Casdatifan/Cabozantinib Reveals Promising Clinical Activity in Metastatic ccRCC

Renal cell carcinoma: © peterschreiber.media - stock.adobe.com

An expansion cohort of the phase 1 ARC-20 trial (NCT05536141) evaluating the combination of the hypoxia-inducible factor 2-alpha (HIF-2α) inhibitor, casdatifan, and cabozantinib (Cabometyx) demonstrated promising clinical activity and manageable toxicity in previously treated patients with metastatic clear cell renal cell carcinoma (ccRCC). Findings from this expansion cohort were presented during the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

At the data cutoff of March 14, 2025, the median follow-up was 5.3 months (range, 2.8-9.1), and the confirmed objective response rate was 46.0% (95% CI, 25.6%-67.2%).

“Only 1 out of 24 patients [4.0%] achieved complete response [CR] and only 1 patient had progressive disease [4.0%],” lead author Toni K. Choueiri, MD, FASCO, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts, said during a presentation of the data.

ARC-20 is a dose-escalation and dose-expansion study that was previously presented during the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium.² The dose-escalation component included patients with advanced solid tumors and who had clear cell RCC. The dose expansion component incorporated casdatifan monotherapy.

Patients who enrolled in the casdatifan plus cabozantinib expansion cohort (n = 42) were previously treated with immunotherapy (IO) alone or with anti-VEGF therapies. Casdatifan (100 mg) and cabozantinib (60 mg) were given orally once daily. End points included the incidence of treatment-emergent adverse events (TEAEs) and objective response rate (ORR) by RECIST v1.1.

TEAEs associated with casdatifan and/or cabozantinib

After a follow-up of a median of 3.7 months (range, 1.1-9.1), a high percentage of patients experienced at least 1 TEAE. Of these, 98% were attributed to casdatifan, 93% to cabozantinib, and 98% to any study drug. The most common TEAEs attributed to casdatifan were anemia (69%), fatigue (48%), and increased levels of alanine aminotransferase (19%). For cabozantinib, the most common TEAEs were fatigue (55%), anemia (43%), and increased levels of alanine aminotransferase (38%). When considering any study drug, the most common TEAEs were anemia (69%), fatigue (55%), and increased levels of alanine aminotransferase (38%).

“Most instances of anemia and fatigue did not necessitate a change in dose and ultimately resolved,” Choueiri said. “Regarding grade 3 or higher TEAEs, anemia and hypoxia were the most common. We did not see any casdatifan-related grade 4 or grade 5 AEs,” Choueiri continued.

Overall, AEs were manageable with few discontinuations. Only 2 patients discontinued a treatment due to a TEAE, which were hypoxia and drug sensitivity, and no patients discontinued both treatments due to TEAE. Twenty-four percent of patients who received casdatifan had an AE leading to dose reduction compared with 38% of patients who received cabozantinib. Fifty-two percent of patients who received any study drug required a dose reduction.

“This regimen shows promising clinical activity in patients with metastatic ccRCC who had at least 1 prior therapy,” Choueiri said. “The toxicity associated with this combination is manageable, with most cases of anemia did not require a change in dosage. I think this is important because the findings support evaluating this agent for the management of ccRCC across settings,” Choueiri said.

Choueiri concluded by highlighting the phase 3 PEAK-1 study (NCT07011719), which was recently launched. The study will randomly assign 700 patients with metastatic ccRCC to receive 100 mg of casdatifan plus 60 mg of cabozantinib vs placebo plus 60 mg cabozantinib. The primary end point is progression-free survival and secondary end points are overall survival, duration of response, and disease-control rate.

REFERENCES:

1. Choueiri TK, Ornstein M, Barata P, et al. Combination casdatifan plus cabozantinib in previously treated patients with clear cell renal cell carcinoma: results from the expansion cohort of the phase 1 ARC-20 study. J Clin Oncol. 2025;43(suppl 16):4506. doi: 10.1200/JCO.2025.43.16_suppl.4506

2. Choueiri T, Lee JL, Merchan J, et al. Casdatifan (Cas) monotherapy in patients (pts) with previously treated clear cell renal cell carcinoma (ccRCC): Safety, efficacy and subgroup analysis across multiple doses from ARC-20, a phase 1 open-label study. J Clin Oncol. 2025; 43(suppl 5): 441. doi:10.1200/JCO.2025.43.5_suppl.441