Abstract P1-13-03: Effects of neratinib after trastuzumab-based adjuvant therapy in hormone receptor-positive HER2+ early-stage breast cancer: Exploratory analyses from the phase III ExteNET trial
Authors: Chia SKL , Martin M , Iwata H , Moy B , Lalani AS , Holmes FA , Mansi J , von Minckwitz G , Buyse M , Delaloge S , Ejlertsen B , Yao B , Murias Rosales A , Hellerstedt B , Cold S , Inoue K , Shen Z-Z , Galeano T , Barrios CH , Chan A 
Published: February 2018

Abstract
Background: The international, randomized, placebo-controlled phase III ExteNET trial showed that a 1-year course of neratinib after trastuzumab-based adjuvant therapy significantly improved 2-year invasive disease-free survival (iDFS) in patients with early-stage HER2+ breast cancer (BC) (hazard ratio 0.67; 95% CI 0.50–0.91; p=0.009) [Chan et al. Lancet Oncol 2016]. The significant iDFS benefit with neratinib was maintained after a median 5 years' follow-up (hazard ratio 0.73; 95% CI 0.57-0.92; p=0.008) [Martin et al. ESMO 2017]. At both time-points, marked benefit with neratinib was evident in patients with hormone receptor (HR)+ tumors, whereas in patients with HR– disease, initial improvements with neratinib diminished after completing treatment. We report exploratory analyses from the ExteNET trial done to better characterize the effects of neratinib in the HR+ subgroup.
Methods: Patients with early-stage HER2+ BC were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year after standard primary therapy and trastuzumab-based adjuvant therapy. Randomization was stratified by HR status (locally assessed), nodal status, and trastuzumab regimen. Adjuvant endocrine therapy was recommended for patients with HR+ disease. Data concerning disease recurrences were collected prospectively during year 1-2 post-randomization, and from medical records during year 3–5 post-randomization. Primary endpoint: iDFS. Secondary endpoints: DFS including ductal carcinoma in situ (DFS-DCIS); time to distant recurrence (TTDR); distant DFS (DDFS); cumulative incidence of central nervous system (CNS) recurrences; overall survival (OS). Hazard ratios (95% CI) were estimated using Cox proportional-hazards models. Data cut-off: March 2017. Clinicaltrials.gov: NCT00878709.
Results: 2840 patients were randomized (neratinib, n=1420; placebo, n=1420); 1631 (57%) patients had HR+ tumors (neratinib, n=816; placebo, n=815). 93% and 94% of HR+ patients in the neratinib and placebo groups, respectively, were receiving adjuvant endocrine therapy at baseline. Efficacy outcomes in the HR+ cohort after a median follow-up of 5.2 years are shown in the table. In subgroup analyses of the HR+ cohort, hazard ratios for iDFS were 0.49 in centrally confirmed HER2+ patients (n=951), and 0.58 in patients who had completed prior trastuzumab ≤12 months before randomization (n=1334). CNS recurrence and OS data are not yet mature.
Updated 2-year analysis5-year analysis Hazard ratiobP-value Hazard ratiobP-value Δ, %a(95% CI)(2 sided)Δ, %a(95% CI)(2 sided)iDFS4.10.49 (0.31–0.75)0.0014.40.60 (0.43–0.83)0.002DFS-DCIS4.80.45 (0.29–0.69)&lt;0.0015.10.57 (0.42–0.79)&lt;0.001DDFS3.10.52 (0.32–0.84)0.0084.00.60 (0.42–0.85)0.004TTDR2.90.52 (0.31–0.85)0.013.80.61 (0.42–0.86)0.006a. Difference in event rates between neratinib vs placebo; b. Neratinib vs placebo
Conclusions: Neratinib was associated with an absolute iDFS benefit of 4.4% in patients with HR+/HER2+ BC after 5 years' follow-up. HR/HER2 receptor cross-talk may underpin the notable effect of neratinib in patients with HR+ tumors when given in combination with endocrine therapy.
Citation Format: Chia SKL, Martin M, Iwata H, Moy B, Lalani AS, Holmes FA, Mansi J, von Minckwitz G, Buyse M, Delaloge S, Ejlertsen B, Yao B, Murias Rosales A, Hellerstedt B, Cold S, Inoue K, Shen Z-Z, Galeano T, Barrios CH, Chan A. Effects of neratinib after trastuzumab-based adjuvant therapy in hormone receptor-positive HER2+ early-stage breast cancer: Exploratory analyses from the phase III ExteNET trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-03.