USE TRASTUZUMAB WITH CHEMOTHERAPY

December 15, 2009 (San Antonio, Texas) — Giving trastuzumab (Herceptin, Genentech-Roche) concurrently — as opposed to sequentially — with adjuvant chemotherapy should be the standard of care, suggested the lead investigator of the only trial designed to compare the 2 approaches.

The recommendation comes from a portion of the trial that involved 1903 women with HER2-positive early breast cancer.

Updated results, now with a median follow-up of 5.3 years, show a rate of disease-free survival of 84.2% for concurrent therapy and 79.8% for the sequential therapy, said Edith Perez, MD, here at the 32nd Annual San Antonio Breast Cancer Symposium. She is chair of the North Central Cancer Treatment Group Breast Committee, which ran the study (N9831), and is from the Mayo Clinic in Jacksonville, Florida.

The difference is not statistically significant, but the 25% reduction in the risk for recurrence or death with concurrent therapy, compared with sequential therapy, shows a "strong trend," said Dr. Perez.

She explained that the result was not statistically significant because there were not as many patient events as the investigators initially projected. "We did not think the drug would be this effective at study design," she added.

The "implication for practice" from the study is that "adjuvant trastuzumab be incorporated in a concurrent fashion with taxane chemotherapy," said Dr. Perez.

"The results of this trial have been awaited all over the world," said Claudine Isaacs, MD, who moderated a meeting press conference highlighting the study. Dr. Isaacs is from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

Trastuzumab is approved for both concurrent and sequential therapy by the US Food and Drug Administration, but concurrent is used by most clinicians in the United States, said Dr. Isaacs. However, in other parts of the world, only sequential therapy is practiced, she continued.

"This could mean that up to 10,000 women around the world each year may have a better outcome if [trastuzumab] is used along with chemotherapy. Given that, I believe this study will lead to a global re-evaluation of the way [trastuzumab] is used," Dr. Perez said in a press statement.

Dr. Perez credited a "positive interaction between chemotherapy and [trastuzumab]" for the additional benefit seen with the concurrent administration.

The chemotherapy in the trial was anthracycline-based, which was a feature of another phase 3 clinical trastuzumab trial presented here — the Breast Cancer International Research Group 006 trial.

Unlike that trial, however, there seemed to be no controversy surrounding Dr. Perez's results.

Dr. Perez highlighted one of the concerns with anthracyclines — cardiac safety — in her presentation, telling reporters during a press conference that it "generates a tremendous amount of interest." The 3-year cumulative incidence of grade 3/4 congestive heart failure or sudden cardiac death was 3.3% for concurrent therapy and 2.8% for sequential therapy. No one in the audience commented on the data, which were previously published (J Clin Oncol. 2004;22:322-329).

"I feel very confident that anthracycline-based therapy is appropriate," said Dr. Perez.

Other experts were also positive about the trial. "It's a very important finding," said Dr. Isaacs.

"An exciting report," is how the director of the meeting, C. Kent Osborne, MD, described the results.

Sequential Therapy Is Effective Too

"Scientifically, this is an important result because it clarifies a previously muddy picture," Eric Winer, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, told Medscape Oncology.

Dr. Winer was referring to an early result from the trial that suggested there was no benefit from sequential therapy with trastuzumab, compared with the chemotherapy alone.

The trial consisted of 2 comparisons, one of which was the abovementioned sequential versus concurrent therapy. The other comparison involved 2448 patients randomly assigned to chemotherapy alone or chemotherapy sequentially followed by trastuzumab.

The chemotherapy in both comparisons was doxorubicin (Adriamycin, Bedford Laboratories) and cyclophosphamide, then paclitaxel (Abraxane, Abraxis Bioscience).

After a median follow-up of 5.5 years, the investigators found that the rate of disease-free survival was 80.1% for chemotherapy with sequential trastuzumab and 71.9% for chemotherapy alone. This difference is statistically significant (P = .019).

The outcome was adjusted for possible confounding variables such as tumor size, number of positive nodes, and estrogen-receptor status, report the investigators.

"Now it's been shown that sequential therapy is beneficial too," said Dr. Winer.

"You get benefit if you give trastuzumab after chemotherapy and you get even more if you give it at the same time," summarized Dr. Winer.

The study was supported by the National Institutes of Health, the Breast Cancer Research Foundation, and Genentech. Dr. Perez reports serving on steering committees for Bayer HealthCare and Genentech and on an independent monitoring committee for Novartis. Dr. Isaacs reports being a member of the speakers bureau for GlaxoSmithKline, Genentech, Novartis, and AstraZeneca. Dr. Osborne reports being on the advisory board of Onyx Pharmaceuticals. Dr. Winer has disclosed no relevant financial relationships.

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract 80. Presented December 12, 2009.