Herceptin Use Postprogression Safe and Potentially Beneficial

SAN ANTONIO—Women with metastatic breast cancer who experience disease progression on trastuzumab (Herceptin) may benefit from continued treatment with the antibody, according to results of a crossover study presented by Debu Tripathy, MD, associate clinical professor of medicine, University of California, San Francisco, School of Medicine. Moreover, trastuzumab cardiotox-icity was only 2.2% among long-term users.

The study involved a subset of the 469 women enrolled in the randomized Trastuzumab Pivotal Combination Chemotherapy Trial, which compared chemotherapy alone to chemotherapy plus trastuzumab. The crossover study was incorporated into the original trial after trastuzumab’s activity as a single agent became apparent from other studies—and at the urging of the scientific and advocacy communities.

"The other important factor was that we really have no safety or outcome data on patients who are continued on trastuzumab after progressing on tras-tuzumab-containing therapy," Dr. Tripathy noted. "This presents a dilemma for the practicing oncologist who wants to take advantage of some of the synergistic interactions that may exist with other chemotherapy agents, even after progression."

Patients who progressed in the randomized trial were given the option to join the crossover study. Participants were then given, at the discretion of the treating physician, trastuzumab alone or trastuzumab in combination with chemotherapeutic or hormonal agents that would be considered standard of care for metastatic breast cancer.

The chemotherapeutic agents used in the original trial were doxorubicin or epirubicin (Ellence) plus cyclophosphamide or, for patients who had received anthracycline therapy in the adjuvant setting, paclitaxel (Taxol).

A total of 247 patients from the randomized trial opted to participate in the crossover study—154 patients from the control (chemotherapy alone) arm and 93 patients from the chemotherapy plus trastuzumab arm.

A significant portion of patients in the crossover study received trastuzumab alone, Dr. Tripathy said. The remaining patients received trastuzumab plus chemotherapeutic agents representative of the community standard for refractory breast cancer. Paclitaxel, vinorelbine (Navelbine), and docetaxel (Taxotere) were the most commonly used agents.

Patients continued on therapy until withdrawn by their physician or through their own choice. Tumor assessments were undertaken when clinically indicated, and responses were judged by the investigators.

Response Rates

Among patients originally given chemotherapy alone in the randomized trial, the crossover to trastuzumab (alone or in combination) yielded a response rate of 14%. The clinical benefit rate (complete response, partial response, or disease stabilization for more than 6 months) in this group was 32%. Response duration was 7.4 months.

In the group of patients who originally received trastuzumab in the randomized trial, the response rate was 11%. In this group, 22% received a clinical benefit from the extended therapy, and response duration was 6.7 months.

"Responses were seen with single-agent Herceptin, including patients who may have received hormonal therapy, and with Herceptin plus paclitaxel, vinorel-bine, and—to a lesser extent—cisplatin [Platinol], docetaxel, and doxorubicin," Dr. Tripathy said.

No clear predictive factors emerged, other than HER-2-neu 3+ overexpression in the group originally assigned to chemotherapy alone, he said. Performance status and the site or number of metastases had no effect. There was, however, a trend toward a greater likelihood of response among patients who had responded in the randomized trial.

"No clear safety signals emerged, which is an important observation here," Dr. Tripathy added. "When you look at severe adverse events, all are less than 15%, and many reflect side effects attributable to chemotherapy or to progression of carcinoma—asthenia, pain, leukopenia.

Among events possibly or probably related to trastuzumab, cardiac events surfaced as a significant factor. The cardiac event rate was 6.5%, half of which were New York Heart Association class III or IV. Among patients already receiving the antibody, however, cardiotoxicity was low—2 out of 93 patients. "Other events, such as infusion reactions, were seen at a very low frequency," Dr. Tripathy said.

The researchers concluded that trastu-zumab may be active in patients who have progressed on a trastuzumab-based therapy and that long-term treatment with the antibody does not seem to increase the risk of cardiotoxicity. The individual contribution of trastuzumab, however, could not be determined from this trial and will need to be addressed in future studies.