Casdatifan Plus Cabozantinib Shows Meaningful Clinical Activity in Pretreated ccRCC

Casdatifan in combination with cabozantinib (Cabometyx) generated responses and was associated with a manageable safety profile in patients with previously treated clear cell renal cell carcinoma (ccRCC), according to updated data from the dose-expansion portion of the phase 1 ARC-20 trial (NCT05536141) that were presented at the 2025 Kidney Cancer Research Summit.

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

“Treatment with casdatifan showed meaningful clinical activity and disease control across doses,” presenting study author Toni K. Choueiri, MD, FASCO, said during the presentation. “Casdatifan was well tolerated across all monotherapy doses and in combination with cabozantinib.”

Choueiri is the 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 in Boston, Massachusetts.

Summarizing the ARC-20 Trial Design

Patients in the casdatifan/cabozantinib combination arm received casdatifan at 100 mg daily plus cabozantinib at 60 mg daily.

Regarding the monotherapy portion of the dose-expansion phase of ARC-20, in cohort 1 (n = 33), patients received 50 mg of casdatifan twice daily; in cohort 2 (n = 31), patients received 30 mg of casdatifan once daily; in cohort 3 (n = 29), patients received 100 mg of casdatifan once daily. Eligible patients had ccRCC, were in at least the second line of therapy, had at least 1 measurable lesion per RECIST 1.1 criteria, and had adequate organ and marrow function.

The trial’s primary end points are adverse effects (AEs) and dose-limiting toxicities. The secondary end points are ORR assessed by the investigator per RECIST 1.1 criteria, and pharmacokinetics and pharmacodynamics; the exploratory end points are progression-free survival, overall survival, and biomarkers.

Revisiting the Monotherapy Cohort Findings

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), respectively; an ECOG performance status of 1 was observed in 52%, 42%, and 52% of patients, respectively; intermediate International Metastatic RCC Database Consortium risk score was reported in 64%, 55%, and 66% of patients, respectively; 2 or more prior regimens had been received by 94%, 84%, and 83% of patients, respectively. All patients in all cohorts had previously received both a VEGFR TKI and a PD-L1 inhibitor.

Findings from the monotherapy cohorts, which were previously presented at the 2025 Genitourinary Cancers Symposium, showed that in the efficacy-evaluable group of patients who received 50 mg of casdatifan monotherapy twice daily (n = 32), at a median follow-up of 15 months (range, 7 to 19+), the confirmed ORR was 25% (95% CI, 11.5%-43.4%). The best ORR was 31%; 0 patients had a CR, 31% of patients had a PR, 50% of patients had SD, and 19% of patients had PD.

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

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

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

Highlighting Casdatifan’s Safety Profile

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

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

With casdatifan monotherapy, any TEAEs related to the study drug occurred in 94% of patients in cohort 1, 90% of those in cohort 2, and 93% of those in cohort 3. TEAEs of grade 3 or higher occurred in 49%, 32%, and 28% of patients, respectively. Serious TEAEs related to the study drugs occurred in 3%, 10%, and 7% of patients, respectively.

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, the rates of these grade 3 or higher TEAEs were 32% and 7%, respectively. In cohort 3, these respective rates were 17% and 10%.

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

During the presentation, Choueiri described the design of 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 ccRCC. He also presented the design of the phase 1b/3 eVOLVE-RCC02 trial (NCT07000149) evaluating volrustomig plus casdatifan in patients with frontline advanced ccRCC.

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.