SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel vs. bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer - a multicenter, randomized phase III trial.

Christoph Rochlitz,Andreas Müller,Sandro Anchisi,Marcus Vetter,Ursula Hasler-Strub,Jürg Bernhard,Kyung-Jae Na,Khalil Zaman,Andreas Trojan,Marc Küng,Roger Von Moos,Richard Cathomas,Ralph Winterhalder,Thomas Ruhstaller,Markus Borner,Martin Bigler,Andreas Wicki,Tamara Rordorf,Daniela Bärtschi,Daniel Rauch,Klazien Matter-Walstra

doi:10.1186/s12885-016-2823-y

Abstract

BackgroundAdding bevacizumab to chemotherapy improves response rates and progression-free survival (PFS) in metastatic breast cancer (mBC). We aimed to demonstrate decreased toxicity with metronomic chemotherapy/bevacizumab compared with paclitaxel/bevacizumab.MethodsThis multicenter, randomized phase III trial compared bevacizumab with either paclitaxel (arm A) or daily oral capecitabine-cyclophosphamide (arm B) as first-line treatment in patients with HER2-negative advanced breast cancer. The primary endpoint was the incidence of selected grade 3–5 adverse events (AE) including: febrile neutropenia, infection, sensory/motor neuropathy, and mucositis. Secondary endpoints included objective response rate, disease control rate, PFS, overall survival (OS), quality of life (QoL), and pharmacoeconomics. The study was registered prospectively with ClinicalTrials.gov, number NCT01131195 on May 25, 2010.ResultsBetween September 2010 and December 2012, 147 patients were included at 22 centers. The incidence of primary endpoint-defining AEs was similar in arm A (25 % [18/71]; 95 % CI 15–35 %) and arm B (24 % [16/68]; 95 % CI 13–34 %; P = 0.96). Objective response rates were 58 % (42/73; 95 % CI 0.46–0.69) and 50 % (37/74; 95 % CI 0.39–0.61) in arms A and B, respectively (P = 0.45). Median PFS was 10.3 months (95 % CI 8.7–11.3) in arm A and 8.5 months (95 % CI 6.5–11.9) in arm B (P = 0.90). Other secondary efficacy endpoints were not significantly different between study arms. The only statistically significant differences in QoL were less hair loss and less numbness in arm B. Treatment costs between the two arms were equivalent.ConclusionThis trial failed to meet its primary endpoint of a reduced rate of prespecified grade 3–5 AEs with metronomic bevacizumab, cyclophosphamide and capecitabine.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2823-y) contains supplementary material, which is available to authorized users.

Highlights

Adding bevacizumab to chemotherapy improves response rates and progression-free survival (PFS) in metastatic breast cancer
The E2100 randomized phase III trial reported a near doubling of PFS and response rates (RR) with paclitaxel plus bevacizumab compared with paclitaxel alone in patients with metastatic breast cancer (mBC) [6]
We evaluated a combination of metronomic chemotherapy and bevacizumab that was described as effective and almost non-toxic in a small phase II trial [13]

Summary

Introduction

Adding bevacizumab to chemotherapy improves response rates and progression-free survival (PFS) in metastatic breast cancer (mBC). Increased rates of sensory neuropathy, febrile neutropenia and infection, and severe fatigue occurred with combination therapy. These data led to the FDA (Food and drug administration) granting accelerated approval to bevacizumab plus weekly paclitaxel for the first-line treatment of HER2-negative mBC in 2008. This approval was later removed because: additional randomized trials [7, 8] showed less pronounced PFS and RR benefits; no trial demonstrated an OS benefit (later confirmed in meta-analyses [9, 10]); and additional safety concerns were discussed [11]

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