Sunitinib versus cabozantinib, crizotinib or savolitinib in metastatic papillary renal cell carcinoma (pRCC): Results from the randomized phase II SWOG 1500 study.

MET signaling is a key molecular driver in papillary renal cell carcinoma (pRCC). Given that there is no optimal therapy for metastatic pRCC, this study sought to compare an existing standard, sunitinib, to putative MET kinase inhibitors.

Eligible patients had pathologically verified pRCC, Zubrod performance status 0-1, and measurable metastatic disease. Patients were randomized 1:1:1:1 to receive either sunitinib 50 mg po qd, cabozantinib 60 mg po qd, crizotinib 250 mg po bid, or savolitinib 600 mg po qd. The primary objective was to compare progression-free survival (PFS) for each experimental arm versus sunitinib. A pre-planned futility analysis was performed after 50% of PFS events occurred.

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. Median PFS was significantly higher with cabozantinib relative to sunitinib. 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.

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.


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