Trastuzumab Approved for Adjuvant Treatment of HER2/Node-Positive Breast Cancer

Genentech, Inc, announced recently that the US Food and Drug Administration (FDA) approved trastuzumab (Herceptin), as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel, for the adjuvant treatment of HER2-positive node-positive breast cancer. Adjuvant therapy is given to women with localized breast cancer who have had initial treatment surgery with or without radiation therapy—with the goal of reducing the risk of cancer recurrence and/or the occurrence of metastatic disease.

Joint Analysis

The FDA approval was based on data from an interim joint analysis of more than 3,500 patients enrolled in two phase III clinical trials. These results showed that the addition of trastuzumab to standard adjuvant therapy significantly reduced the risk of breast cancer recurrence, the primary endpoint of the studies, by 52% (or a hazard ratio of 0.48) in women with HER2-positive breast cancer, compared to those patients who received standard adjuvant therapy alone.

"The results of the joint analysis show that, for women with early-stage HER2-positive breast cancer, the addition of Herceptin to chemotherapy reduces the relative risk of breast cancer recurrence by approximately half, which translates into fewer women dying from one of the most aggressive types of breast cancer," said Edward Romond, MD, professor of medicine, Division of Hematology/Oncology at the University of Kentucky. "This is the largest improvement in outcome for any group of women with breast cancer in 25 years."

Greatest Impact

"Our work with Herceptin exemplifies our commitment to developing the right drug for the right patient. We designed Herceptin for the approximately 25% of women whose breast cancers overexpress HER2 because we believed that we could make a significant impact for these patients battling a very aggressive, difficult-to-treat disease," said Susan Desmond-Hellmann, MD, MPH, Genentech's president, product development. "These adjuvant studies showed that, in women with HER2-positive lymph node-positive breast cancer, Herceptin reduces the risk of developing metastatic disease, which could benefit thousands of lives worldwide each year."

"This approval also highlights a first step in a major initiative to conduct studies of Genentech targeted therapies in earlier stages of disease where they have the potential to have the greatest impact," added Desmond-Hellmann.

After 31⁄2 years in the study, 87% of women treated with trastuzumab plus chemotherapy were disease-free, compared to 71% of women treated with chemotherapy alone. A survival analysis conducted after patients had been followed for a median of 24 months showed a 33% reduction in the risk of death (based on a hazard ratio of 0.67), which is equivalent to a 49% improvement in overall survival.

Additional Study Background

The two phase III trials were sponsored by the National Cancer Institute and 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.

These randomized, controlled trials studied four cycles of doxorubicin and cyclophosphamide followed by paclitaxel, either every 3 weeks or weekly for 12 weeks, compared with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel.

Each study had an independent external Data Monitoring Committee (DMC) that reviewed data from the studies, including cardiac safety data, on a regular basis. According to the investigators, serious or life-threatening (and in rare cases, fatal) cardiac events, most commonly congestive heart failure, occurred approximately 3% to 4% more often in the trastuzumab-plus-standard therapy arms than in the standard therapy-alone arms. Other adverse events reported in both studies included dyspnea and interstitial pneumonitis, which occurred at a rate of less than 1%.

The joint analysis results were first presented at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO) in May 2005 and subsequently published in the New England Journal of Medicine in October 2005.