Abstract P1-13-05: Timing of initiation of neratinib after completion of trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: Exploratory analyses from the phase III ExteNET trial
Authors: Ejlertsen B , Chan A , Gnant M , von Minckwitz G , Delaloge S , Buyse M , O'Shaughnessy J , Mansi J , Moy B , Iwata H , Wong A , Ye Y , Means-Powell J , Hui R , Ruiz-Borrego M , Ruiz Simon A , Shen Z-Z , Holmes FA , Lesniewski-Kmak K , Martin M 
Published: February 2018

Abstract
Background: The international, randomized, placebo-controlled phase III ExteNET trial showed that 1 year of neratinib after trastuzumab-based adjuvant therapy significantly improved 2-year invasive disease-free survival (iDFS) in early-stage HER2+ breast cancer (HR 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 of 5 years' follow-up (HR 0.73; 95% CI 0.57-0.92; p=0.008) [Martin et al. ESMO 2017]. We present exploratory analyses from the ExteNET trial examining the effects of the interval between completion of trastuzumab and randomization to commence neratinib on iDFS.
Methods: Women with early-stage HER2+ breast cancer were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year after standard primary therapy and trastuzumab-based adjuvant therapy. Under the original study protocol, (neo)adjuvant trastuzumab was to be completed ≤24 months before randomization; this was revised to ≤12 months before randomization after the NCCTG-N9831/NSABP B-31 4-year analysis showed that the risk of relapse is greatest during the first 12 months after completing trastuzumab. Disease recurrences were collected prospectively during 1 and 2 years post-randomization, and from medical records during 3–5 years post-randomization. Patients randomized ≤12 months after completion of adjuvant trastuzumab were further separated to look at those who initiated neratinib ≤6 months of completing adjuvant trastuzumab. Primary endpoint: iDFS. HR (95% CI) estimated using Cox proportional-hazards models. Data cut-off: March 1, 2017. Clinicaltrials.gov: NCT00878709.
Results:The intention-to-treat population comprised 2840 patients (neratinib, n=1420; placebo, n=1420). Median time from last trastuzumab dose to randomization was 4.4 and 4.6 months in the neratinib and placebo groups, respectively. 81% of patients were randomized ≤12 months of completing trastuzumab. The effects of the interval between the last dose of trastuzumab and randomization/initiation of neratinib on iDFS after a median follow-up of 5.2 years are shown in the table.
Estimated 5-year iDFS rate, % P-valueInterval from last dose of trastuzumab to randomizationnNeratinibPlaceboHR (95% CI)a(2-sided)≤6 months164190.085.40.62 (0.46–0.84)0.002≤12 monthsb229789.786.50.70 (0.54–0.90)0.006&gt;12 monthsb54392.392.61.00 (0.51–1.94)0.992a. Neratinib vs placebo; b. Protocol-defined subgroups
Conclusions: In ExteNET, patients who initiated neratinib within 12 months of completing trastuzumab-based adjuvant therapy appeared to derive greater benefit from treatment than those who started neratinib later. Further, exploratory analyses suggest that the magnitude of benefit with neratinib is greater if initiated sooner (i.e. within 6 months of completing trastuzumab). Given the benefits of neratinib overall in those initiating treatment ≤12 months from the end of adjuvant trastuzumab, extended adjuvant treatment with neratinib should be initiated early following completion of trastuzumab.
Citation Format: Ejlertsen B, Chan A, Gnant M, von Minckwitz G, Delaloge S, Buyse M, O'Shaughnessy J, Mansi J, Moy B, Iwata H, Wong A, Ye Y, Means-Powell J, Hui R, Ruiz-Borrego M, Ruiz Simon A, Shen Z-Z, Holmes FA, Lesniewski-Kmak K, Martin M. Timing of initiation of neratinib after completion of trastuzumab-based adjuvant therapy in early-stage HER2+ 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 P1-13-05.