Trastuzumab Trials in HER2-positive Breast Cancer Stopped Early Due to Superior Efficacy

Paula Moyer, MA

May 23, 2005 (Orlando) — Treatment with trastuzumab (Herceptin) in HER2-positive breast cancer provides a clear and striking benefit to patients with HER2-positive breast cancer, according to findings presented here the annual meeting of the American Society of Clinical Oncology 2005 Annual Meeting.

The results were significant, with a 52% risk reduction for a recurrence compared with controls. The investigators halted two simultaneous studies early, in accordance with the study protocols.

"This benefit should change the standard of care," said Edward Romond, MD, in the presentation at a late-breaking session. "The addition of trastuzumab to standard treatment reduced the risk of distant recurrence by 53% at three years, and the hazard of developing distant metastases appears to decrease over time." Dr. Romond presented the findings on behalf of the National Surgical Adjuvant Breast and Bowel Project B-31 (NSABP B-31).

Dr. Romond summarized the findings of two studies that have been approved for joint analyses of their respective datasets: the NSABP B-31 and the North Central Cancer Treatment Group N-9831 (NCCTG N-9831). Both trials were initiated to assess the use of paclitaxel and trastuzumab following anthracycline chemotherapy in the adjuvant treatment of high-risk HER2-positive breast cancer. Both trials were launched in the year 2000 to test whether addition of HER2 is superior to chemotherapy alone.

The NSABP B-31 investigators randomized patients into two treatment groups. The controls received four cycles of standard doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every three weeks, followed by four cycles of paclitaxel at 175 mg/m2 every three weeks. The investigative group had the same chemotherapy regimen, but with trastuzumab added weekly for 52 weeks, starting with the first paclitaxel dose. Trastuzumab was given at an initial loading dose of 4 mg/kg the first week and 2 mg/kg for the remaining 51 weeks. The dose of paclitaxel was later reduced to 80 mg/m2 weekly for 12 weeks. Patients who were hormone-receptor positive also received tamoxifen or anastrozole.

NCCTG N-9831 followed a similar protocol that patients with hormone-receptor–positive tumors received either tamoxifen or an aromatase inhibitor. Also, the study had a third group in which patients received trastuzumab at the completion of all chemotherapy so that investigators could assess the risks and benefits of giving trastuzumab sequentially vs concurrently. That group was not included in the analysis, Dr. Romond said.

The studies' design called for the trials to terminate early if the interim analysis showed a clear benefit of one treatment strategy over the others at a probability value of 0.0005. This interim analysis reflected the findings on 3,351 patients; 1,736 from NSABP B-31, who had been followed up for a median of 2.4 years; and 1,615 from N-9831, who had been followed up for a median of 1.5 years. Half of the participants were younger than 50 years.

"The first review, involving 353 recurrence events, determined that the threshold for efficacy had been crossed," said Dr Romond. He noted that the first analysis involved 395 events that had been recorded, including 261 in the paclitaxel groups and 134 in the trastuzumab groups, had a hazard ratio of 0.48 and a P value of 3 x 10-12. "This represents an overall reduction at three years of 52% for a first breast cancer event," Dr. Romond said. "The prolongation of disease-free survival was 12% at three years and 18% at four years."

The results were the same in both studies, with a risk reduction in NCCTG N-9831 of 45% and 55% in NSABP B-31. Distant metastases occurred in 198 patients, 102 in control groups, and 96 in investigational groups and reflected a 53% reduction. "The hazard rate is 0.67, corresponding to a 33% reduction in mortality," Dr. Romond said. "Surprisingly, despite the fact that the median follow-up is only two years, it is significant at P = .015.

Earlier research had shown that cardiotoxicity was associated with trastuzumab, and the events observed in the two studies were consistent with previous findings, Dr. Romond said. In the NSABP B-31 cohort, approximately 19% of those who started trastuzumab had to withdraw due to cardiac dysfunction, including 15% who did not have clinical congestive heart failure.

The findings provide a new approach in the treatment of breast cancer, said Gabriel N. Hortobagyi, MD. "Trastuzumab is the first drug developed to treat women with HER2-positive tumors," said Dr. Hortobagyi, the president-elect of ASCO and the chair of the breast medical oncology department at the University of Texas M. D. Anderson Cancer Center in Houston. "The risk of recurrence was reduced by 50% and prolonged survival by 20%. In oncology we get excited about improvements of 2% to 4%. We have not seen anything of this magnitude in breast cancer research in 30 years."

ASCO 2005 Annual Meeting: Late-breaking session. Presented May 19, 2005.

Reviewed by Gary D. Vogin, MD