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(Drug information on doxorubicin), cyclophosphamide(Drug information on cyclophosphamide), and paclitaxel(Drug information on 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/m² and cyclophosphamide at 600 mg/m². Patients in study 1 received either 80 mg/m² of paclitaxel weekly or 175 mg/m² 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