Welireg Plus Cabometyx Shows Tumor Control in Kidney Cancer Trial

In patients with previously treated clear cell renal cell carcinoma, a specific kind of kidney cancer, adding casdatifan to Cabometyx (cabozantinib) treatment showed encouraging activity and was generally well tolerated, according to results from an expansion group in the phase 1 ARC-20 trial presented at the 2025 Kidney Cancer Research Summit.

In the group of patients who received 50 milligrams (mg) of Welireg twice daily (32 patients), at the median follow-up of 15 months, the confirmed overall response rate was 25%. The best overall response rate was 31%; zero patients had a complete response, 31% had a partial response, 50% had stable disease, and 19% had progressive disease.

In patients who received 50 mg once daily (28 patients), at the median follow-up of 12 months, the confirmed overall response rate was 29%. The best overall response rate was 32%; 4% of patients had a complete response, 29% had a partial response, 54% had stable disease, and 14% had progressive disease.

In those who received 100 mg once daily (27 patients), at the median follow-up of five months, the confirmed overall response rate was 33%. The best overall response rate was 33%; 0% of patients had a complete response, 33% had a partial response, 52% had stable disease, and 7% had progressive disease.

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 Welireg plus Cabometyx (24 patients) showed, with a median follow-up of 5.3 months, the confirmed overall response rate was 46%; 4% had a complete response, 42% had a partial response, 50% had stable disease, and 4% had progressive disease.

“Treatment with Welireg showed meaningful clinical activity and disease control across doses,” wrote presenting study author, Dr. Toni K. Choueiri, 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. “Welireg was well tolerated across all monotherapy doses and in combination with Cabometyx.”

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 Welireg twice daily; in cohort 2, patients received 30 mg of Welireg once daily; and in cohort 3, patients received 100 mg of Welireg once daily. Eligible patients had clear cell renal cell carcinoma, were in at least the second line of therapy, had at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors version 1.1, and had adequate organ and marrow function.

The median age of patients in cohorts 1, 2, and 3 were 62 years, 65 years, and 60 years; an Eastern Cooperative Oncology Group performance status of 1 was observed in 52%, 42%, and 52%, respectively; the most common International Metastatic Renal Cell Carcinoma 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 vascular endothelial growth factor receptor–tyrosine kinase inhibitor and a programmed death-ligand 1 inhibitor.

The trial’s primary end points were side effects and dose-limiting toxicities. Secondary end points were overall response rate assessed by the investigator per Response Evaluation Criteria in Solid Tumors version 1.1 and pharmacokinetics and pharmacodynamics; exploratory end points were progression-free survival, overall survival, and biomarkers.

With Welireg monotherapy, any treatment-emergent side effect 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 side effects occurred in 3%, 10%, and 7%.

Grade 3 or higher side effects 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 Welireg plus Cabometyx (42 patients), with a median follow-up of 3.7 months, any side effects related to Welireg occurred in 98%, grade 3 or higher side effects occurred in 31%, and serious side effects in 7%. Any side effects related to Cabometyx occurred in 93%, grade 3 or higher side effects occurred in 38%, and serious side effects occurred in 12%. Any side effects related to any study drug occurred in 98%, grade 3 or higher side effects occurred in 48%, and serious side effects occurred in 17%.

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

Further, in the monotherapy group, 9% of patients in cohort 1, 3% in cohort 2, and 7% in cohort 3 experienced any side effect leading to dose reduction. In the combination group, side effects leading to dose reduction were related to Welireg in 24%, related to Cabometyx 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 evaluating 100 mg of daily Welireg plus 60 mg of daily Cabometyx compared with placebo plus Cabometyx in patients with advanced or metastatic clear cell renal cell carcinoma was announced, as well as the phase 1b/3 eVOLVE-RCC02 trial evaluating volrustomig plus Welireg in frontline advanced clear cell renal cell carcinoma.

Reference

“Combination casdatifan plus cabozantinib in previously treated patients with clear cell renal cell carcinoma: results from an expansion cohort of ARC-20 (NCT05536141),” by Dr. Toni Chouieri, et al. Presented at the 2025 Kidney Cancer Research Summit; July 17-18, 2025; Boston, MA.

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