ArticlesMaintenance 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
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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2024, Cancer Pathogenesis and TherapySwitch maintenance endocrine therapy plus bevacizumab after bevacizumab plus paclitaxel in advanced or metastatic oestrogen receptor-positive, HER2-negative breast cancer (BOOSTER): a randomised, open-label, phase 2 trial
2022, The Lancet OncologyCitation Excerpt :By contrast, the MANTA 1 study4 found no improvements in progression-free survival or overall survival with administration of additional courses of paclitaxel in patients with metastatic breast cancer who had disease control after first-line combination treatment with anthracycline plus paclitaxel chemotherapy compared with no additional chemotherapy administration. Among studies evaluating switch maintenance therapy, the IMELDA study5 showed improvements in progression-free survival and overall survival (despite premature accrual termination) with switch maintenance chemotherapy with capecitabine plus bevacizumab compared with bevacizumab alone after first-line bevacizumab plus docetaxel in patients with HER2-negative metastatic breast cancer. In the AROBASE study,6 which enrolled patients with ER-positive, HER2-negative metastatic breast cancer with no evidence of progression after first-line taxane plus bevacizumab, progression-free survival was similar in patients who switched to maintenance therapy with exemestane plus bevacizumab and those continuing taxane plus bevacizumab.
First-line bevacizumab-containing therapy for HER2-negative locally advanced/metastatic breast cancer: Real-world experience from >2000 patients treated in the multicentre AVANTI study
2021, BreastCitation Excerpt :Detailed documentation is permitted for a maximum of 15 months, making it difficult to capture patterns of subsequent therapy, especially with median PFS approaching the maximum follow-up allowed. In addition, switch maintenance therapy is not approved in Germany (or indeed anywhere in Europe), so while the strategy of switching from bevacizumab plus a taxane to BEV–CAP after an induction period demonstrated a statistically significant OS benefit in the IMELDA trial [15], such an approach is used less often than may be expected in clinical practice because of regulatory and funding challenges. A strength of the study is its real-world patient population, providing insight into everyday oncology practice.