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IMELDA trial: efficacy and safety of maintenance Bevacizumab with or without Capecitabine after initial first-line Bevacizumab plus Docetaxel in HER2-negative metastatic breast cancer


Prolonging first-line chemotherapy results with maintenance treatment may influence overall survival. In HER2-negative patients with locally recurrent/metastatic breast cancer, combining Bevacizumab ( Avastin ) with first-line chemotherapy significantly improves progression-free survival. Bevacizumab benefit is most pronounced when combined with a taxane. Cumulative toxicity prevents taxane continuation until disease progression.

Until regulatory withdrawal of Bevacizumab / Docetaxel in 2011, this combination was considered as a valid first-line option for HER2-negative metastaic breast cancer based on results of a phase III trial. The progression-free survival and response rate ( RR ) with maximum 9 cycles of first-line Docetaxel were significantly improved by adding Bevacizumab continued until disease progression.

The open-label randomised phase III IMELDA trial tested whether switching to a more tolerable chemotherapy with a different mechanism of action while continuing VEGF inhibition may be more effective. It was meant that by adding Capecitabine ( Xeloda )to maintenance Bevacizumab continued until disease progression after initial Bevacizumab / Docetaxel will improve progresion-free survival.

Patients with HER2-negative measurable metastatic breast cancer, ECOG PS less than 2 and no prior chemotherapy were eligible for study inclusion.

After 3-6 cycles of Bevacizumab / Docetaxel, patients without disease progression were randomised to Bevacizumab alone or Bevacizumab / Capecitabine until disease progression. Stratification factors were oestrogen receptor ( ER ) status, presence of visceral metastases, response status and LDH concentration.

The primary endpoint was progression-free survival from randomisation to progression / death; secondary endpoints included response rate, clinical benefit rate, time to disease progression, overall survival from randomisation, safety and quality of life. The sample size was calculated based on a PFS hazard ratio ( HR ) of 0.70 with median PFS improvement from 5.8 to 8.3 months.
In total 360 enrolled patients were required for 290 randomised patients. It was planned that 244 PFS events provide 80% power at 5% 2-sided alpha.
The study was not designed for formal overall survival comparison.

During the period 2009-2011 when enrolment was prematurely terminated, 287 patients were enrolled and 284 of them treated with 185 ( 65% ) who completed initial treatment and subsequently randomised to maintenance treatment. The protocol was amended to continue follow-up for 2 years after last randomisation.

Median age in the Bevacizumab arm was 54 years and 49 years in the Bevacizumab / Capecitabine arm. Triple-negative disease was recorded in 22% of patients included in the Bevacizumab arm and 27% of patients in the Bevacizumab / Capecitabine arm.
Visceral metastases were nearly identical in both group ( 69% vs 68% ), however their presence in 3 organs or more was higher in Bevacizumab arm at enrolment to the initial phase ( 57% vs 47% ).

In the maintenance arm, median treatment duration was longer in Bevacizumab / Capecitabine group ( 8.3 vs 3.5 months ). Adding Capecitabine to maintenance Bevacizumab provided statistically significant and clinically meaningful improvements in progression-free survival from time of randomisation ( HR=0.38, p less than 0.001; median 11.9 vs 4.3 months ) and exploratory analysis ( progression-free survival from start of first-line therapy ), as well as improvement in median overall survival from time of randomisation ( HR=0.42, p less than 0.001; 39 vs 23.3 months ), despite the smaller than planned sample size because of early termination of accrual. However, at the time of report there was insufficient duration of overall survival follow-up with low event rate.

There was a manageable increase in adverse events mainly due to hand-foot syndrome experienced in 33% of patients in Bevacizumab / Capecitabine arm.
Hypertension was recorded in 9% of patients in the combined arm and 3% of patients in the Bevacizumab only arm.
The rate of proteinuria was same ( 4% ) in both groups. Gastroenteritis occured in 3 patients in the Bevacizumab single agent arm. ( Xagena )

Source: ESMO Congress, 2014

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