Phase Ib study of sorafenib and vinorelbine as first-line treatment in patients with metastatic breast cancer.

Abstract

1093 Background: Sorafenib is an oral inhibitor of Raf and VEGFR/PDGFR. In preclinical models, favorable effects were noted combining sorafenib and vinorelbine. Both vinorelbine and sorafenib undergo hepatic metabolism. We aimed to determine the recommended doses in a phase 1b study. Methods: Patients were eligible with HER2-negative metastatic breast cancer, measurable (RECIST), not previously treated with chemotherapy for advanced stage; ECOG PS 0-1, adequate renal, liver and bone marrow functions, and LVEF ≥50%. Treatment was in two subsequent cohorts of 6 patients each: vinorelbine (30 mg/m2 days 1, 8 every 21) + sorafenib 200 mg BID continuously (cohort 1); vinorelbine (same as cohort 1) + sorafenib 400 mg BID continuously (cohort 2). Patients still benefiting after 8 cycles of treatment were allowed to continue on single-agent sorafenib. Results: Six patients in each cohort (n=12) were evaluated. Patients received a median of 8 cycles of treatment. Dose-limiting toxicities with the first cycle included: grade 3 (G3) pancreatitis + cholangitis (n=1, cohort 1; gallstones were also found), and asymptomatic G4 increase in serum amylase/lipase (n=1, cohort 2; spontaneously resolved). With repeated cycles, other significant (G2-4) toxicities included: uncomplicated G3-4 neutropenia (92%); G3 enteritis (8%); G2-3 diarrhea (33%); G2-3 AST/ALT increase (33%); G2 bilirubin increase (25%), fatigue (50%), stomatitis (25%), vomiting (17%), hand-foot syndrome (17%), dyspepsia, nausea, anorexia, dry skin, sensorial neuropathy (8% each); G2 alopecia (17%). One patient discontinued treatment for recurrent G2 LVEF decrease after 8 cycles. Of 12 patients 50% showed a partial response, and 92% had clinical benefit (including stable disease after 4 cycles of treatment). Conclusions: The combination of vinorelbine and sorafenib is feasible, and shows promising efficacy in advanced breast cancer. Toxicity is quite variable, with uncomplicated neutropenia being very common. Full doses of both agents are tolerated in most patients, but patients at high risk for toxicity can more safely start on a lower dose. We recommend close monitoring for the first 2 cycles, including amylase and lipase. No significant financial relationships to disclose.