SABRE-B: a randomized phase II trial evaluating the safety and efficacy of combining sunitinib (S) with paclitaxel (P) + bevacizumab (B) as first-line treatment for HER2-negative metastatic breast cancer (MBC): final results.

Abstract

Abstract Abstract #3126 Background: B, a humanized monoclonal antibody that neutralizes VEGF, improves progression-free survival (PFS) when combined with taxanes in 1st-line MBC. S, an oral inhibitor of receptor tyrosine kinases, including PDGFRs and VEGFRs, has shown activity in MBC. Preclinical models suggest that the addition of S to B may increase the inhibition of the VEGF signaling pathway. SABRE-B was a Phase II randomized open-label study comparing the safety and efficacy of S in combination with P/B to P/B alone.
 Methods: Patients (pts) with HER2-negative MBC receiving 1st-line chemotherapy were eligible. P (90 mg/m2 qwk x 3 every 4 weeks), B (10 mg/kg q2wk) and S (25 mg qd x 21d) were administered in 28-day cycles. S dose was to be adjusted for myelosuppression, fatigue, or other treatment-related toxicities. Planned enrollment had 3 phases: an initial 2-arm phase with P/B vs. P/B/S (25 mg) to assess tolerability of S plus P/B. If P/B/S (25 mg) was tolerable, a second phase comparing P/B to P/B/S (25 mg) to P/B/S (37.5 mg) would begin. A final phase with the selected S dose would compare the clinical efficacy (PFS) of P/B/S to P/B.
 Results: From 3/2007-1/2008, 46 pts were randomized, 23 to P/B and 23 to P/B/S (25 mg). At the time of this analysis, the estimated mean treatment duration was longer in the P/B arm (14.7 weeks) compared with the P/B/S arm (10.9 weeks), reflecting a higher number of pts who discontinued early in the P/B/S arm. The percentage of pts with a Grade ≥3 AE was greater in the P/B/S arm compared with P/B (73.9% vs. 39.1%) and SAEs were greater in the P/B/S arm compared with P/B (43.5% vs. 30.4%). Neutropenia, febrile neutropenia, and fatigue were the most frequently reported AEs resulting in modifications to S dosing. Seventy percent of pts had an AE resulting in S dose interruption or modification. In addition to S doses being held, 17% required S dose reduction to 12.5 mg and 30% required discontinuation of S. Pts receiving P/B/S required more interruptions in B administration compared with P/B (52% vs. 44%), and more pts receiving P/B/S discontinued B compared with P/B (22% vs. 0%) because of AEs. There was one on-treatment death with P/B/S due to disease progression. Because of poor tolerability of the addition of S (25 mg) to P/B, the second phase of enrollment (S 37.5 mg) was never initiated.
 Conclusion: Given the high rate of S dose modifications and/or treatment discontinuations in the first phase of SABRE-B, it was determined that in 1st line MBC, adding S at these doses and schedules to the approved P/B regimen was not feasible and the study was closed. Targeted VEGF inhibition with B in combination with VEGFR tyrosine kinase inhibitors is of clinical interest, but will require additional clinical studies to define how to safely combine these agents. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3126.