ASCO--In two phase III trials, the anti-HER-2/neu monoclonal antibody (MoAB) Herceptin (trastuzumab, Genen-tech) showed significant activity both as a single agent and in combination with traditional cytotoxic chemotherapy in the treatment of HER-2/neu overexpressing metastatic breast cancer.
The protein expressed by the HER-2/neu proto-oncogene is a transmembrane receptor that has potent tyrosine kinase activity. "And you can read that as growth-stimulating activity," Melody Cobleigh, MD, of Rush Presbyterian-St. Lukes Medical Center, Chicago, said at an ASCO integrated symposium devoted to HER-2/neu research.
Normal cells generally contain two HER-2/neu genes. The presence of extra copies of this gene within cells appears to cause rapid proliferation and cancerous growth that metastasizes beyond the original site. HER-2/neu is overexpressed in approximately 25% to 30% of human breast cancers.
Herceptin is a recombinant, humanized anti-HER-2 antibody that targets the extracellular domain of the HER-2 growth factor receptor, inhibiting signal transduction and cell proliferation. In vivo, Herceptin enhances antibody-dependent, cell-mediated cytotoxicity.
Dr. Cobleigh and her coworkers studied the safety and efficacy of intravenous Herceptin in 222 women in an open-label, multinational trial. All patients had progressive metastatic breast cancers that overexpressed HER-2 and had experienced disease progression after one or two prior chemotherapy regimens for metastatic disease.
At a median follow-up of 11 months, the overall response rate in this heavily pretreated, poor-prognosis population was 16%. "The median duration of response (9.1 months) was gratifying," Dr. Cobleigh noted. Estimated median survival at the time of the report was 13 months. Only two patients discontinued the study due to adverse effects.
Phase II studies had demonstrated that Herceptin possessed significant antitu-mor activity that increased when used in combination with chemotherapy. These findings led Dennis Slamon, MD, PhD, UCLA School of Medicine, and his group to initiate a large, randomized phase III trial that evaluated the efficacy of Herceptin plus chemotherapy as first-line therapy for metastatic breast cancer in 469 women.
Patients were randomized into four groups: 145 patients received doxorubicin (Adriamycin)/cyclophosphamide (AC), 146 received AC plus Herceptin, 89 received paclitaxel (Taxol), and 89 received paclitaxel plus Herceptin.
Of patients who received chemotherapy alone, 32% responded to treatment vs 49% of patients who received Her-ceptin plus chemotherapy, a 53% increase in response rate. In addition, the Hercep-tin arms were associated with a 58% improvement in median duration of response (9.3 month vs 5.9 months) and a 65% increase in median time to progression (7.6 months vs 4.6 months).
In the AC group, the response rate increased from 43% with AC alone to 52% with AC plus Herceptin. In the paclitaxel arm, those who also received Herceptin had a response rate of 42% vs 16% for those getting paclitaxel alone.
"These results indicate that Herceptin in combination with chemotherapy is well tolerated and provides substantial clinical benefit in first-line treatment of HER-2 overexpressing metastatic breast cancer," Dr. Slamon said. "HER-2-positive tumors, really do subtend a different type of breast cancer," he continued. "These patients have a more aggressive form of the disease, and they should be treated accordingly. We are excited that now we have a therapy that can offer some benefit to these patients."
Dr. Slamon said that a Biologics License Application for Herceptin has been submitted to the FDA where it has been designated a Fast Track Product that could be approved by the end of the year.