ABSTRACT
BACKGROUND: The vascular endothelial growth factor (VEGF) pathway can be targeted through VEGF neutralization or VEGF receptor (VEGFR) blockade using tyrosine kinase inhibition. Because laboratory models suggest that combining these approaches might be synergistic, we sought to evaluate the feasibility and efficacy of combining sunitinib with paclitaxel + bevacizumab (PB). METHODS: Patients with human epidermal growth factor receptor 2 (HER2)-negative, metastatic breast cancer receiving first-line chemotherapy were randomized to PB or PB with sunitinib (PBS), with planned escalation of the sunitinib dose. RESULTS: Forty-six patients were randomized to PB or PBS with sunitinib dosed at 25 mg p.o. daily. Patients receiving PBS encountered substantial toxicity that precluded adequate treatment. The percentage of patients with grade ≥3 adverse events was greater in the PBS arm than the PB arm (83% versus 57%), and sunitinib dosing was modified in 78% of patients, most often due to neutropenia, febrile neutropenia, and fatigue. In addition, 44% of patients had sunitinib dose reduction to 12.5 mg, and 39% required discontinuation. Patients receiving PBS had more bevacizumab treatment interruptions and discontinuations because of toxicity. Median treatment duration was longer in the PB arm compared with the PBS arm (14.1 versus 11.1 weeks), reflecting early treatment discontinuation of PBS. Because of poor tolerability of the addition of sunitinib to PB, the planned sunitinib dose escalation was halted and the study accrual was terminated. CONCLUSION: Adding sunitinib to standard doses of bevacizumab plus paclitaxel for metastatic breast cancer is not feasible. Different strategies will be required to evaluate whether there is additional clinical benefit to combining VEGF/VEGFR-targeted agents.
