Combination casdatifan plus cabozantinib expansion cohort of phase 1 ARC-20 study in previously treated patients with clear cell renal cell carcinoma
Recommended Citation
Choueiri TK, Ornstein MC, Barata PC, Matrana MR, Merchan JR, Gedye C, Hwang C, Kumar R, Lee J, Guan Y, Ghasemi M, Quadri S, Negro C, Chen J, Foster PG, Monga M, McGregor BA, Rha S, Drakaki A. Combination casdatifan plus cabozantinib expansion cohort of phase 1 ARC-20 study in previously treated patients with clear cell renal cell carcinoma. 2025; (16_suppl).
Document Type
Conference Proceeding
Publication Date
5-28-2025
Abstract
Background: Hypoxia-inducible factor 2-alpha (HIF-2a) 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-2a inhibitor. We investigated the safety and efficacy of casdatifan in combination with the anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) cabozantinib in previously treated patients with ccRCC in an expansion cohort (casdatifan + cabozantinib) of the phase 1, open-label ARC-20 (NCT05536141) trial. Methods: Patients enrolled in the casdatifan + cabozantinib expansion cohort were previously treated with immunotherapy (IO) alone or 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. This study is ongoing; data as of January 3, 2025, are reported. Results: Overall, 27 patients with a median (range) follow-up of 2.9 (0.1-6.8) months were enrolled. At data cut off, prior treatment settings included adjuvant only (n = 5/26) and metastatic (1L n = 17/26; 2L n = 4/26). Prior therapies included IO only (n = 15/26) or IO plus VEGFR-TKI (n = 11/26). All grade AEs occurred in 89% of patients with the most common being anemia (n = 16 [59%]) and fatigue (n = 15 [56%]). Most common (.10%) grade≥3 AEs were anemia (n = 7 [26%]) and hypoxia (n = 3 [11%]). No cardiac events were reported. AEs leading to casdatifan-only, cabozantinib-only, or both casdatifan + cabozantinib dose reductions occurred in 3 (11%), 7 (26%), and 2 (7%) patients, respectively. Only one (4%) pt discontinued due to an AE, hypoxia related to casdatifan. Responses continue to be observed among the efficacy evaluable population (n = 22; as of January 27, 2025) with ORR of 41% (n = 1 complete response; n = 8 partial response). Activity was seen across all IMDC risk groups. Conclusions: In previously treated patients with ccRCC, casdatifan 100 mg in combination with 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.
Issue
16_suppl
