NEW ORLEANSIn a phase II study, combined treatment with Herceptin (trastuzumab) and vinorelbine (Navelbine) improved response rates and survival in women with HER2-positive metastatic breast cancer.
The clinical trial finding supports preclinical research suggesting a synergistic interaction between Herceptin and vinorelbine, Harold J. Burstein, MD, of Harvard Medical School, said at the 36th Annual Meeting of the American Society of Clinical Oncology (ASCO). Dr. Burstein and his colleagues at Dana-Farber/Partners Cancer Care were involved with this trial.
Further rationale for the study came from the fact that both agents have activity in advanced breast cancer with side effect profiles favorable for combination therapyand both are given on a weekly schedule, Dr. Burstein said. He noted also that vinorelbine is not associated with cardiotoxicity, nausea, vomiting, or alopecia, and does not require steroid premedication.
The primary objective was to define a response rate to the combination in women with HER2-positive metastatic breast cancer and to characterize the safety/toxicity profile of the regimen. The study included patients with measurable metastatic disease and tumors (either primary or metastatic) that were HER2 positive at the +2 or +3 level by immunohistochemistry.
While participants with up to two prior chemotherapy regimens for advanced breast cancer were allowed, prior therapy with Herceptin or vinorelbine was not permitted. Patients with impaired cardiac function were also excluded. Sixty-five percent of patients had either two or three metastatic sites.
Dr. Burstein noted that while the study opened with the Herceptin/vinorelbine combination as a second- or third-line therapy, eligibility was later extended to first-line treatment of metastatic breast cancer.
Forty patients (median age, 51) received Herceptin (4 mg/kg first dose, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m²/wk IV push). Doses of vinorelbine were reduced to 15 mg/m² for absolute neutrophil counts (ANC) between 750 and 1,250/µL or withheld for a week if the ANC dropped below 750/µL. Restaging and cardiac function tests were performed after every 8-week cycle.
Out of a total of 982 weeks of treatment for the entire cohort, vinorelbine doses were reduced in 13% of weeks and omitted in 7%.
Complete responses, Dr. Burstein said, were seen in 2 patients (5%) and partial responses in 28 (70%), for an overall response rate of 75%. Two patients (5%) had stable disease for more than 6 months, and eight (20%) had progressive disease. The response rate was 80% among the 30 patients with +3 HER2 status and 55% among the 9 patients with +2 status.
Activity was noted regardless of prior chemotherapy for metastatic disease, Dr. Burstein said. Among the patients who had undergone two prior regimens, 71% responded, as did 64% of patients who had undergone one prior regimen. The response rate was 84% for first-line-therapy patients.
The combination regimen was well tolerated, Dr. Burstein said, with minimal alopecia (13% grade 1, 2% grade 2) and few gastrointestinal side effects (44% grade 1 nausea, 15% grade 2). Leukopenia (grade 3-4) occurred in 36% of patients. While grade 1 sensory neuropathy occurred in 31% of patients and grade 2 in 8%, there were no grade 3-4 neuropathies, he said.
Grade 1-2 cardiotoxicities occurred in 13% of patients. The three patients who had grade 2 cardiotoxicities (asymptomatic declines in left ventricular ejection fraction) were taken off study medications. No symptomatic heart disease or heart failure occurred, and no significant changes in ejection fraction were noted after the second cycle of treatment.
It looks like this is going to be a valuable regimen, Dr. Burstein said in an interview with ONI. Our study doesnt allow us to say whether its better than anything else, but we know that it is very well tolerated, which our patients like.
Dr. Burstein noted that further research is being conducted to answer other key questions pertaining to the optimal use of Herceptin. We really have no idea when to stop Herceptin, he said. New studies will look at patients who have already undergone chemotherapy with a taxanepaclitaxel (Taxol) or docetaxel(Drug information on docetaxel) (Taxotere)and Herceptin, and have had disease progression. Participants will receive vinorelbine with or without Herceptin.
Another study among chemotherapy-naïve women with advanced breast cancer will evaluate Herceptin alone or with vinorelbine. The question is, do you need to start chemotherapy right away or can you defer it until Herceptin is clearly not working, Dr. Burstein said.