Background: New therapeutic approaches in RCCvh are needed. Herein, we report on treatment intensification with the combination of Cabo/Nivo/Ipi in patients with metastatic RCCvh in a multi-institutional prospective single arm phase II trial. (NCT04413123). Methods: Eligible patients (pts) had metastatic RCCvh with ECOG performance status of 0-1 and may have received one line of prior therapy excluding immunotherapy or Cabo. Pts underwent a baseline biopsy and received treatment with Nivo 3 mg/kg and Ipi 1 mg/kg intravenously Q3 weeks (W) for 4 cycles followed by Nivo 480 mg IV Q4W. Cabo was given continuously at dose of 40 mg daily; reductions to 20 mg daily and 20 mg every other day were allowed. The primary endpoint was objective response rate (ORR) by RECIST 1.1. Safety was a secondary endpoint. Results: 40 pts have been enrolled. At the time of data cut-off (Dec 9, 2022), 38 pts received at least 1 study drug. 11% (n=4) pts received prior systemic therapy. 45% (n=17) received all 4 doses of Nivo and Ipi; 18% (n=7) received 3 and 37% (n=14) received ≤ 2 doses. 61% (n=23) (15 of whom received 4 cycles Nivo/Ipi) received Nivo maintenance (median number of cycles, 5 (range, 1-21)). 71% (n=27) and 13% (n=5) required Cabo dose reduction to 20 mg and 20 mg every other day, respectively. Median follow-up was 8.4 (range, 2.1-23) months. Objective response was achieved in 8 pts (ORR 21%, two-sided 80% CI, 13%-32%). Median duration of response was not reached with 5 pts maintaining response > 6 months. Median progression-free survival was 8.9 (95% CI, 4.2-12.7) months. 74% (n=28) developed treatment-related grade 3 or higher toxicities; 37% (n=14) developed ≥ grade 3 elevation in AST or ALT. 29% (n=11) required high dose steroids (prednisone ≥ 40 mg daily or equivalent). 13% (n=5) discontinued all study drugs due to toxicity. No grade 5 toxicity has been reported. Conclusions: The study suggests activity for this combination in patients with RCCvh particularly among those without chromophobe histology. An additional cohort of 20 pts is enrolling with Cabo starting dose of 20 mg daily. Clinical trial information: NCT04413123.

PR=partial response, SD=stable disease, PD=progressive disease, NE=not evaluable.