Cabozantinib (Cabo) is an oral, potent inhibitor of MET, AXL and VEGFR2 that increases progression free-survival (PFS) and overall survival (OS) in mRCC patients (pts) after VEGF-targeted therapy. This randomized phase II multicenter trial compared the PFS of Cabo to Sunitinib (Sun) as front-line targeted therapy in pts with mRCC.
Eligible pts had untreated clear-cell mRCC, ECOG performance status 0-2, and were intermediate or poor risk, per the International mRCC Database Consortium Criteria (IMDC, Heng JCO 2009). Pts were randomized 1:1 to Cabo (60 mg QD) or Sun (50 mg QD, 4 weeks on/2 weeks off). Pts were stratified by IMDC risk groups (intermediate vs. poor risk) and bone metastasis (yes, no). With 123 events (progression or deaths), the log-rank statistic has 85% power to detect a hazard ratio of 0.67 for PFS assuming a one-sided type I error of 0.12.
From July 2013 to April 2015, 157 pts were randomized (79 to Cabo and 78 to Sun). Median follow up was 20.8 months (mo). 13 (16.46%) pts remained on therapy in the Cabo arm vs. 2 (2.56%) pts in the Sun arm. 80.9% of pts were IMDC intermediate risk and 36.3% had bone metastases and were equally distributed across arms. Median PFS was significantly increased at 8.2 mo (95% CI = 6.2-8.8) for Cabo vs. 5.6 mo (95% CI = 3.4-8.2) for Sun, with 31% reduction in rate of progression or death (adjusted HR 0.69, 95% CI 0.48 to 0.98, one-sided P = 0.012). ORR was 46% (95% CI 34-57%) for Cabo vs. 18% (95% CI 10-28%) for Sun. Median OS was 26.4 mo. for Cabo vs. 23.5 mo for Sun (adjusted HR 0.87, 95% CI 0.55-1.4). All-causality grade 3 or higher adverse events were 70.5% for Cabo and for 72.2% for Sun, and included diarrhea (Cabo 10%, Sun 11%), fatigue (Cabo 6%, Sun 15%), hypertension (Cabo 28%, Sun 22%), palmar-plantar erythrodysesthesia (Cabo 8%, Sun 4%) and hematological (Cabo 2.6%, Sun 22.2%). In each arm, 16 pts ended treatment due to toxicity.
Cabozantinib demonstrated a significant benefit in PFS and ORR over standard sunitinib in untreated intermediate and poor risk mRCC pts.
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T.K. Choueiri: Institutional funds from Exelixis and Pfizer. Advisory board compensation from Pfizer. All other authors have declared no conflicts of interest.