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Genentech’s study of Avastin in patients with colorectal cancer in the adjuvant setting should examine the drug’s effect on a primary endpoint of overall survival, physicians told Pharmawire.
Avastin has been approved by the FDA for the treatment of metastatic colorectal cancer, non-small cell lung cancer and metastatic breast cancer.
Genentech, in an attempt to broaden the drug’s label to the adjuvant colorectal cancer setting, is studying Avastin in the ongoing C-08 study. The Phase III trial is comparing the addition of Avastin to infusional 5-Fluorouracil (5-FU), Leucovorin and Oxaliplatin (mFOLFOX6) to the same therapeutic regimen without Avastin. The primary endpoint of the study is the combination therapy’s impact on prolonging disease-free survival (DFS) while the secondary endpoint is prolonging survival.
The standard endpoint to evaluate in cancer trials is overall survival, according to Dr Brian Czito, an associate professor at Duke University. Avastin was initially approved because it demonstrated an impact on overall survival in the metastatic setting and no less should be expected of the drug in the adjuvant cancer setting, Czito added.
“Overall survival is the gold standard, especially in adjuvant studies,” noted Dr Steven Sorscher, an assistant professor of medicine at the Washington University School of Medicine. Physicians do not want to administer a drug that could potentially keep the cancer at bay but killing patients at the same time because it is so toxic. Still, if the drug makes a statistically significant impact on disease free survival for a long time, then it’s a good way to analyze studies, Sorscher said.
For example, if statisticians analyze the results of the C-08 trial and 10% of patients receiving the Avastin and mFOLFOX6 regimen are disease free at three years, it does not mean that the drug will prolong survival. However, if they are disease free at five years, then the drug definitely has a survival advantage.
Progression free survival was a recognized endpoint by the FDA, according to Dr Carmen Allegra, the chief of hematology at the University of Florida and an investigator on the study. Allegra further explained that the trial will be analyzed using survival analysis, after a certain number of events have occurred.
“I am not sure that there is a date or a time for the completion of the study since it is event driven,” said Allegra. “3 year disease free survival was shown and accepted by the FDA in this particular setting.”
Even if Avastin therapy does not make a dent in overall survival, patients may ask to be given the drug, said Dr Rakesh Jain a professor of tumor biology, at Harvard-MIT Health Sciences and Technology Program. If a drug does not impact overall survival, the drug’s administration depends on the opinions of the physician and insurance companies. These therapies are expensive, so it’s important for patients to receive insurance coverage, Jain added.
A major problem associated with measuring overall survival in adjuvant studies is that patients may have to wait for many years until the results are available, Sorcsher explained. If a drug could potentially improve disease outcomes, patients want to know about it as soon as possible and have access to the therapy, Sorcsher added.
Avastin has a peak sales forecast of 9,319 bn USD in 2012.
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