Final Analysis of the PHARE Trial: 6 Months vs 12 Months of Adjuvant Trastuzumab in HER2-Positive Breast Cancer
In the French phase III PHARE trial reported in The Lancet, Pivot et al found that noninferiority of 6 months vs 12 months of adjuvant trastuzumab combined with standard chemotherapy could not be demonstrated for disease-free survival in HER2-positive early breast cancer. An earlier interim analysis report also did not establish noninferiority.
Study Details
In the open-label trial, 3,380 patients from 156 sites in France were randomly assigned between May 2006 and July 2010 to receive 6 months (n =1,690) or 12 months (n =1,690) of adjuvant trastuzumab. Patients must have received at least four cycles of standard chemotherapy and must have started receiving adjuvant trastuzumab; eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab between the 3rd and 6th months of adjuvant trastuzumab treatment. Trastuzumab was administered via intravenous infusion every 3 weeks at a loading dose of 8 mg/kg and 6 mg/kg thereafter. Stratification factors included concomitant vs sequential administration of chemotherapy and trastuzumab.
The primary objective was noninferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival, with a prespecified hazard margin of 1.15.
Disease-Free Survival
At a median follow-up of 7.5 years, disease-free survival events had occurred in 21.2% of the 6-month group vs 20.4% in the 12-month group (adjusted hazard ratio for disease-free survival in 12-month vs 6-month group = 1.08, 95% confidence interval [CI] = 0.93–1.25, P = .39), with the noninferiority margin included in the 95% CI. During follow-up, death occurred in 11.0% vs 10.1% of patients.
Updated Safety Analysis
Adverse events were infrequent following completion of trastuzumab therapy, with the safety analysis being similar to that in the earlier report from the trial. No change in the comparison of cardiac toxicity was observed, and no new cases of heart failure were observed. Three additional cases of left ventricular ejection fraction reduction to < 50% were reported in the 12-month group during long-term follow-up.
The investigators concluded, “The PHARE study did not show the noninferiority of 6 months vs 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months.”
Xavier Pivot, MD, of Centre Paul Strauss, Strasbourg, is the corresponding author for The Lancet article.
Disclosure: The study was funded by The French National Cancer Institute. For full disclosures of the study authors, visit thelancet.com.
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