ODAC Votes to Recommend FDA Approval of Herceptin

BETHESDA, Md--Herceptin (trastuzumab, Genentech) has become the first monoclonal antibody to win support from the Oncologic Drugs Advisory Committee (ODAC) for use in treating breast cancer. The group voted unanimously to recommend that the FDA approve Herceptin for treatment of women with metastatic breast cancers that overexpress the HER2/neu gene, both as a single agent after first-line chemotherapy has failed and in combination with paclitaxel (Taxol) as first-line treatment.

Panel member Richard L. Schilsky, MD, director of the University of Chicago Cancer Research Center, called the studies supporting Herceptin "perhaps the greatest demonstration of clinical therapy I’ve seen in a solid tumor."

In making the recommendation, ODAC members devoted considerable time to discussing two issues--the incidence of serious cardiotoxicity revealed in clinical trials and whether the use of Herceptin should be limited to women whose tumors carry three times or more the normal number of HER2 receptors.

Concerns about cardiotoxicity led the panel to vote 9-to-2 against recommending use of Herceptin in combination with an anthracycline, while the idea of excluding women with less than triple HER2 expression from Herceptin therapy garnered a mixed reaction from the panel.

HER2 receptors play a role in cell division and multiplication. About 25% to 30% of women have breast tumors that overexpress the gene. Overexpression is associated with more aggressive tumor growth, shorter disease-free survival, and a negative prognosis. Herceptin is a monoclonal antibody (95% human-5% mouse) that binds to HER2 receptors and blocks their growth signals.

Genentech presented two trials in support of its biologics license application for Herceptin. H0649g was a multicenter, open-label, single-arm study that involved 222 patients who had had extensive prior treatment for their metastatic disease. H0648g was a multicenter, randomized controlled trial in 469 women, none of whom had been previously treated with a cytotoxic agent for their metastatic cancer. It compared Herceptin combined with either paclitaxel or an anthracycline (doxorubicin or epirubicin) plus cyclophosphamide against chemotherapy alone (paclitaxel alone or anthracycline/cyclophosphamide).

In both studies, patients received a 4 mg/kg infusion of Herceptin to start and then a weekly dose of 2 mg/kg throughout the course of the study until they showed evidence of disease progression. In the Herceptin-alone study, physicians had the option of giving the weekly dose at 4 mg/kg when they believed it was appropriate for a patient.

According to analyses presented by the company, 34 (15%) of the 222 women in H0649g responded: 8 complete responders and 26 partial responders. The median time to treatment failure for responders was 11 months; the median duration of response was 9.1 months; median survival for all patients was 13 months.

In study H0648g, 143 women received Herceptin plus anthracycline/cyclophosphamide, and 138 received anthracycline/cyclophosphamide alone; another 92 women got Herceptin plus paclitaxel, while 96 received paclitaxel only.

Total responses were seen in 114 patients (49%) in the Herceptin-chemotherapy arms vs 74 (32%) in the chemotherapy-only groups, a difference of 53%. Median time to disease progression was 7.6 months, and median duration of response was 9.3 months in the Herceptin-chemotherapy women, compared with 4.6 months and 5.9 months, respectively, in the chemotherapy-only arms.

Survival at 1 year was as follows: Herceptin-anthracycline, 58%; anthra-cycline-only, 52%; Herceptin-paclitaxel, 78%; paclitaxel-only, 62.5%.

Much of the common toxicity associated with Herceptin--diarrhea, abdominal pain, and stomatitis--was self-limited and could be controlled with medications and/or adjustments to the infusion rate, the company and FDA agreed. However, both described an incidence of cardiotoxicity that troubled the panel.

Cardiotoxicity Concerns

Genentech first learned about the problem in 1997 when it heard of four serious cases of cardiotoxicity, Steven Shak, MD, a company senior scientist told the committee. This finding was unexpected because no heart problems had been noted in previous animal studies and phase I and II trials. The company has screened the records of 1,024 women who have taken Herceptin and identified 97 with some form of cardiac dysfunction, ranging from mild and easily treatable to severe, said Virginia Paton, PharmD, a Genentech clinical scientist.

The FDA analysis said that car-diotoxicity occurred in 7% of the patients in H0649g. In the second study, cardiotoxicity rates were 28% in Hercep-tin-anthracycline patients; 7% in the anthracycline-only arm; 11% with Her-ceptin-paclitaxel; 1% for paclitaxel only.

Who Is At Risk?

The company attributed no deaths in the study to cardiotoxicity. However, FDA reviewer Susan Jerian, MD, raised issue with four deaths, two in the Her-ceptin-anthracycline arm and two in the anthracycline-only arm. "We certainly feel that cardiotoxicity contributed to these deaths," she said.

Dr. Shak said that extensive analysis had failed to identify any particularly high-risk group, with the possible exception of women over age 60. "So we don’t have any way of figuring out who is at greatest risk," remarked panel member Kathy S. Albain, MD, of Loyola University Medical Center, Maywood, Illinois.

ODAC members urged further research on the issue and recommended that the FDA describe the cardiotoxicity issue thoroughly in labeling Herceptin.

How Much Gene Expression?

In examining the Herceptin results, some committee members questioned its use in women with less than triple (3+) HER2 gene expression. Data presented by Genentech showed significant benefit in 3+ women, but little difference in benefit below that level, although the trend favored women receiving Herceptin.

"I, myself, feel there is no benefit for women with 2+; I would say restrict Herceptin to 3+ women," said panel member Richard M. Simon, DSc, chief of NCI’s Biometric Research Branch. But Timothy O’Leary, of the Armed Forces Institute of Pathology, who served as a guest expert for the committee, argued that one could expect 20% of 2+ women to benefit from Herceptin. And Julie M. Vose of the University of Nebraska, another ODAC consultant, opposed restricting Herceptin to 3+ women.