ESMO 2014-MAINTENANCE CAPECITABINE-BEVACIZUMAB FOR COLORECTAL CANCER

Regulatory approval of bevacizumab (Avastin) plus docetaxel in metastatic breast cancer was withdrawn in Europe in February 2011 and in the United States in November 2011. The phase III IMELDA trial comparing maintenance capecitabine/bevacizumab vs bevacizumab after first-line bevacizumab/docetaxel in HER2-negative metastatic breast cancer was started prior to and terminated early upon approval withdrawal. As reported in The Lancet Oncology by Gligorov et al, maintenance capecitabine/bevacizumab improved progression-free survival and overall survival vs bevacizumab alone in the trial. Details of postprogression treatment in the trial population are not known.

Study Details

In this open-label trial, conducted at 54 hospitals in Brazil, China, Egypt, France, Hong Kong, India, Italy, Poland, Spain, and Turkey, 284 patients with HER2-negative measurable metastatic breast cancer were treated with three to six cycles of first-line bevacizumab (15 mg/kg) and docetaxel (75–100 mg/m2) every 3 weeks between July 2009 and March 2011, when enrollment was prematurely terminated.

Progression-free patients were randomly assigned to receive bevacizumab at 15 mg/kg on day 1 with or without capecitabine at 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks until progression. Of the 284 patients, 185 (65%) were randomly assigned to receive capecitabine/bevacizumab (n = 91) or bevacizumab (n = 94). Randomization was stratified by estrogen receptor status, visceral metastases, response status, and lactate dehydrogenase level. The primary endpoint was progression-free survival in the intent-to-treat population.

Improved Progression-Free and Overall Survival

Median duration of follow-up in the maintenance period was 31.6 months in the combination group and 30.4 months in the bevacizumab group. Median progression-free survival was 11.9 months (95% confidence interval [CI] = 9.8–15.4 months) in the capecitabine/bevacizumab group vs 4.3 months (95% CI = 3.9–6.8 months) in the bevacizumab group (stratified hazard ratio [HR] = 0.38, P < .0001). Median overall survival was 39.0 months (95% CI = 32.3 months to not reached) vs 23.7 months (95% CI = 18.5–31.7 months; stratified HR = 0.43, P = .0003). Progression-free survival and overall survival benefits with combination treatment were consistent across most analyzed subgroups.

Objective response occurred in 86% vs 77% of patients and clinical benefit occurred in 99% and 98%. Mean change from baseline in global health score on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 did not differ significantly between groups.

Adverse Events

Adverse events of grade ≥ 3 during the maintenance phase were observed in 49% of the capecitabine/bevacizumab group and 27% of the bevacizumab group, with the most common being hand-foot syndrome (31% vs 0%), hypertension (9% vs 3%), and proteinuria (3% vs 4%). Serious adverse events occurred in 11% vs 8%. Bevacizumab was discontinued due to grade ≥ 3 adverse events in 15% of the combination group vs 13% of the bevacizumab group, and adverse events led to bevacizumab treatment delay in 13% vs 5%. In the combination group, grade ≥ 3 adverse events led to capecitabine dose reduction in 16%, interruption in 21%, and discontinuation in 18%. The most common adverse events leading to discontinuation were hand-foot syndrome (10% vs 0%), hypertension (2% vs 2%), and proteinuria (1% vs 2%).

 The investigators concluded: “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.”

Joseph Gligorov, MD, of University Cancer Institute-Pierre & Marie Curie, Sorbonne University, is the corresponding author for The Lancet Oncology article.

The study was funded by F. Hoffmann-La Roche. For full disclosures of the study authors, visit www.thelancet.com.