Adding capecitabine to maintenance bevacizumab delays progression and prolongs survival in women with HER2-negative metastatic breast cancer
The outcome of the phase III IMELDA study demonstrates that adding capecitabine (CAP) to bevacizumab (BEV) maintenance therapy results in a significant improvement in progression-free survival (PFS) and overall survival (OS) in women with HER2-negative, metastatic breast cancer (mBC) who responded to a first-line, bevacizumab-containing treatment regimen.
Until regulatory withdrawal of BEV in combination with docetaxel (DOC) in 2011, this combination was considered a valid first-line treatment option for HER2-negative mBC. In fact, the PFS and response rate (RR) with first-line DOC (maximum of 9 cycles) were significantly improved by adding BEV continued until disease progression. In the open-label randomised phase III IMELDA trial, investigators tested whether adding CAP to maintenance BEV continued until disease progression after initial BEV–DOC also had an impact on the PFS. In the initial phase of the study, a total of 284 patients were treated with DOC plus BEV. After 3–6 cycles of BEV–DOC, the 185 patients without disease progression were randomised to BEV (N= 94) alone or BEV-CAP (N=91) (BEV 15 mg/kg q3w; CAP 1000 mg/m2 bid d1-14 q3w) until disease progression. The primary endpoint was PFS (from randomisation), while secondary endpoints included response rate, OS from randomisation, safety and quality of life.
IMELDA met its primary endpoint with a median PFS from the time of randomisation of 11.9 months in the BEV+CAP arm vs. 4.3 months in the BEV only arm (HR[95%CI]: 0.38 [0.27-0.55]; p < 0.0001).
In an exploratory analysis assessing the PFS from the start of first-line therapy, BEV+CAP was associated with a median PFS of 16.4 months compared to 8.6 months with BEV alone (HR[95%CI]: 0.38 [0.27-0.55]). Looking at the secondary endpoint of OS, BEV+CAP was associated with a median OS of 39 months compared to 23.7 months in the group of patients who only received BEV (HR[95%CI]: 0.43 [0.26-0.69]; p = 0.0003). The 1-year survival rate was 72% with BEV alone compared to 90% with BEV+CAP. The 2-year OS rate was 49% with BEV alone vs. 69% with the combination of BEV and CAP.
The combination did result in some added toxicity. The percentage of patients with grade 3 or higher adverse events was 27% with BEV compared to 49% with BEV+CAP. However, it is important to note that the vast majority of these events was grade 3 in severity. The most common adverse events seen with BEV+CAP were hand-foot syndrome (31%) and hypertension (8%). The hand-foot syndrome led to treatment discontinuation of CAP in 9 patients (10%).
In summary, adding CAP to maintenance BEV provided statistically significant and clinically meaningful improvements in PFS and OS at study closure, despite the smaller than planned sample size because of early termination of accrual, with a manageable increase in adverse events, mainly due to hand-foot syndrome.
Gligorov J, Doval D, Bines J, et al. Efficacy and safety of maintenance bevacizumab (BEV) with or without capecitabine (CAP) after initial first-line BEV plus docetaxel (DOC) for HER2-negative metastatic breast cancer (mBC): IMELDA randomised phase III trial. Presented at ESMO 2014; Abstract 352O.