ExteNET, sponsored by Puma Biotechnology, enrolled 2,840 women who had completed adjuvant chemotherapy and trastuzumab (Herceptin) for early breast cancer that was HER2 positive by local assessment. The women were randomized evenly to neratinib – an oral irreversible inhibitor of HER 1, 2, and 4 shown to be active in trastuzumab-pretreated patients – or placebo.
The study had a complex evolution, with several major amendments of the protocol due to new results from other trials and changes in sponsorship, Dr. Chan noted. Initially, women were required to have stage 1 to 3c disease with receipt of the last trastuzumab dose no more than 2 years earlier; later, that was modified to stage 2 to 3 disease and receipt of the last trastuzumab dose no more than 1 year earlier. Also, the duration of follow-up was temporarily shortened from 5 years to 2 years.
In intention-to-treat analyses, the 2-year rate of invasive disease–free survival was 93.9% with neratinib and 91.6% with placebo (hazard ratio, 0.67; P = .009), reported Dr. Chan, who disclosed that she has a consulting or advisory role with Pfizer, and that she is on the speakers’ bureau and is provided with travel, accommodation, and expenses by Pierre Fabre.
In some noteworthy subgroup findings, benefit was even greater among women with hormone receptor–positive disease (hazard ratio, 0.51; P = .001) or centrally confirmed HER2-positive disease (hazard ratio, 0.51; P = .002).
The neratinib group also had a significantly better rate of survival with freedom from invasive and in situ disease combined (93.9% vs. 91.0%; hazard ratio, 0.63; P = .002).
In terms of adverse events of special interest, neratinib was associated with a sharply higher rate of grade 3 or 4 diarrhea when compared to placebo (40% vs. 2%), as expected from its mechanism of action, Dr. Chan said. But rates of cardiac toxicity and interstitial lung disease did not differ between groups.