Background: Tivozanib, a selective inhibitor of vascular endothelial growth factor receptor-1, -2, and -3, plus mFOLFOX6 in an advanced gastrointestinal cancer phase Ib study had encouraging antineoplastic activity and a tolerable safety profile. This randomized, open-label, phase II trial of tivozanib/mFOLFOX6 vs. bevacizumab/mFOLFOX6 in patients with previously untreated metastatic colorectal cancer (mCRC) evaluated tivozanib activity vs. bevacizumab. Methods: Treatment-naïve patients received mFOLFOX6 every 2 weeks of each 28-day cycle plus either tivozanib orally 1.5 mg once daily for 21 days or bevacizumab intravenously 5 mg/kg every 2 weeks. Investigator-assessed progression-free survival (PFS) was the primary endpoint; some secondary endpoints included safety, overall survival, overall response rate (ORR), duration of response, time to treatment failure, and biomarker subgroup analyses. Results: A prespecified interim futility analysis demonstrated that the futility boundary for superiority of tivozanib/mFOLFOX6 over bevacizumab/mFOLFOX6 for PFS in the intent-to-treat population was crossed; median PFS was 9.4 vs. 10.7 months (HR=1.091; CI 0.693-1.718; P = 0.706). Tivozanib/mFOLFOX6 resulted in PFS and ORR comparable to bevacizumab/mFOLFOX6; interim analyses biomarker results revealed no significant PFS association. Post hoc final analyses demonstrated a potential statistical difference in tivozanib-specific PFS in patients with low neuoropilin-1 (NRP-1), but not in patients with high NRP-1. Tivozanib/mFOLFOX6 was tolerable and adverse events were comparable to both bevacizumab/mFOLFOX6 and previous tivozanib studies. Conclusions: The efficacy of tivozanib/mFOLFOX6 was comparable to bevacizumab/mFOLFOX6 in patients with previously untreated mCRC; safety and tolerability profile of tivozanib/mFOLFOX6 was consistent with other tivozanib trials. NRP-1 is a potential predictive biomarker for tivozanib activity.
- Received January 13, 2016.
- Revision received May 19, 2016.
- Accepted June 20, 2016.
- Copyright ©2016, American Association for Cancer Research.