Poor efficacy undermines Genentech metastatic breast cancer indication for Avastin
This article was originally published in Scrip
Genentech's strategy of asking for a hearing at the US FDA on whether the agency should remove the metastatic breast cancer (MBC) indication for Avastin (bevacizumab), its VEGF-targeting drug, for appears not to have paid off. The six members of the agency's oncology drug advisory committee who were on the panel for the hearing on July 29 all voted to recommend that FDA Commissioner Margaret Hamburg drop the label language immediately.
All also voted "yes" to three other questions: yes, the confirmatory trial Genentech was counting on to support a continuation of the indication failed to verify the clinical benefit of the drug for MBC; yes, the available evidence does not support the efficacy claim; and, yes, Avastin's risks are too great when weighed against its benefits.
"There's not enough data to support continued availability," explained panel member Dr. Frank Balis, University of Pennsylvania oncology researcher.
Except for Dr. Balis, the other five voting members of the panel served on the full advisory committee that last July came to the same conclusion about the results of the AVADO and Ribbon 1 trials, and voted that the drug should no longer be approved for MBC. The hearing is the first such procedure FDA has ever held to consider removing an indication from a drug's label.
Given the known toxicities and the new doubts about efficacy "if we allow this drug to stay on accelerated approval, we may be harming more people than we're helping," argued Wyndom Wilson, chief of the lymphoma therapeutics section of the US National Cancer Institute, another panel member.
There has been no new evidence about the risk of Avastin; the dangers weighed by the panel were known when the drug was first approved for MBC and are indicated in a black box on the label. What's changed is that the advisors now have substantial doubts about the benefit side of the equation. "If we don't think it's effective, then we can't tolerate any toxicity," Dr. Balis declared.
"We are very disappointed by the committee's recommendation and hope the Commissioner does not decide to remove this important medicine," Dr. Hal Barron, chief medical officer of the Roche Group member company, said in a written statement after the session. Dr. Hamburg will not take up the issue until the hearing docket closes on July 28. That means that for the time being the drug still carries the MBC indication in the US - and so is likely to continue to be covered by health insurance programs - as well as indications for advanced colon, lung, kidney and brain (glioblastoma) cancers, which were not in any way involved in the proceedings.
After FDA's Center for Drug Evaluation and Research (CDER) had on July 28 laid out its case why the MBC indication should be removed from the Avastin label, the first half of the July 29 session was taken up with Genentech making its case. The drug had been originally approved for breast cancer on an accelerated basis, an approval based almost entirely on the impressive gain in progression-free survival (PFS) - a median improvement of 5.5 months - shown in a single trial, E2100. A condition of such accelerated approval is that the sponsor later present confirmation evidence from other clinical trials. But the gains in PFS reported in AVADO and Ribbon 1 were of a much lesser magnitude, and the trials did not provide other evidence of the drug working, such as extending patients' overall survival or improving their quality of life.
Genentech devoted some of its presentation at the hearing to trying to establish that CDER's demand that the improvement on PFS be at least close to the results shown in E2100 were a switch in policy, and that had they been made earlier Genentech would not have relied on AVADO and Ribbon 1. The company asked for time now to do a new trial to duplicate E2100. But Dr. Wilson insisted that "the regulatory aspect of what happened is not going to be our focus."
Genentech has promised to continue with its plan to do a study to duplicate the E2100 results and as well to identify biomarkers that could be used to select the patients most likely to benefit from Avastin. Dr. James Reimann, the company's global head of biostatistics, outlined a study that would enroll 480 patients, mostly outside the US, would begin enrolling next year, and have initial data 42 months after that. But panel members said that it would be unfair to suggest through a continued label indication that the efficacy had been proved while the study was ongoing. And they expressed doubts that the study could be completed on schedule, because women would be reluctant to sign up for a trial in which they might get a placebo when there is an approved drug available.
The panel also rejected a middle ground compromise suggested by Genentech - and endorsed by panel member Dr. Gregory Curt of AstraZeneca, who, as the industry representative, did not have a vote - to change the Avastin labeling so it would remain approved for a subclass of MBC patients who are particularly hard to treat. Genentech consultant Dr. Joyce O'Shaughnessy, a breast cancer expert at Baylor University, called on FDA "to work with the sponsor to keep Avastin/paclitaxel available as an approved option, even by limiting the indication to patients with metastatic triple negative and aggressive ER+ breast cancer." The outside advisers said they knew of no evidence that any identifiable subset of MBC patients got special benefit from the drug.