The primary end point of the trial was intent-to-treat (ITT) PFS, which was defined as time from randomization to objective disease based on RECIST criteria or death from any cause. The protocol-specific interim analysis was performed after observing 333 PFS events, Dr. Gelmon noted, with the trial to stop if the 2-sided P-value from the stratified log-rank test was <0.03. The NCIC CTG independent data safety monitoring committee reviewed the interim analysis data on April 27, 2012, and recommended disclosure, noting the superiority boundary had been crossed. A secondary analysis utilized central laboratory-confirmed HER2+ status.

Secondary end points included overall survival (OS) and adverse events—results of which were presented at ASCO—as well as incidence of CNS metastases (first progression) and time to CNS metastases, objective response rate, clinical benefit rate, time to response and duration of response, quality of life, and correlative studies.

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The trial was activated July 17, 2008 and, between October 7, 2008, and December 1, 2011, 652 patients were accrued; data from 636 were included in the interim analysis with a clinical cutoff date of November 7, 2011 (195 events), and database lock of April 13, 2012 (333 PFS events by ITT). Median follow-up was 13.6 months, 12.9 months for the lapatinib arm and 14.0 months for the trastuzumab arm.

The ITT analysis included 318 patients in the lapatinib arm (266 with centrally confirmed HER2/neu status) and 318 in the trastuzumab arm (259 centrally confirmed). Baseline characteristics were similar between the two arms. Median age was 55.4 years in the lapatinib arm and 54.1 years in the trastuzumab arm. A total of 18% of patients in each arm had received prior (neo)adjuvant anti HER2/neu therapy and 21% in the lapatinib group and 22% in the trastuzumab group, prior (neo)adjuvant taxane treatment. A primary diagnosis of metastatic breast cancer was noted in 42% of patients in the lapatinib arm and 43% in the trastuzumab arm; 46% of patients in both groups had liver metastasis.

In the ITT analysis, PFS was 11.4 months (95% CI 10.8–13.7) in the trastuzumab arm and 8.8 months (95% CI 8.3–10.6) in the lapatinib arm (HR 1.33 [95% CI 1.06–1.67]; P=0.01). In patients with centrally confirmed HER2+ disease, median PFS was 13.7 months in the trastuzumab arm and 9.0 months in the lapatinib arm (HR 1.48; [95% CI 1.15–1.92]; P=0.003).

No difference in OS was detected between the two arms (HR 1.1 [95% CI 0.75–1.61]; P=0.62), including utilizing the centrally confirmed HER2+ analysis (HR 1.25 [95% CI 0.81-1.93]; P=0.32).

The toxicity pattern of the two arms was different, Dr. Gelmon said, with more grade 3 and 4 rash and diarrhea observed in the lapatinib arm (P<0.001) and a higher incidence of decrease in LVEF from baseline in the trastuzumab arm.

She noted that future analyses of these trial data will include a focus on incidence of brain metastasis as site of first recurrence, treatment exposure, response rate, quality of life, and correlative studies.