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Breast cancer drug likely to be disapproved by FDA

When clinical trials suggest an expensive cancer drug is ineffective but individual cases highlight its benefits, the methods for evaluating clinical research come into question.

Avastin, a drug for use against metastatic breast cancer—an advanced stage of the disease—is currently pending final approval by the Food and Drug Administration. Recent clinical trials do not show overall improvements in survival rates, casting doubts on the drug’s practical effectiveness. But some oncologists are saying that if ways to see which patients would respond positively to Avastin are developed, it could be a very effective treatment for metastatic breast cancer.

“Some patients do benefit from Avastin,” said Dr. Gary Lyman, medical oncologist and professor of medicine. “The problem is that most don’t.”

Lyman was part of the FDA’s Oncologic Drug Advisory Committee, which in 2007 placed Avastin on an accelerated track for use against breast cancer. Accelerated approval is uncommon, and it was granted partially due to promising results of a clinical trial and Avastin’s previous success as a treatment for colorectal cancer, Lyman said. Avastin, though potentially beneficial, is also toxic, like most cancer drugs. It was approved with the provision that the drug be assessed again when two other clinical trials concluded.

When the trials ended in 2010, they showed unexpected results.

“The [new] data reviewed this past year was not as encouraging as we had hoped based on the initial, accelerated approval decision,” Lyman said. “None of the [new] trials have shown an overall survival improvement indication.”

Compared to the first trial, the new trials indicated a shorter period of progression-free survival, the time during or after medication in which the cancer ceases to worsen. They did not demonstrate a survival advantage or an improved quality of life on average, Lyman said. He and other oncologists noted, however, that there are certain patients for whom Avastin works very well, a phenomenon that might not be reflected in a large clinical study.

“In individual patients, we have seen remarkable responses to Avastin, but we have not yet learned to tell who will be one of those people with the remarkable response,” Dr. Gretchen Kimmick, associate professor of oncology, wrote in an email Monday. “Here, further research needs to be done.”

The FDA, however, required the advisory board to either unconditionally approve the drug—which would have exempted Avastin’s developer from providing more clinical data—or deny it. The board ultimately rescinded its approval. Lyman and 10 others voted against Avastin, and one member voted for it.

“If we had been given the opportunity to extend approval, I think several panel members including myself would have voted for that,” Lyman said.

The FDA has yet to make the final decision, though historically it has rarely deviated from the advisory board’s decision, he said. If it rescinds Avastin’s approval, then it is likely that insurance companies will cut off funding for the drug for breast cancer use.

“To me, [the end of insurance coverage] would almost be the worst case scenario,” Lyman said. “It’s very likely that those with means would be able to pay for the drug and many patients would not, or they would end up mortgaging their homes or end up going into great debt in order to get the treatment they or their doctor thinks they need.”

Dr. Neil Spector, associate professor of medicine and associate professor of pharmacology and cancer biology, said there is financial need to develop an identifying method.

“If we prescribe expensive drugs to 100 people in order to get two responders, our health care system will not be sustainable,” Spector wrote in an email Tuesday. “That is not being harsh, it’s being realistic.... We need to develop effective therapies, understand who is most likely to benefit and make them available to likely responders at costs that patients can afford.”

Economics may limit developers’ ability to tailor a drug to specific individuals, added Dr. Erich Huang, a surgical oncologist and the director of cancer research at Sage Bionetworks in Seattle, Wash.

“The question then is, are we incentivizing people to figure out which drug works for which patient?” Huang said. “It’s the kind of question that needs economic analysis because it is more profitable for [pharmaceutical companies] to market an agent to a larger, un-selected group of patients.”

Lyman said he is confident that Avastin’s usefulness as a drug will emerge as ways of finding which patients would respond well to it are developed.

“I sincerely believe in the near future there will be a marker, a gene, gene pattern or protein that will tell us which patient is most likely to respond,” he said. “To me, that’s the holy grail for Avastin because of [its toxicity].”

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