Background: The optimal duration of adjuvant therapy with targeted agents remains a question of ongoing relevance in oncology. ExteNET, an international, randomized, placebo-controlled phase III trial, showed that neratinib given for 12 months after trastuzumab-based 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. Lancet Oncol 2016; Martin et al. Lancet Oncol 2017]. We examined the influence of duration of neratinib therapy on efficacy in the ExteNET study. Methods: Patients with early-stage HER2+ breast cancer were randomly assigned to oral neratinib 240 mg/day or placebo for 12 months (or until disease recurrence) after standard primary therapy and trastuzumab-based (neo)adjuvant therapy. Patients who received neratinib for ≤3 or ≥11 months (the median duration of neratinib treatment) were each compared with the ITT placebo group. iDFS (primary endpoint) was analyzed using Kaplan-Meier methods and Cox proportional-hazards models adjusted for prognostic factors. Data cut-off: March 1, 2017. Clinicaltrials.gov: NCT00878709. Results: ITT population comprised 2840 patients (neratinib, n = 1420; placebo, n = 1420). Median treatment duration (ITT population) was 11.6 and 11.8 months in the neratinib and placebo groups, respectively. 391 patients received neratinib for ≤3 months. 872 patients received neratinib for ≥11 months or stopped treatment prior to 11 months due to recurrence. Results after a median of 5.2 years' follow-up are shown below. Conclusions: These exploratory data suggest that patients who remained on neratinib for ≥11 months derived clear benefits from therapy, whereas neratinib efficacy was considerably reduced in those who stopped treatment early (≤3 months).Clinical trial information: NCT00878709

^a14 patients stopped treatment before 11 months due to recurrence.

^bAdjusted for stratification factors.