Background: MET signaling is a key molecular driver in pRCC. Given that there is no optimal therapy for metastatic pRCC, we sought to compare an existing standard (sunitinib) to putative MET kinase inhibitors. Methods: Eligible patients had pathologically verified pRCC, Zubrod performance status 0-1, and measurable metastatic disease. Patients may have received up to 1 prior systemic therapy excluding VEGF-directed agents. Patients were randomized 1:1:1:1 to receive either sunitinib 50 mg po qd (4 wks on/2 wks off), cabozantinib 60 mg po qd, crizotinib 250 mg po bid, or savolitinib 600 mg po qd. Patients were stratified by prior therapy and pRCC subtype (I vs II vs not otherwise specified [NOS]) based on local review. The primary objective was to compare progression-free survival (PFS) for each experimental arm versus sunitinib. With 41 eligible patients per arm, we estimated 85% power to detect a 75% improvement in median PFS with a 1-sided alpha of 0.10 using intent-to-treat analysis. A pre-planned futility analysis was performed after 50% of PFS events occurred. Secondary endpoints included toxicity, response rate, and overall survival. Results: Between 4/2016 and 12/2019, 152 patients were enrolled; 5 were ineligible. Median age was 66 (range:29-89) and 76% were male; 92% had no prior therapy. By local pathologic review, 18%, 54% and 28% of patients were characterized as having type I, type II and NOS histology, respectively. In contrast, the frequency of type I, type II, and NOS by central review was 30%, 45% and 25%, respectively. Accrual to the savolitinib and crizotinib arms was halted early for futility (PFS hazard ratio > 1.0 for both); accrual continued to completion in the sunitinib and cabozantinib arms. Median PFS was significantly higher with cabozantinib relative to sunitinib (Table). Grade 3 or 4 adverse events occurred in 69%, 72%, 37% and 39% of patients receiving sunitinib, cabozantinib, crizotinib and savolitinib, respectively; one grade 5 adverse event was seen with cabozantinib. Overall survival and response data will be presented. Conclusions: In this multi-arm randomized trial, only cabozantinib resulted in a statistically significant and clinically meaningful prolongation of PFS in pRCC patients compared to sunitinib. These data support cabozantinib as a reference standard for eligible patients with metastatic pRCC. Clinical trial information: NCT02761057.

* Cox model, adjusted for stratification factors

** Closed to accrual early due to futility analysis