Docetaxel, Platinum, Plus Trastuzumab Effective in HER2-Positive Advanced Breast Cancer

Laurie Barclay, MD

May 18, 2004

May 18, 2004 — The combination of docetaxel, platinum salts, and trastuzumab is effective in treating advanced breast cancer expressing HER2, according to the results of two phase II randomized trials published in the May 19 issue of the Journal of the National Cancer Institute. Phase III trials are underway.

"The median times to progression emerging from the trials are among the longest times reported to date for a patient population with HER2-amplified metastatic breast cancer," lead author Mark D. Pegram, from the Jonsson Cancer Center at the University of California in Los Angeles (UCLA), says in a news release. "Response rates were extraordinary — superior to what was expected."

The investigators first tested drug combinations on cell lines in hopes of finding those most effective in patients with HER2/neu amplification, a genetic alteration found in 20% to 25% of patients, which is associated with an aggressive form of breast cancer. In laboratory models of HER2/neu amplification, docetaxel, vinorelbine, cyclophosphamide, and the platinum salts cisplatin and carboplatin acted synergistically to increase the activity of trastuzumab.

In two phase II clinical trials, each enrolling 62 HER2/neu-positive women, docetaxel was given with trastuzumab in combination with either cisplatin or carboplatin. Response rate was 79% (95% confidence interval [CI], 66% - 89%) in one of the studies and 58% (95% CI, 44% - 70%) in the other, and median times to progression were 9.9 months (95% CI, 8.3 - 13.1 months) and 12.7 months (95% CI, 8.6 - 15.5 months).

"This shows you can actually predict what will work in patients," says senior author Dennis J. Slamon, also from UCLA's Jonsson Cancer Center, referring to bridging the gap from laboratory to clinic.

One patient in each study developed reversible congestive heart failure, but overall toxicity was said to be manageable and comparable to that observed in other clinical settings. Large, randomized phase III studies are underway.

Aventis and Hoffman-LaRoche supported these studies. Some of the authors have various financial arrangements with Aventis, Hoffman-LaRoche, Genentech, Bristol-Myers Squibb, Pierre Fabry Oncology, Orthobiotechnology, and/or Novartis.

In an accompanying editorial, George W. Sledge, Jr., from the Indiana University School of Medicine, calls these studies "an impressive example of translational research at its best.

"Preclinical studies and metastatic phase II trials rarely lead to anything useful for patients; they are wasteful in a profound and disturbing sense," he writes. "Designing a sequential series of experiments, both laboratory and clinical, that lead intentionally to proof-of-concept adjuvant trials is all too rare. But, as Pegram et al. remind us, it is not impossible."

J Natl Cancer Inst. 2004;96:759-769

Reviewed by Gary D. Vogin, MD

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