Abstract P2-13-21: Improved central nervous system outcomes in patients with early-stage HER2-positive breast cancer who receive neratinib for the recommended duration: Findings from the phase 3 ExteNET trial
Authors: Holmes Frankie Ann , Patt Debra , Manalo Yvonne , Smith Julie C , Papish Steven W , Efrat Noa , Arance Ana , Zhang Bo , Lalla Deepa , Wong Alvin , Martin Miguel 
Published: March 2022

Abstract
Background: Non-adherence or early discontinuation from systemic adjuvant therapy is associated with an increased risk of disease recurrence and mortality. In the phase 3 ExteNET trial, neratinib (NERLYNX®), an oral irreversible pan-HER tyrosine kinase inhibitor, significantly improved invasive disease-free survival (iDFS) when given for 12 months in patients with early-stage HER2-positive (HER2+) breast cancer after trastuzumab-based therapy. Anti-diarrheal prophylaxis was not mandated by protocol and 17% of patients discontinued neratinib early because of diarrhea. Improved iDFS, distant disease-free survival, and overall survival (OS) have since been reported in patients who completed the planned duration of neratinib therapy compared with all randomized patients [ASCO 2021]. Here we assess central nervous system disease-free survival (CNS-DFS) in 3 discrete groups of patients who completed planned therapy with neratinib in ExteNET: intent-to-treat (ITT) population; patients with hormone receptor-positive disease who initiated neratinib within 1 year after prior trastuzumab (HR+/≤1 year, the population for which neratinib is approved in the EU); and HR+/≤1 year with residual disease post-neoadjuvant therapy (i.e. no pathologic complete response [pCR]). Methods: Patients with early-stage HER2+ breast cancer received oral neratinib 240 mg/day or placebo after trastuzumab-based (neo)adjuvant therapy for 12 months. Patients who completed neratinib therapy (defined as treatment duration ≥11 months or cessation of neratinib if recurrence occurred prior to 11 months) were compared with placebo (all randomized patients). CNS-DFS was defined as time from randomization to any CNS recurrence or death from any cause (exploratory endpoint). Kaplan-Meier methods were used to estimate CNS-DFS and OS rates. Hazard ratios (HR) with 95% confidence intervals (CI) for neratinib versus placebo were estimated using a Cox proportional hazards model. Data cutoffs: March 2017 (CNS-DFS); July 2019 (OS); median follow-up 8.0 (range 0-9.8) years. Results: 2840 patients were included in the ITT population (1420 per group). Among patients who completed neratinib therapy, CNS-DFS was improved versus placebo in each of the 3 patient groups (see Table). For CNS-DFS, the magnitude of effect of neratinib versus placebo was consistently greater in patients who completed neratinib therapy than in the corresponding overall randomized patient group: ITT HR, 0.70 vs 0.73; HR+/≤1 year HR, 0.27 vs 0.41; HR+/≤ 1 year no pCR HR: 0.16 vs 0.24, respectively.
Conclusions: These descriptive findings suggest that, in addition to improved OS, patients who receive the recommended 12-month course of neratinib may have improved CNS outcomes. A dose-escalation strategy, which was shown to improve the tolerability of neratinib, decrease the proportion of patients who discontinue treatment due to diarrhea (3.3%), and allow more patients to stay on treatment for 11 months or longer in the CONTROL trial (NCT02400476) compared with ExteNET, may help to realize these benefits in the real-world setting.
Table: CNS-DFS and OS in patients who completed planned therapy with neratinib (ITT, HR+/≤1 year and HR+/≤1 year no pCR)NCNS-DFS rate (5 years)OS rateaPopulation/group NeratinibPlaceboDifference, %bHR (95% CI)Difference, %bHR (95% CI)ITT14201420+1.10.73 (0.45-1.17)-0.10.95 (0.75-1.21)cCompleted therapyd8721420+1.20.70 (0.40-1.19)+2.00.78 (0.58-1.04)HR+/≤1 yeare670664+2.70.41 (0.18-0.85)+2.10.79 (0.55-1.13)Completed therapyd402664+3.20.27 (0.08-0.69)+5.80.49 (0.29-0.78)HR+/≤1 yearb no pCRf131164+6.40.24 (0.04-0.92)+9.10.47 (0.23-0.92)Completed therapyd92164+6.90.16 (0.01-0.81)+13.20.29 (0.10-0.68)aOS analysis after a median follow-up of 8.0 (range 0-9.8) years; bDifference (neratinib vs placebo); cStratified by randomization stratification factors; dDefined as ≥11 months of therapy or ended treatment due to disease recurrence (neratinib arm), and all randomized subjects (placebo arm); eHR+ and ≤1 year after prior trastuzumab; fResidual disease post-neoadjuvant therapy. Abbreviations: CI, confidence interval; CNS-DFS, central nervous system disease-free survival; HR, hazard ratio; HR+, hormone receptor-positive; OS, overall survival; pCR, pathologic complete response.
Citation Format: Frankie Ann Holmes, Debra Patt, Yvonne Manalo, Julie C Smith, Steven W Papish, Noa Efrat, Ana Arance, Bo Zhang, Deepa Lalla, Alvin Wong, Miguel Martin. Improved central nervous system outcomes in patients with early-stage HER2-positive breast cancer who receive neratinib for the recommended duration: Findings from the phase 3 ExteNET trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-21.