tumors treated with the combination compared to either single agent, suggesting that the combination has greater antiangiogenic activity. Primary human endothelial cells treated with cabozantinib showed partial inhibition of mTORC1 activity (as assessed by phosphorylation of substrates S6 and 4-EBP1), while the combination with KO-2806 led to near complete loss of mTORC1 signaling due to inhibition of RHEB farnesylation. Tumor transcriptomic and cell signaling studies suggest that KO-2806 also negatively affects the cell cycle, a well-documented effect of farnesyl transferase inhibition. Based on these findings, we posit that the enhanced antiangiogenic activity is a more prominent mechanism of KO-2806 in RCC and that the combined effects on the tumor and the vasculature lead to greater tumor growth inhibition for the combination over cabozantinib alone. Taken together, our findings demonstrate that KO-2806 augments the antitumor activity of cabozantinib, even after prior exposure to anti-VEGFR treatment, largely by enhancing anti-angiogenesis via mTORC1 signaling inhibition in endothelial cells. These data strongly support our clinical evaluation of KO-2806 as a combination partner with cabozantinib in ccRCC as part of the ongoing Phase 1 FIT-001 trial (NCT06026410). Citation Format: Jovylyn G. Gasendo, Stacia Chan, Hetika Vora Patel, Alison Smith, Linda Kessler, Francis Burrows, Shivani Malik. Farnesyl transferase inhibitor KO-2806 enhances the antitumor activity of cabozantinib in ccRCC tumors that progress on anti-VEGFR agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6370.