Roche has managed to reverse the European Medicines Agency's rejection of use of Avastin in combination with capecitabine for treatment of first-line metastatic breast cancer.

While this is a different indication than the one under appeal with FDA, the success of overcoming the regulator's concerns with a re-presentation of the data and an oral defense can only be confidence boosting as Genentech prepares for a similar interaction with FDA on combination use with paclitaxel, which is supported by better data.

Genentech will present its appeal of FDA's decision to withdraw the Avastin (bevacizumab) approval for metastatic breast cancer at a June 28-29 hearing (Also see "Genentech Asks A Lot From Avastin Hearing" - Pink Sheet, 12 April, 2011.).

The CHMP issued a positive opinion on April 14 on the indication for use with capecitabine, though with a limitation. The summary of product characteristics will restrict use to patients in whom other chemotherapy options, including taxanes or anthracyclines, is not considered appropriate. Further, patients who have received taxane or anthracycline-containing regimens in the adjuvant setting within the last 12 months should also be excluded, CHMP decided.

CHMP's original decision not to allow the indication was issued Dec. 16, 2010 - the same day that FDA similarly decided against a label expansion for use in combination with capecitabine, but more importantly, also announced it was moving to withdraw the metastatic breast cancer indication for Avastin in the U.S. (Also see "Avastin's Next Stop May Be Hearing As FDA Starts Withdrawal Process For Breast Cancer Claim" - Pink Sheet, 16 December, 2010.).

The initial breast cancer approvals were based on a strong progression-free survival advantage when used with paclitaxel chemotherapy in the E2100 study. Roche subsequently submitted other studies with different chemotherapy combinations - AVADO with docetaxel and RIBBON1 with capecitabine (Roche's Xeloda).

But those other studies failed to live up to the magnitude of the benefit in E2100. EMA had granted a full approval for Avastin use in combination with paclitaxel and decided the new findings did not impact that determination. FDA, however, had issued an accelerated approval on the condition that the other studies confirmed the benefit. When that didn't happen, it decided to rescind the approval - an action Genentech is now appealing.

The proposed label expansions based on the AVADO and RIBBON1 studies were denied by both EMA and FDA. While Genentech's efforts in the U.S. are currently aimed at keeping the paclitaxel indication, in Europe Roche requested a re-examination of the capecitabine indication.

In a Q&A posted on the EMA website, CHMP explains that the initial negative opinion was that although there was a "modest improvement" in PFS for the capecitabine combination, there were no meaningful effects for other measurements such as overall survival or health-related quality of life. And the insufficient benefit came with significant toxicity.

"As capecitabine is aimed at patients for whom a relatively mild treatment is appropriate, the increased toxicity of adding Avastin was also considered important," it states.

The re-examination entailed another review of the data previously assessed and an oral explanation from the company. It appears Roche proposed the restricted indication at that time.

Changing the patient population altered the risk-benefit outlook. In reversing its opinion, the committee noted that there are limited treatment options for the restricted patient population. Thus for those patients, it determined that the improvement in PFS was relevant and the toxicity profile of the combination was acceptable.

-Mary Jo Laffler (m.laffler@elsevier.com)

Roche Succeeds In Changing EMA Ruling On Avastin

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