Casdatifan/cabotinib is effective in pretreated ccRCC

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

Preliminary efficacy in the efficacy-evaluable cohort of patients (n=24) treated with Casdatifan plus cabozantinib showed that at a median follow-up of 5.3 months (range 2.8-9.1), overall confirmed The 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 demonstrated meaningful clinical activity and disease control across doses. Casdatifan was well tolerated at all single treatment doses and in combination with cabozantinib.

ARC-20 Trial

Patients in the casdatifan/cabountinib combination group received casdatifan 100 mg daily and cabozantinib 60 mg daily. Regarding the monotherapy portion of the ARC-20 dose expansion phase, in Cohort 1 (n=33), patients received Casdatifan 50 mg twice daily; in Cohort 2 (n=31), patients received Casdatifan 50 mg once daily; and in Cohort 3 (n=29), patients received Casdatifan 100 mg once daily. Eligible patients had ccRCC, were on at least second-line therapy, had at least 1 measurable lesion according to RECIST 1.1 criteria, and had adequate organ and bone marrow function.

The primary endpoints of the trial are adverse effects (AEs) and dose-limiting toxicities. Secondary endpoints were ORR assessed by investigators based on RECIST 1.1 criteria and pharmacokinetics and pharmacodynamics; exploratory endpoints were progression-free survival, overall survival, and biomarkers.

Review of Monotherapy Cohort Study Results

No.The median age of patients in groups 1, 2, and 3 was 62 years (range 41-79 years), 65 years (range 43-82 years), and 60 years (range 45-77 years), respectively; ECO was observed in 52%, 42%, and 52% of patients G performance status was 1; 64%, 55%, and 66% of patients reported an International Metastatic Renal Cell Carcinoma Database Consortium intermediate risk score; 94%, 84%, and 83% of patients had received 2 or more prior lines of therapy. All patients in all cohorts had been previously treated with VEGFR tyrosine kinase inhibitors and PD-L1 inhibitors.

Results from the monotherapy cohort previously presented at2025 Genitourinary Cancers Symposium showed that in the efficacy-evaluable group of patients (n=32) who received 50 mg of Casdatifan monotherapy twice daily, with 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 CR, 31% had PR, 50% had SD, and 19% had PD.

In patients evaluable for efficacy (n=28) who received Casdatifan 50 mg monotherapy once daily, with 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 CR, 29% had PR, 54% had SD, and 14% had PD. In efficacy-evaluable patients (n=27) who received casdatifan 100 mg once daily as monotherapy, with 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 CR, 33% had PR, 52% had SD, and 7% had PD.

Patients who received Casdatifan at a dose of 100 mg showed a trend toward a reduction in the sum of target lesion diameters and responded rapidly.

Security Overview

Among patients who receivedCasdatifan plus cabozantinib (n=42), with a median follow-up of 3.7 months (range, 1.1-9.1), the incidence of any treatment-emergent adverse event (TEAE) related to Casdatifan was 98%, with grade 3 or higher TEAEs occurring in 31%, and serious TEAEs occurring in 7%. Any TEAE related to cabozantinib occurred in 93% of patients, with grade 3 or higher TEAEs occurring in 38% of patients, and serious TEAEs occurring in 12% of patients. Ninety-eight percent of patients experienced any TEAE related to any study drug, with 48% experiencing grade 3 or higher TEAEs and 17% experiencing serious TEAEs.

In the combination treatment group, vs.TEAEs related to Casdatifan are anemia, hypoxia, and neutrophil count decrease; TEAEs related to cabozantinib include anemia, hyponatremia, hypertension, and neutrophil count decrease. TEAEs related to any study drug included anemia, hyponatremia, hypoxia, hypertension, and decreased neutrophil count.

Any TEAE related to study drug occurred in 94% of patients in Cohort 1, 90% in Cohort 2, and 93% in Cohort 3. Grade 3 or higher TEAEs occurred in 49%, 32%, and 28% of patients, respectively. Serious TEAEs related to study drug occurred in 3%, 10%, and 7% of patients. More than 5% of patients in Cohort 1 experienced grade 3 or higher TEAEs, anemia and hypoxia, respectively. In Cohort 2, the incidence of these grade 3 or higher TEAEs was 32% and 7%, respectively. In Cohort 3, these two rates were 17% and 10% respectively.

In addition, in the monotherapy group, 9% of patients in Cohort 1, 3% of patients in Cohort 2, and 7% of patients in Cohort 3 experienced any adverse event leading to dose reduction. In the combination therapy group, TEAEs leading to dose reductions were related to casdatifan in 24% of patients, to cabozantinib in 38% of patients, and to any study drug in 52% of patients. Of note, most patients who had their dose reduced on either drug had their dose reduced by only 1 level.

In the report, The design of the phase 3 PEAK-1 trial (NCT07011719), which evaluated casdatifan 100 mg daily plus cabozantinib 60 mg daily versus placebo plus cabozantinib in patients with advanced or metastatic ccRCC. He also introduced the design of the phase 1b/3 eVOLVE-RCC02 trial (NCT07000149), which evaluated the combination of volrustomig and casdatifan in patients with first-line advanced ccRCC.

Reference materials:https://www.targetedonc.com/view/casdatifan-cabozantinib-shows-efficacy-in-pretreated-ccrcc