Herceptin Approved for Adjuvant Use

ROCKVILLE, Maryland—Following a priority review, the US Food and Drug Administration (FDA) has approved Herceptin (trastuzumab for infusion, Genentech) in combination with three other agents for the adjuvant treatment of HER2-positive, node-positive breast cancer following lumpectomy or mastectomy.

The agency endorsed the drug's new indication based on combined data from two large phase III trials showing that women treated with Herceptin in combination with doxorubicin, cyclophosphamide, and paclitaxel (AC-T) had a significantly lower risk of recurrence after surgery than patients who received only the chemotherapy regimen.

HER2 overexpression occurs in 25% to 30% of primary breast cancers. Herceptin is a recombinant DNA-derived humanized monoclonal antibody that binds to HER2, the human epidermal growth factor receptor 2 protein. The drug mediates antibody-dependent cellular toxicity. In vitro assays and human studies have shown that it preferentially inhibits the proliferation of human tumor cells that overexpress HER2. Herceptin was initially approved in 1998 for metastatic breast cancer.

The combined efficacy data submitted by Genentech to FDA covered 3,752 participants in two randomized, open-label, phase III clinical trials sponsored by the National Cancer Institute. They were conducted by a network of researchers led by the National Surgical Adjuvant Breast and Bowel Project and the North Central Cancer Treatment Group in collaboration with the Cancer and

Leukemia Group B, the Eastern Cooperative Oncology Group, and the Southwest Oncology Group. Results of the joint analysis were first reported at the 2005 annual meeting of the American Society for Clinical Oncology and published in October 2005 in the New England Journal of Medicine.

Researchers pooled data from patients in both arms of one study and two of the three arms in a second study, all of whom were randomized to receive either AC-T alone or with Herceptin. NCI halted the two studies early after an interim analysis showed a significantly lower recurrence risk in patients treated with Herceptin.

Researchers randomized patients in the two studies 1:1 to receive four 21-day cycles of doxorubicin at 60 mg/m

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and cyclophosphamide at 600 mg/m

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. Patients in study 1 received either 80 mg/m

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of paclitaxel weekly or 175 mg/m

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every 3 weeks for a total of 12 weeks. In study 2, patients only received paclitaxel on the once-a-week schedule. Researchers in both studies administered 4 mg/kg Herceptin on the first day that patients received paclitaxel and then at a 2 mg/kg dose weekly for 52 weeks.

Study Results

Of the 1,872 women in the Herceptin-treatment arm, at 3.5 years, 133 had a recurrence of their breast cancer, compared with 261 of the 1,880 women in the control group (HR 0.48, P = .0001). "These adjuvant studies showed that, in women with HER-2-positive, lymph node-positive breast cancer, Herceptin reduces the risk of developing metastatic disease, which could benefit thousands of lives worldwide each year," said Susan Desmond-Hellmann, MD, Genentech's president for product development.

Also after 3.5 years, 239 Herceptin-treated patients (87%) remained disease free, compared with 195 (71%) of the control arm, an absolute risk reduction of 15.3%. A survival analysis of patients followed for a median of 2 years found that 62 of the Herceptin-treated women had died, compared with 92 in the control arm, the equivalent of a 49% improvement in overall survival, but this difference was not statistically significant at the time of the analysis.

"It is too soon to know whether Herceptin combined with chemotherapy will increase the cure rate or lower the risk of death from breast cancer," FDA said in announcing the new indication.

Herceptin's labeling carries Black Box Warnings that the drug can result in left ventricular dysfunction and congestive heart failure, as well as serious infusion reactions and pulmonary toxicity. Because of the potential for heart problems, FDA said patients must be screened for heart function before and during Herceptin treatment. It recommended that only HER2-positive patients receive the drug and that no one with heart failure or cardiomyopathy be treated with it.