Background: ExteNET, an international, randomized, placebo-controlled phase III trial, showed that neratinib given for 1 year after trastuzumab-based adjuvant therapy significantly improved 2- (HR 0.67, p = 0.009) and 5-year (HR 0.73, p = 0.008) invasive disease-free survival (iDFS) in early-stage HER2+ breast cancer [Chan et al. 2016; Martin et al. 2017]. Prespecified subgroup analyses showed greater benefit with neratinib in HR+ than HR- tumors, and in patients who initiated neratinib ≤12 months of completing trastuzumab. To better understand the effects of neratinib in patients with HR- disease, we examined the impact on efficacy of the interval from prior trastuzumab to start of neratinib in the HR- subpopulation. Methods: Patients with early-stage HER2+ breast cancer received oral neratinib 240 mg/day or placebo for 1 year after standard trastuzumab-based (neo)adjuvant therapy. iDFS, the primary study endpoint, was examined in subgroups categorized according to the interval between completing trastuzumab and randomization (i.e. 0-6, 6-12 and > 12 months). Data cut-off: March 1, 2017. Clinicaltrials.gov: NCT00878709. Results: The ITT population comprised 2840 patients; 1209 (43%) had HR- disease (neratinib, n = 604; placebo, n = 605). Results after a median of 5.2 years in the HR- subgroup are shown below. Conclusions: Patients with HER2+ HR- tumors tend to recur early. The risk of recurrence is higher in patients who have recently completed trastuzumab-based therapy (reflected in the iDFS rates of the placebo group). Consistent with these observations, our analyses suggest that the benefits of neratinib in HR- disease are greater when treatment is started closer to completion of trastuzumab (i.e. ≤6 months). Clinical trial information: NCT00878709

^aNeratinib vs placebo