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FDA Expands the Use of Trastuzumab (Herceptin) for Early Stage Breast Cancer After Primary Therapy

On November 16, 2006, the U.S. Food and Drug Administration granted approval to trastuzumab (Herceptin, Genentech) as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel for the adjuvant treatment of women with node-positive, HER2-overexpressing breast cancer.  The approval is based on evidence of a significant prolongation in disease-free survival in women receiving Herceptin and chemotherapy compared to those receiving chemotherapy alone.

An integrated interim analysis of 3752 women from two NCI-Cooperative Group trials (NSABP B31 and NCCTG N9831) were reviewed.  Both studies restricted enrollment to women whose breast cancer demonstrated 3+ overexpression by immunohistochemistry or gene amplification (FISH).  All women received standard adjuvant chemotherapy [four 21-day cycles of doxorubicin and cyclophosphamide (AC) followed by paclitaxel administered weekly or every 3 weeks for a total of 12 weeks].  As appropriate, women also received hormonal therapy and local radiotherapy.  Patients were randomized to receive either no additional therapy or to receive Herceptin at 4 mg/kg on the day of paclitaxel initiation and subsequently at 2 mg/kg weekly for a total of 52 weeks.

Disease-free survival (DFS), defined as the time from randomization to recurrence, occurrence of contralateral breast cancer, other second primary cancer, or death, was the primary endpoint of the combined efficacy analysis.  There were 401 patients without follow-up assessment for DFS at the interim analysis and were censored at study day 1.

At the time of the interim analysis, there were 261 events among 1880 women in the chemotherapy alone arm and 133 events among 1872 women in the Herceptin plus chemotherapy arm.  The reduction in the risk of recurrence, second primary or death was 52% (hazard ratio 0.48, 95% CI: 0.39; 0.59).  An analysis of overall survival was conducted showing fewer deaths in the Herceptin plus chemotherapy arm; however, the findings were not significantly different and were based on small number of deaths with 96% of the population alive.

The most serious Herceptin toxicities were cardiomyopathy, pulmonary toxicity (respiratory failure, pneumonitis, pulmonary infiltrates), infusion reactions, and febrile neutropenia/exacerbation of chemotherapy-induced neutropenia.  The most common adverse reactions with Herceptin were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.  Adverse reactions requiring Herceptin interruption or discontinuation included severe infusion reactions, congestive heart failure, and significant declines in left ventricular cardiac function.

Serial measurement of left ventricular ejection fraction (LVEF) was obtained in the two clinical trials.  Six percent of patients were unable to receive Herceptin following completion of AC chemotherapy due to cardiac dysfunction (LVEF 50% or 15 point decline in LVEF from baseline to end of AC).

Following initiation of Herceptin therapy, the incidence of new-onset, dose-limiting myocardial dysfunction was higher among patients receiving Herceptin and paclitaxel as compared to those receiving paclitaxel alone.  Of those patients with normal LVEF prior to initiation of Herceptin/paclitaxel, 16% discontinued Herceptin therapy due to clinical evidence of myocardial dysfunction or significant declines in LVEF.  Approximately 2% in the Herceptin plus chemotherapy arm and 0.4% in the chemotherapy experienced clinically symptomatic, laboratory-confirmed cardiomyopathy determined by an external review committee.  One death was observed among 32 Herceptin-treated patients with clinical evidence of cardiomyopathy.  Among the 31 surviving patients, all were receiving cardiac medication at last follow-up and approximately half had evidence of recovery to a normal LVEF (defined as 50%) on continuing medical management.

Full prescribing information including clinical trial information, safety, dosing, drug-drug interaction and contraindications is available in Drugs@FDA

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by phone at 1-800-FDA-1088, by facsimile 1-800-FDA-0178, by mail, or by using the Form 3500 


Page Last Updated: 02/16/2016
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