Summary Background Longer duration of first-line chemotherapy for patients with metastatic breast cancer is associated with prolonged overall survival and improved progression-free survival. We ...investigated capecitabine added to maintenance bevacizumab after initial treatment with bevacizumab and docetaxel in this setting. Methods We did this open-label randomised phase 3 trial at 54 hospitals in Brazil, China, Egypt, France, Hong Kong, India, Italy, Poland, Spain, and Turkey. We enrolled patients with HER2-negative measurable metastatic breast cancer; each received three to six cycles of first-line bevacizumab (15 mg/kg) and docetaxel (75–100 mg/m2 ) every 3 weeks. Progression-free patients were randomly assigned with an interactive voice-response system by block (size four) randomisation (1:1) to receive either bevacizumab and capecitabine or bevacizumab only (bevacizumab 15 mg/kg on day 1; capecitabine 1000 mg/m2 twice per day on days 1–14, every 3 weeks) until progression, stratified by oestrogen receptor status (positive vs negative), visceral metastases (present vs absent), response status (stable disease vs response vs non-measurable), and lactate dehydrogenase concentration (≤1·5 vs >1·5 × upper limit of normal). Neither patients nor investigators were masked to allocation. The primary endpoint was progression-free survival (from randomisation) in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , NCT00929240. Findings Between July 16, 2009, and March 7, 2011 (when enrolment was prematurely terminated), 284 patients received initial bevacizumab and docetaxel; 185 (65%) were randomly assigned (91 to bevacizumab and capecitabine versus 94 to bevacizumab only). Progression-free survival was significantly longer in the bevacizumab and capecitabine group than in the bevacizumab only group (median 11·9 months 95% CI 9·8–15·4 vs 4·3 months 3·9–6·8; stratified hazard ratio 0·38 95% CI 0·27–0·55; two-sided log-rank p<0·0001), as was overall survival (median 39·0 months 95% CI 32·3–not reached vs 23·7 months 18·5–31·7; stratified HR 0·43 95% CI 0·26–0·69; two-sided log-rank p=0·0003). Results for time to progression were consistent with those for progression-free survival. 78 (86%) patients in the bevacizumab and capecitabine group and 72 (77%) in the bevacizumab only group had an objective response. Clinical benefit was recorded in 92 (98%) patients in the bevacizumab alone group and 90 (99%) in the bevacizumab and capecitabine group. Mean change from baseline in global health score did not differ significantly between groups. Grade 3 or worse adverse events during the maintenance phase were more common with bevacizumab and capecitabine than with bevacizumab only (45 49% of 91 patients vs 25 27% of 92 patients). The most common grade 3 or worse events were hand–foot syndrome (28 31% in the bevacizumab and capecitabine group vs none in the bevacizumab alone group), hypertension (eight 9% vs three 3%), and proteinuria (three 3% vs four 4%). Serious adverse events were reported by ten (11%) patients in the bevacizumab and capecitabine group and seven (8%) patients in the bevacizumab only group. Interpretation Despite prematurely terminated accrual and the lack of information about post-progression treatment, both progression-free survival and overall survival were significantly improved with bevacizumab and capecitabine compared with bevacizumab alone as maintenance treatment. These results might inform future maintenance trials and current first-line treatment strategies for HER2-negative metastatic breast cancer. Funding F Hoffmann-La Roche.
Summary Background Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the ...efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy. Methods In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov , number NCT01250379. Findings Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15·9 months (IQR 9·1–21·7) in the chemotherapy-alone group and 16·1 months (10·6–22·7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6·3 months 95% CI 5·4–7·2 vs 4·2 months 3·9–4·7, respectively, stratified hazard ratio HR 0·75 95% CI 0·61–0·93, two-sided stratified log-rank p=0·0068). The most common grade 3 or more adverse events were hypertension (33 13% of 245 patients receiving bevacizumab plus chemotherapy vs 17 7% of 238 patients receiving chemotherapy alone), neutropenia (29 12% vs 20 8%), and hand-foot syndrome (27 11% vs 25 11%). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (<1%) of 238 patients receiving chemotherapy alone. Serious adverse events were reported in 61 (25%) of 245 patients receiving bevacizumab plus chemotherapy versus 44 (18%) of 238 patients receiving chemotherapy alone. Interpretation These results suggest that continued VEGF inhibition with further bevacizumab is a valid treatment option for patients with locally recurrent or metastatic HER2-negative breast cancer whose disease was stabilised or responded to first-line bevacizumab with chemotherapy. Funding F Hoffmann-La Roche.
