By Lisa Seachrist
SILVER SPRING, Md. - An FDA advisory panel refused to endorse The Liposome Co. Inc.'s Evacet, a liposomal formulation of doxorubicin, in combination with cyclophosphamide for the first-line treatment of metastatic breast cancer.
The Oncologic Drugs Advisory Committee voted 9-2 in declining to endorse the Princeton, N.J.-based company's product.
"In my heart, I believe this drug is effective and has a role," said panel member David Johnson, director of the division of medical oncology at Vanderbilt University in Nashville. "The data we've been presented today just doesn't support that view."
Doug Farrell, director of investor relations for the company, told BioWorld Today, "The company will progress as planned with Evacet [in other indications, including in combination with taxotere and Herceptin in breast cancer]. We're still a profitable company and we'll be using our $60 million in cash to develop and advance our products."
Doxorubicin is a derivative of an antibiotic that has anticancer activity. It has been used for 36 years as a treatment for metastatic breast cancer. However, doxorubicin has serious and debilitating side effects, including severe nausea and vomiting, ulcers of the lining of the esophagus and intestines, bone marrow suppression and, most notably, heart damage culminating in congestive heart failure.
Patients are most likely to develop congestive heart failure when they have received a cumulative lifetime dose of doxorubicin exceeding 450 milligrams per meter squared.
Evacet is designed to lessen the cardiotoxicity of the drug by encapsulating it as a doxorubicin citrate complex in liposomes. As a result, the drug is much less likely to find its way into the heart muscle, where it can do damage. In addition, preclinical studies of the drug show it is more likely to concentrate in tumors where leaky blood vessels provide a route for the drug.
The company presented to the panel two randomized clinical trials comparing Evacet to doxorubicin in first-line therapy for breast cancer. In addition, Liposome presented data from a pivotal trial comparing Evacet to the anthracycline epirubicin, which is a conventional therapy in Europe marketed by Pharmacia & Upjohn. Epirubicin received FDA approval late Wednesday as a component of adjuvant therapy following surgery to remove breast cancer.
Study 1 compared similar doses of Evacet and cyclophosphamide to doxorubicin and cyclophosphamide in 297 patients. The study examined cardiac toxicity and tumor response rate in assessing Evacet. Patients on the doxorubicin arm were five times more likely to suffer from cardiac toxicity than those receiving Evacet. Patients had similar response rates - 44 percent for Evacet and 43 percent for doxorubicin.
Study 2 compared Evacet to doxorubicin as single-agent therapies. Patients receiving doxorubicin were 3.7 times more likely to suffer cardiac toxicity than Evacet. The response rate for both arms of the study was 26 percent. However, in this study patients in the doxorubicin group had a median survival 5.5 months longer than Evacet.
Study 3 was a European study that was stopped early with only 57 percent of patients accrued due to "resource issues," said Lily Lee, vice president for biostatistics and clinical and regulatory operations at Liposome. That study comparing Evacet to epirubicin showed Evacet had a response rate of 46 percent vs. 39 percent for epirubicin.
The FDA highlighted the survival difference between patients receiving Evacet and those receiving doxorubicin in Study 2. Members of the panel also voiced concern on that issue.
"I'm equally concerned about this difference in survival," said Johnson. "I'm looking for some explanation for this difference beyond the fact that this is less efficacious than doxorubicin."
In addition, the agency had difficulty with the fact that the Evacet/doxorubicin studies were designed under the assumption there would be a 60 percent response rate, making the study results underpowered in the agency's opinion. FDA presenters also considered the dosage of epirubicin too small to have a clinical effect.
The panel voted 11-0 that Evacet was much less toxic than doxorubicin and voted 9-1 with one abstention that Study 1 was an adequate and well-controlled pivotal trial demonstrating the efficacy of Evacet. The problem, in the committee's opinion, was with the supporting data.
The panel voted 10-0 with one abstention that Study 2 didn't meet the necessary standards, and didn't vote on whether Study 3 was relevant. In the end, the committee decided there was no compelling need for Evacet as an option.
"I'm not sure we should lower the bar," said panel member Derek Raghavan, head of medical oncology for the University of Southern California in Los Angeles. "There must be 15 other drugs that can be used. We can make a worse mistake by forgetting there are alternatives."
James Krook, an oncologist in Duluth, Minn., disagreed with his colleagues. He said, "The pivotal trial would sway me that this drug would have a role and the other two studies are enough for me to say that this drug works."
The company's stock (NASDAQ:LIPO) had gained 9.37 cents Thursday to $16.812 before trading was halted.