Casdatifan +/- Cabozantinib Showed Early Efficacy, Safety in Pretreated RCC

Patients with RCC who received 100 mg once daily casdatifan had an ORR of 33%, and those who received casdatifan plus cabozantinib had an ORR of 46%.

Combining casdatifan plus cabozantinib (Cabometyx) led to meaningful clinical activity and was well tolerated as a therapy for patients who were pretreated with clear cell renal cell carcinoma (RCC), according to results from an expansion cohort of the phase 1 ARC-20 trial (NCT05536141) shared at the 2025 Kidney Cancer Research Summit.

In the group of patients who received 50 mg of casdatifan twice daily (n = 32), at the median follow-up of 15 months (range, 7-19+), the confirmed overall response rate (ORR) was 25% (95% CI, 11.5%-43.4%). The best overall response rate (ORR) was 31%; 0 patients had a complete response (CR), 31% had a partial response (PR), 50% had stable disease (SD), and 19% had progressive disease (PD).

In patients who received 50 mg once daily (n = 28), at the median follow-up of 12 months (range, 9-14+), the confirmed ORR was 29% (95% CI, 13.2%-48.7%). The best ORR was 32%; 4% of patients had a CR, 29% had a PR, 54% had SD, and 14% had PD.

In those who received 100 mg once daily (n = 27), at the median follow-up of 5 months (range, 2-6+), the confirmed ORR was 33% (95% CI, 16.5%-54.0%). The best ORR was 33%; 0% of patients had a CR, 33% had a PR, 52% had SD, and 7% had PD.

Patients who received the 100 mg dose demonstrated a trend of decreasing sum of target lesion diameters, as well as rapid response.

Preliminary efficacy from the cohort of patients who received casdatifan plus cabozantinib (n = 24) showed, with a median follow-up of 5.3 months (range, 2.8-9.1), the confirmed ORR was 46% (95% CI, 25.6%-67.2%); 4% had a CR, 42% had a PR, 50% had SD, and 4% had PD.

“Treatment with casdatifan showed meaningful clinical activity and disease control across doses,” wrote presenting study author Toni K. Choueiri, MD, FASCO, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, co-leader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center, and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School, said during the presentation. “Casdatifan was well tolerated across all monotherapy doses and in combination with cabozantinib.”

In the dose expansion phase of ARC-20, approximately 30 patients were enrolled in each of the 3 cohorts. In cohort 1, patients received 50 mg of casdatifan twice daily; in cohort 2, patients received 30 mg of casdatifan once daily; and in cohort 3, patients received 100 mg of casdatifan once daily. Eligible patients had clear cell RCC, were in at least the second line of therapy, had at least 1 measurable lesion per RECIST v1.1, and had adequate organ and marrow function.

The median age of patients in cohorts 1, 2, and 3 were 62 years (range, 41-79), 65 years (range, 43-82), and 60 years (range, 45-77); an ECOG performance status of 1 was observed in 52%, 42%, and 52%, respectively; the most common International Metastatic RCC Database Consortium risk score was intermediate in 64%, 55%, and 66%; and 2 or more prior regimens were received by 94%, 84%, and 83%. All patients in all cohorts received both a VEGFR-tyrosine kinase inhibitor and PD-L1 inhibitor.

The trial’s primary end points were adverse effects (AEs) and dose-limiting toxicities (DLTs). Secondary end points were ORR assessed by the investigator per RECIST v1.1, and pharmacokinetics and pharmacodynamics; exploratory end points were progression-free survival (PFS), overall survival (OS), and biomarkers.

With casdatifan monotherapy, any treatment-emergent AE (TEAE) related to the study drug occurred in 94% of cohort 1, 90% of cohort 2, and 93% of cohort 3; of grade 3 or higher occurred in 49%, 32%, and 28%, respectively; and serious TEAEs occurred in 3%, 10%, and 7%.

Grade 3 or higher TEAEs that occurred in more than 5% of patients in cohort 1 were anemia (42%) and hypoxia (9%); in cohort 2, they were 32% and 7%; and in cohort 3, they were 17% and 10%.

In patients who received 100 mg of casdatifan plus cabozantinib (n = 42), with a median follow-up of 3.7 months (range, 1.1-9.1), any TEAEs related to casdatifan occurred in 98%, grade 3 or higher TEAEs occurred in 31%, and serious TEAEs in 7%. Any TEAEs related to cabozantinib occurred in 93%, grade 3 or higher TEAEs occurred in 38%, and serious TEAEs occurred in 12%. Any TEAEs related to any study drug occurred in 98%, grade 3 or higher TEAEs occurred in 48%, and serious TEAEs occurred in 17%.

In the combination group, TEAEs related to casdatifan were anemia (24%), hypoxia (7%), and neutrophil count decreased (2%); TEAEs related to cabozantinib were anemia (14%), hyponatremia (7%), hypertension (5%), and neutrophil count decreased (5%); and TEAEs related to any study drug were anemia (24%), hyponatremia (7%), hypoxia (7%), hypertension (5%), and neutrophil count decreased (5%).

Further, in the monotherapy group, 9% of patients in cohort 1, 3% in cohort 2, and 7% in cohort 3 experienced any AE leading to dose reduction. In the combination group, TEAEs leading to dose reduction were related to casdatifan in 24%, related to cabozantinib in 38%, and related to any study drug in 52%. It was noted that most patients who had a dose reduction of either agent were reduced by only 1 level.

The phase 3 PEAK-1 trial (NCT07011719) evaluating 100 mg of daily casdatifan plus 60 mg of daily cabozantinib compared with placebo plus cabozantinib in patients with advanced or metastatic clear cell RCC was announced, as well as the phase 1b/3 eVOLVE-RCC02 trial (NCT07000149) evaluating volrustomig plus casdatifan in frontline advanced clear cell RCC.

Reference

Choueiri TK, Ornstein M, Barata P, et al. Combination casdatifan plus cabozantinib in previously treated patients with clear cell renal cell carcinoma: results from an expansion cohort of ARC-20 (NCT05536141). Presented at the 2025 Kidney Cancer Research Summit; July 17-18, 2025; Boston, MA.