A phase III trial of adjuvant neratinib (NER) after trastuzumab (TRAS) in women with early-stage HER2+ breast cancer (BC).

Abstract

TPS137 Background: The human epidermal growth factor receptors (HER1-4) are frequently overexpressed in human tumors. Increased HER receptor signaling is associated with increased resistance to standard therapies and poor prognosis. TRAS, an anti-HER2 monoclonal antibody, reduces recurrences and improves disease-free survival (DFS) in patients (pts) with HER2+ early BC. However, 15% to 25% of TRAS-treated pts still experience relapsed disease at 5 yrs. NER is a small molecule, irreversible tyrosine kinase inhibitor of HER2 as well as HER1 and HER4. In a phase II study, orally administered NER 240 mg/d was well tolerated with significant antitumor activity in pts with HER2+ BC, with or without prior TRAS (objective response rates of 24% and 56%; median progression-free survival of 22 wks and 40 wks, respectively). The current study will evaluate the efficacy and safety of NER in pts with early-stage HER2+ BC after adjuvant TRAS. Methods: This double-blind, placebo-controlled, multicenter, phase III study will include approximately 3,300 women with early-stage HER2-overexpressing/amplified, node-positive BC (or no pathologic complete response after neoadjuvant therapy) at high risk for recurrence. Pts will be randomized within 1 yr of prior adjuvant TRAS to oral NER 240 mg or placebo daily for 1 yr. Pts will be followed for up to 5 yrs post-randomization for recurrence and/or survival. Primary endpoint is DFS (time to disease recurrence or death), using a 1-sided log-rank test to compare treatment arms and a Cox proportional hazards regression model for hazard ratio estimation. Other efficacy endpoints include DFS including ductal carcinoma in situ, time to distant recurrence, distant DFS, incidence of central nervous system recurrence, and overall survival. Safety will be monitored, with particular attention to diarrhea. Biomarker analyses (including HER2 confirmation from archived samples) and health-related quality of life (FACT-B and EQ-5D) will also be assessed. Results: As of Jan 25, 2011, a total of 2,050 pts have been randomized, including 934 high-risk pts. Conclusions: Recruitment is planned to continue until late 2013. As of Nov 3, 2010, the IDMC recommended the trial to continue.