Abstract
BACKGROUND: Hypoxia-inducible factor 2-alpha (HIF-2α) is highly dysregulated in clear cell renal cell carcinoma (ccRCC), resulting in increased expression of proteins involved with angiogenesis, proliferation, and cancer cell survival. Casdatifan is an orally bioavailable small-molecule HIF-2α inhibitor that has demonstrated monotherapy activity in patients receiving 2 L+ treatment for ccRCC. We investigated the safety and efficacy of casdatifan plus the anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) cabozantinib in previously treated patients with ccRCC in an expansion cohort (casdatifan plus cabozantinib) of the phase 1, open-label ARC-20 (NCT05536141) trial. METHODS: Patients enrolled in the casdatifan plus cabozantinib expansion cohort were previously treated with immunotherapy (IO) alone or combined with anti-VEGF therapies. Casdatifan 100 mg and cabozantinib 60 mg were given orally once daily. Endpoints included the incidence of treatment-emergent adverse events (AEs) and objective response rate (ORR) by RECIST v1.1. The efficacy evaluable population was defined as patients who received any study treatment and achieved a minimum of 12 weeks follow-up. This study is ongoing; data as of March 14, 2025, are reported. RESULTS: Overall, 42 patients with a median (range) follow-up of 3.7 (1.1–9.1) months were enrolled. At the data cutoff date, prior treatment settings included adjuvant only (n = 8/42) and locally advanced/metastatic (1 L n = 29/42; 2 L n = 5/42). Twenty-five (60%) patients had received prior IO alone, and 17 (41%) patients had received prior IO plus VEGFR-TKI treatment. All grade AEs occurred in 98% of patients, with the most common being anemia (69%) and fatigue (57%). Most common (> 5%) grade ≥ 3 AEs were anemia (n = 10 [24%]), hyponatremia (n = 4 [10%]), and hypoxia (n = 3 [7%]). No casdatifan-related grade 4 or 5 AEs were observed. AEs leading to casdatifan only, cabozantinib only, or any study drug dose reductions occurred in 10 (24%), 16 (38%), and 22 (52%) patients, respectively. Two (5%) patients discontinued due to an AE related to casdatifan (hypoxia and drug hypersensitivity; n = 1 each). For patients in the efficacy evaluable population (n = 24), 1 (4%) patient achieved a complete response, and 10 (42%) patients achieved a partial response for a confirmed ORR of 45.8% (Table). Activity was seen across all IMDC risk groups. [Image: see text] CONCLUSIONS: In previously treated patients with ccRCC, casdatifan 100 mg plus cabozantinib 60 mg had a manageable AE profile with promising clinical activity. These data support continued evaluation of this combination in the phase 3 PEAK-1 clinical trial.