ASCO – Avastin in breast cancer - the drug is approved but the work is not done

The results of the Avado trial presented at this year’s ASCO help to confirm that Avastin in combination with a taxane chemotherapy agent significantly extends progression free survival in women with metastatic breast cancer.

What is still in doubt is whether the drug prolongs overall survival. Some doctors at the oncology conference said they do not believe evidence of that will emerge when the overall survival data does become available. As to whether the more expensive high dose is any more effective than the low dose, the trial suggested it might be, but the results were not significant.

Debates around both issues, and what that means for the commercial future of the drug, will continue. But for now, the FDA's tentative approval in the indication at the high dose looks safer, as do analysts' sales forecasts.

Positive trial

Overall, the Avado trial was positive for Genentech and Roche, and the researchers presenting the data said they remain convinced that the drug is an important tool in helping prolong what is likely to be the last few months of a woman's life.

Positive results were important because the FDA has only granted Avastin accelerated approval in metastatic breast cancer, pending the final read out from this trial and another called Ribbon 1, due late this year. The regulator wants to see an overall survival benefit.

Overall survival data from Avado will not be available until the end of 2009 or early 2010, but the companies are taking comfort in strong progression free survival data. Plus, Avado was more robust than ECOG 2100, the trial on which that accelerated approval was based. The former was a double blind placebo controlled trial, while the latter was open label.

High or low

In Avado, two different doses of Avastin were examined. The percentage of patients who had their tumours shrink was 44.4% in the standard chemotherapy group, 55.2% in the low dose group, and 63.1% in the high-dose group. Disease progression was significantly slower in the two groups which received Avastin, however because of the low numbers in the arms it was not possible to statistically compare the two doses.

Dr David Miles, of the Mount Vernon Cancer Centre in the UK, who conducted the trial for Roche, said he believed that the trend seen indicates the higher dose is more effective. The lack of statistical evidence has not convinced everyone, however.

Unusual policy

Dr Eric Winer of the Dana-Farber Cancer Institute is of the opinion that Avastin will not demonstrate a survival benefit, and is not convinced that the high dose is necessary. However, he strongly believes that the drug should remain on the market, arguing that progression free survival is an important measure in metastatic breast cancer.

In insisting on overall survival, “the FDA is pursuing an unusual policy,” he commented. “Quality of life is hard to measure. For some, having disease under control is worth it.”

Dr Miles agreed. “Progression free survival may be but a small fraction of the rest of that patient’s remaining life. When we have a patient whose disease is controlled, that’s a benefit. The recurrent problem we have is recognising the utility and usefulness of drugs, and therefore there is uncertainty around what approval should be based on.”

Cost benefit

Of course, the debate would not exist if Avastin cost $2 a dose. While recognising the drug’s benefit and other biologics like it on the market, a recurring message from the doctors at this year’s ASCO was that to justify their huge expense, techniques must be developed to identify which patients will, or will not benefit, from these therapies.

"The big question is, how are we going to be able to afford these therapies," commented Dr Julie Gralow, a breast cancer specialist at the University of Washington. "We need to define who will respond."

The confirmation of the role of the KRAS gene in EGRf inhibitors in colorectal cancer is likely to be the first of many molecular markers discovered. Many doctors presenting urged researchers to include biomarker analysis when designing large scale trials with biologics in the future.

“Avastin might not make all people live longer, but we need to pull out the people who will benefit. The drug is approved, but the work is not done,” Dr Winer said.

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