Phase I Trial of Combination Therapy With Avelumab and Cabozantinib in Patients With Newly Diagnosed Metastatic Clear Cell Renal Cell Carcinoma

BACKGROUND: Combination immunotherapy is now considered the standard first-line therapy for patients with metastatic clear cell renal cell carcinoma (mccRCC) after multiple clinical trials demonstrated improved overall survival compared with single-agent tyrosine kinase inhibitors. Cabozantinib modulates critical components of the immune system, such as decreasing regulatory T cells and increasing T-effector cell populations, and is approved for the treatment of mRCC. Avelumab is a human IgG1 monoclonal antibody that binds to programmed death-ligand 1 protein and inhibits the interaction with PD-1. This phase I trial assessed the safety and clinical activity of avelumab and cabozantinib combination therapy in mccRCC. METHODS: This study was a phase I, 3+3 dose escalation clinical trial. The primary endpoint was the safety and identification of the recommended phase II dose (RP2D). Secondary endpoints included objective response rate (ORR) and radiographic progression-free survival (rPFS). There were 3 dose cohorts: cabozantinib 20, 40, and 60 mg/day, each combined with avelumab (10 mg/kg intravenously every 2 weeks). An additional 3 patients were included in the final dose cohort as a confirmation of the RP2D. No dose modifications were allowed for avelumab, but dose delays were permitted. Both dose reductions and holds were allowed for cabozantinib. Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was used to determine ORR, and treatment beyond progression was allowed. RESULTS: Twelve patients with newly diagnosed mccRCC were enrolled from July 2018 until March 2020. Three patients were enrolled in the 20 and 40 mg cohorts each, and 6 were enrolled in the 60 mg cohort. The International Metastatic RCC Database Consortium (IMDC) risk categories for these patients were: 4 patients (favorable risk), 6 patients (intermediate risk), and 2 patients (poor risk). No dose-limiting toxicities (DLTs) were observed in any cohort. Six patients developed serious adverse events related to study treatment after the DLT window period. Immune-related adverse events (iRAEs) were reported in 11 patients; fatigue and diarrhea were the most common (each with n = 4, 33.3%), followed by maculopapular rash and hand-foot syndrome (each with n = 3, 25%). Dose reductions were required in 5 of 6 patients in the cabozantinib 60 mg cohort after the DLT period. One patient discontinued avelumab due to irAE (nephritis), while none discontinued cabozantinib due to toxicity. The ORR was 50%, with one complete response (CR) and 5 partial responses (PR). The disease control rate (CR + PR + stable disease) was noted in 92% of the patients. Radiological PFS survival rate at 6 and 12 months was reported in 67.7% and 33.5% of patients, respectively. CONCLUSION: Combination therapy with avelumab and cabozantinib is safe and showed preliminary clinical activity in mccRCC. Even though the DLT was not met in any of the 3 cohorts, the recommended RP2D dose for the combination is cabozantinib 40 mg/day due to a high incidence of grade 2 toxicity for cabozantinib 60 mg/day after the DLT period. (ClinicalTrials.gov Identifier: NCT03200587)