Herceptin research took a long-expected next step in March with the opening of the first large randomized trial to evaluate the monoclonal antibody as the initial treatment in non-metastatic breast cancer.
The trial will pit chemotherapy with cyclophosphamide, adriamycin, and paclitaxel against the same three drugs plus Herceptin as adjuvant treatment for node-positive tumors. The National Surgical Adjuvant Breast and Bowel Project is conducting the study.
A second phase III trial, an intergroup study led by the North Central Cancer Treatment Group, will follow soon. It will involve the same drugs but will be assessing two different schedules for Herceptin as well as a novel weekly schedule for paclitaxel.
Herceptin won Food and Drug Administration approval in September 1998 for use in metastatic breast tumors that overexpress the HER2 protein. The drugs success in this arena raised hopes that it would prove at least as effective when tried earlier and up front. Smaller phase II trials and pilot studies are already doing that, but the new trials, with thousands of patients, are the first major phase III studies with Herceptin in the adjuvant setting.
How best to design this next generation of trials has been a topic of much debate, according to Elizabeth Tan-Chiu, M.D., protocol officer for the NSABP study. Paramount among these issues was Herceptins cardiotoxicity, especially in combination with adriamycin.
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But other uncertainties about the monoclonal antibody also needed attention. These include why some HER2-positive tumors respond to Herceptin and others do not; the relative performance of various assays used to measure HER2 levels; and whether HER2-positive tumors respond less well to tamoxifen than those that are HER2 negative.
Tan-Chiu said that concerns about cardiac dysfunction led to NSABPs decision to break the protocol into two stages. This studys two arms will compare adriamycin and cyclophosphamide followed by paclitaxel to the same regimen plus Herceptin. In the first stagethe first 1,000 patientsinvestigators will compare cardiotoxicity between the two groups. If the incidence of cardiotoxicity falls within established boundaries, the study will proceed to the second stage, in which the remaining 1,700 patients will be enrolled.
Potential heart problems were also a major concern in developing the NCCTG/intergroup study, which is led by Edith Perez, M.D., of the Mayo Clinic in Jacksonville, Fla. This trial will approach the issue by assessing different schedules for administering Herceptin. In one arm of the 3000-patient trial, patients will receive adriamycin and cyclophosphamide followed by weekly paclitaxel and Herceptin given concomitantly, while in a second arm, Herceptin will follow the paclitaxel. (Women on a third arm will receive adriamycin and cyclophosphamide followed by weekly paclitaxel without Herceptin.)
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Looking for Markers
How to predict response to Herceptin is another thorny issue that influenced trial design. Because only a subset of women with HER2-positive tumors respond to the drug, the new studies include a raft of biological studies to search for markers that will predict who those patients are.
Investigators will look, for instance, at the presence of activated or phosphorylated HER2, other closely related molecules that may interact with HER2, chromosomal or gene copy abnormalities, and, in the words of the NSABP protocol, "any additional potentially predictive markers of response to Herceptin which may be discovered in the future."
The laboratory results will then be compared with clinical data, said Tan-Chiu, who is looking forward to the insights that could come from this confluence of clinical and biological research. "We are doing them side by side, which is the beauty of this study," she said.
Another question both trials are tackling relates to the performance of various assays that can be used to measure HER2 levels (see News, Feb. 16, p. 292). Investigators can use any available assay to determine eligibility for the trials. However, they will also send tissue samples from participants to central laboratories where a battery of different assays will be performed. The results should show how the various HER2 assays relate to each other and with response to Herceptin.
Tamoxifen Question
A final major question woven into the study designs is: Do women with HER2-positive tumors have a poor response to the hormonal drug tamoxifen?
Both studies will include tamoxifen, which is now standard in early breast cancer for women whose tumors are positive for hormone receptors. To tackle the issue of its effectiveness in HER2-positive tumors, patients will be stratified according to their hormone receptor status before they are randomized. This strategy is expected to yield data on how HR-positive women respond to tamoxifen with and without Herceptin.
How long will it take to get answers to these questions? The answer as always depends on how long it takes to accrue patients to the trials, and as Tan-Chiu noted, not every early breast cancer patient is node-positive and HER2-positive. The investigators best guess is somewhere between 3 and 5 years.
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