The BEST trial (E2804): A randomized phase II study of VEGF, RAF kinase, and mTOR combination targeted therapy (CTT) with bevacizumab (bev), sorafenib (sor), and temsirolimus (tem) in advanced renal cell carcinoma (RCC).
McDermott, DF; Manola, J; Pins, M; Flaherty, KT; Atkins, MB; Dutcher, JP; George, DJ; Margolin, KA; DiPaola, RS
Published in: Journal of Clinical Oncology
345 Background: Single-agent VEGF and MTOR directed targeted therapy have improved outcomes for pts with RCC. Phase I trials suggested that CTT might delay resistance. This randomized phase II trial was designed to find the best CTT regimen in comparison to bev alone for potential comparison to the best available single-agent therapy in a phase III trial. Methods: 361 treatment naïve RCC pts were randomized to receive Bev (10mg/kg Q2wks), Tem (25mg Qwk) + Bev (10mg/kg), Bev (5mg/kg Q2wks) + Sor (200mg po 5d on/2d off), or Sor (200mg QD) + Tem (25mg Qwk) until disease progression or unacceptable toxicity. The study was designed to detect a 67% improvement in median PFS on the combination arms, compared to single-agent bev (median 9 vs. 15 mo). Results: The median PFS was 8.7 mo for Bev versus 7.3 mo for Bev/Tem (HR = 0.91; 95% CI, 0.68-1.23), 11.3 mo for Bev/Sor (HR = 0.84; 95% CI, 0.62-1.13), 7.7 mo for Sor/Tem (HR = 1.11; 95% CI, 0.83-1.49). The response rates (CR+PR) were 12% for Bev versus 28% for Bev/Tem, 30% for Bev/Sor and 27% for Sor/Tem. No difference in OS was observed. Common toxicities included hypertension, fatigue, hand-foot syndrome, and diarrhea. Grade 3/4 adverse events and dose reductions were more common on CTT. Conclusions: CTT was not superior to single-agent Bev for the PFS primary endpoint. Common severe toxicities were expected, but more prevalent with CTT than with Bev alone. The VEGF/VEGFR co-inhibition strategy may warrant further investigation possibly with more selective VEGFR inhibitors. Clinical trial information: NCT00378703.
