Pharma Strategy Blog

Well, the long awaited decision by the FDA on bevacizumab (Avastin) in breast cancer has finally been published and is probably the least surprising decision by the agency in 2010:

“The Office of New Drugs (OND) recommends withdrawing approval of the breast cancer indication for bevacizumab (Avastin).  This indication was approved on February 22, 2008, under accelerated approval provisions for use in combination with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer.

As a condition of the accelerated approval, Genentech was required to submit data from two ongoing trials (AVADO and RIBBON1) to provide verification of the treatment effect on progression free survival (PFS) and to provide additional information on the effects on overall survival (OS).  These two trials failed to confirm the magnitude of benefit originally observed in the E2100 study on which accelerated approval was based.  In addition, there was an overall increase in serious adverse events related to bevacizumab.

The modest benefit observed with Avastin together with the substantial adverse reactions observed in breast cancer trials to date fail to provide a favorable risk-benefit profile to support continued marketing of Avastin for a first-line metastatic breast cancer indication.  It is the conclusion of OND that the breast cancer indication for Avastin be withdrawn.”

Source: FDA

This is not a surprising decision following the recent ODAC vote of 12-1 to withdraw the drug for the treatment of breast cancer based on the AVADO and RIBBON1 trial results, which was discussed in detail previously on this blog.  The overall survival data actually showed a slight benefit in favour of the chemotherapy (docetaxel) only arm in AVADO, for example, (31.9 vs. 30.2 months).

Also of interest to many is the more results from the neoadjuvant trial with bevacizumab prior to surgery.   Negative trial results were announced at the San Antonio Breast Cancer Symposium last week, essentially adding another nail in the coffin for a solid rationale for earlier use in breast cancer.

For now, the drug will remain on the market and available in this indication, but the clear intent by the FDA is that they plan on withdrawal following the lack of confirmation for full approval.  The company, Roche/Genentech, have 15 days to request a hearing and judging by the press releases so far, this will be sought.  No doubt significant patient advocacy will also be mobilised in support.

There is no question that some women with breast cancer have benefitted from treatment with bevacizumab, but without a biomarker to determine who is most likely to respond to the therapy, it is difficult to see how it can remain on the market given three overwhelming negative trials demonstrating little overall benefit and some not insignificant risk of systemic side effects.

For me, though, what this body of data consistently shows is that, combined with the negative bevacizumab in adjuvant colorectal cancer, VEGF plays a much clearer role in metastatic disease such as colorectal cancer where the tumours are more vascular and often larger.  In breast cancer, the tumours are typically much smaller by comparison.  It may well be that we learn more about the process of angiogenesis from negative data and how tumours grow.  Angiogenesis is a highly complex process and we still need to learn how other growth factors such as PDGF, angiopoeitins, Tie-2 etc, may play a role in tumour growth.  This has yet to be elucidated but research is ongoing.  The recent post discussing cancer cell seeding teaches us that we have much to learn about the whole process of angiogenesis from early growth to metastasis.  VEGF is clearly not the only target involved.

Meanwhile, this developing story will clearly continue to unfold in 2011.  The New York Times has a different angle on this story, so check it out for yourselves.