Background: We assessed, in a double-blinded placebo-controlled trial, the effect of adding motesanib (M), a small molecule antagonist of VEGF, PDGF and Kit receptors, to paclitaxel (P) as first line treatment of subjects with MBC. A P plus bevacizumab (B) open-label arm was included. The study was supported by Amgen Inc.Methods: 282 subjects with HER2-negative and measurable MBC were randomly assigned treatment with P 90mg/m2 on days 1, 8 and 15 in combination with blinded placebo (Arm A), blinded M 125mg once daily (Arm B) or open-label B 10mg/kg on days 1 and 15 (Arm C). Treatment was administered in 28-day cycles until disease progression, toxicity or consent withdrawal. The primary objective was to compare objective response rate (ORR: CR or PR) between Arm A and B. Treatment efficacy was assessed every 8 weeks according to RECIST version 1.0 and scans were centrally reviewed.Results: 277 subjects received study treatment. Subject characteristics at entry were balanced: median age was 55, 80% had hormone receptor positive tumors and 66% had received adjuvant chemotherapy. At this analysis, 10 months after last enrolled subject, 235 subjects had completed treatment (median duration: 6 cycles). The median cumulative dose of P was similar across the arms: 1530, 1455 and 1652 mg/m2 in Arms A, B and C, respectively. Subjects received a median cumulative dose of 179 mg/kg of B (Arm C) and a median daily dose of 111 mg of M (Arm B). The table displays the efficacy results and relevant differences in toxicity incidences:More adverse events were reported in Arm B compared to the other arms, mainly grade 3 and 4 gastrointestinal toxicities, hepatobiliary toxicities and hypertension. Infections and stomatitis were more frequently reported in Arm C. Venous thrombo-embolic events were similar across all three arms. Among serious hepatobiliary disorders, 5 subjects experienced serious cholecystitis or gallbladder enlargement: 4 of them were managed by surgery and 4 subjects could resume study treatment.The ORR favored Arms B and C as compared to Arm A, with 49%, 52% and 41% respectively but the difference between Arm A and B was not statistically significant (p=.31, adjusting for stratification factors). Stable disease lasting at least 24 weeks was reported for 34%, 36% and 33% of subject in Arms A, B and C respectively. The Progression-Free Survival (PFS) did not significantly differ between the three arms.Conclusion: The antitumor effect of P and M is comparable to P and B as treatment of subjects with HER2-negative MBC but P and M increases toxicities compared to the other arms.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 47.