Combination casdatifan plus cabozantinib in previously treated patients with clear cell renal cell carcinoma: results from an expansion cohort of ARC-20 (NCT05536141)
Recommended Citation
Choueri T, Ornstein M, Barata PC, Matrana M, Merchan J, Gedye C, Hwang C, Kumar R, Lee J, Guan Y, Ghasemi M, Quadri S, Negro C, Chen J, Foster P, Warad D, McGregor BA, Rha S, Drakaki A. Combination casdatifan plus cabozantinib in previously treated patients with clear cell renal cell carcinoma: results from an expansion cohort of ARC-20 (NCT05536141). 2025; (S2).
Document Type
Conference Proceeding
Publication Date
10-9-2025
Abstract
Background: Hypoxia-inducible factor 2-alpha (HIF-2α) is highly dysreg_ulated 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 2L+ treatment for ccRCC. We investigated the safety and effi_cacy of casdatifan plus the anti-vascular endothelial growth factor recep_tor 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 expan_sion cohort were previously treated with immunotherapy (IO) alone or combined with anti-VEGF therapies. Casdatifan 100mg and cabozan_tinib 60mg were given orally once daily. Endpoints included the inci_dence 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 12weeks 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/meta_static (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%]), hypona_tremia (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. Conclusions: In previously treated patients with ccRCC, casdatifan 100mg plus cabozantinib 60mg 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.
Issue
S2
