Elsevier

The Lancet Oncology

Volume 15, Issue 12, November 2014, Pages 1351-1360
The Lancet Oncology

Articles
Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial

https://doi.org/10.1016/S1470-2045(14)70444-9Get rights and content

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.

Introduction

In patients with HER2-negative metastatic breast cancer, combining bevacizumab with first-line chemotherapy significantly improves progression-free survival and the proportion of patients who achieve an objective response compared with chemotherapy alone.1, 2, 3 In the AVADO trial,2 objective responses were reported in 64% of patients treated with first-line bevacizumab and docetaxel, which is among the highest rates in this setting. However, the benefit of bevacizumab seems greatest when combined with paclitaxel,1 and is more modest with docetaxel.2 A possible explanation for this difference is that, at least for metastatic breast cancer, bevacizumab is more effective when given concomitantly with chemotherapy than as monotherapy. In the AVADO trial,2 docetaxel was given for a maximum of nine cycles, after which bevacizumab was continued alone. The median duration of docetaxel treatment was 5·5 months. At present, no evidence is available about the optimum duration of first-line chemotherapy for metastatic breast cancer; international guidelines recommend tailoring the number and duration of regimens to each individual.4, 5 In clinical practice, the duration of chemotherapy is usually determined by the patient's response, individual tolerance, and physician preferences. However, a meta-analysis of 11 randomised trials showed that longer first-line chemotherapy is associated with longer overall survival and substantially longer progression-free survival, suggesting that treatment should be given until disease progression or unacceptable toxic effects.6

Prolongation of docetaxel exposure until disease progression is unrealistic because of cumulative toxic effects. However, switching to a more tolerable chemotherapy, such as capecitabine, with a different mechanism of action, while continuing VEGF inhibition, might be a more effective treatment strategy, and could enable concurrent chemotherapy and bevacizumab treatment until disease progression. Several small trials (150–230 patients) have assessed various maintenance strategies for metastatic breast cancer, although none has assessed maintenance treatment continued until disease progression. In the MANTA1 trial,7 neither progression-free nor overall survival was improved with continued paclitaxel alone every 3 weeks for eight cycles after anthracycline and paclitaxel induction treatment. However, in the GEICAM 2001-01 trial,8 switching to six cycles of pegylated liposomal doxorubicin after induction treatment (three cycles of doxorubicin followed by three cycles of docetaxel) significantly improved time to disease progression compared with observation (hazard ratio [HR] 0·54, p=0·0002), although overall survival did not differ significantly between groups. In a third trial, KCSG-BR07-02,9 continuation of gemcitabine and paclitaxel for six cycles after six initial cycles of gemcitabine and paclitaxel significantly improved both progression-free survival (HR 0·73, p=0·026) and overall survival (HR 0·65, p=0·047). However, the applicability of these results to routine clinical practice is perhaps questionable, because no treatment was permitted after completing six cycles of chemotherapy in the control group, thus leaving these patients untreated.10

The IMELDA trial was designed during the period when combined bevacizumab and docetaxel was approved for patients with metastatic breast cancer to assess switching to bevacizumab and capecitabine maintenance treatment. Several factors led to the selection of capecitabine as maintenance chemotherapy in this trial: its favourable safety profile, enabling prolonged treatment continuation; its lack of cross-resistance with taxanes; and its proven activity combined with bevacizumab for first-line (approved by the European Commission) and second-line treatment of HER2-negative metastatic breast cancer.

Section snippets

Study design and participants

We did this open-label, randomised, phase 3 trial in 54 hospitals in Brazil, China, Egypt, France, Hong Kong, India, Italy, Poland, Spain, and Turkey. Eligibility criteria included being a woman with HER2-negative metastatic breast cancer with at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0); having an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 0; a life expectancy of at least 12 weeks; adequate renal,

Results

287 patients were enrolled from 54 hospitals between July 16, 2009, and March 7, 2011. Recruitment was terminated prematurely after withdrawal of European Commission approval of bevacizumab plus docetaxel combination treatment for metastatic breast cancer on Feb 28, 2011. Of the 284 patients treated in the initial phase, 99 (35%) discontinued initial study treatment, and were therefore ineligible for randomisation (figure 1). The remaining 185 (65%) of 284 patients completed the initial phase

Discussion

The addition of capecitabine to maintenance bevacizumab treatment after initial taxane-based treatment for patients with HER2-negative metastatic breast cancer provided significant and clinically meaningful improvements in both progression-free survival and overall survival, despite the early discontinuation of enrolment and randomisation, resulting in a smaller sample size and fewer progression-free survival events than originally planned. The effect on overall survival was apparent early

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