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

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.

Optimizing the treatment of bevacizumab as first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer: an updated meta-analysis of published randomized trials

“…Although the primary endpoint in this trial was the incidence of pre-specified grade 3–5 AEs instead of ORR, PFS and OS, its results might also offer some clues. The SAKK 24/09 trial showed no statistical significance between bevacizumab plus paclitaxel and bevacizumab plus metronomic capecitabine-cyclophosphamide in terms of ORR, PFS and OS 18. Taken together, these findings clarify that the combination of bevacizumab and capecitabine may function as a valid first-line treatment option.…”

“…Three of these studies were used to evaluate the efficacy of adding bevacizumab to chemotherapy, including 1,558 women who received bevacizumab combined with chemo-therapy and 896 women who were administered chemotherapy alone 12,13,17. The other 4 trials were obtained to assess the optimal chemotherapy partner of bevacizumab 16,18–20. All of them were published as full articles and described as Phase III randomized controlled trials.…”

“…All of them were published as full articles and described as Phase III randomized controlled trials. The former 3 trials were double blinded,12,13,17 and the latter 4 studies were open label 16,18–20. Of note, the E2100 trial was considered ineligible for this meta-analysis despite its inclusion in the previous reports on this topic 21,22.…”

Efficacy of bevacizumab combined with chemotherapy in the treatment of HER2-negative metastatic breast cancer: a network meta-analysis

“…Finally, sixteen studies were identified involving 589 patients that fulfilled the inclusion criteria in Fig. 1 [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Figure 2 demonstrates all available direct comparisons across outcomes in this network meta-analysis.…”

Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies—A review

“…For example, bevacizumab is largely used only in combination with other drugs. While the progression‐free survival of patients treated with bevacizumab as first‐line therapy has shown marked improvement in many phase III studies, overall survival failed to differ significantly between experimental and control groups . Even as a second‐line treatment, bevacizumab has failed to show improvement in progression‐free survival .…”