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Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial

Open AccessPublished:October 05, 2020DOI:https://doi.org/10.1016/j.clbc.2020.09.014

      Abstract

      Background

      The ExteNET trial demonstrated improved invasive disease-free survival (iDFS) with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, versus placebo in patients with human epidermal growth factor receptor 2-positive (HER2+)/hormone receptor-positive (HR+) early-stage breast cancer (eBC).

      Patients and Methods

      ExteNET was a multicenter, randomized, double-blind, phase III trial of 2840 patients with HER2+ eBC after neoadjuvant/adjuvant trastuzumab-based therapy. Patients were stratified by HR status and randomly assigned 1-year oral neratinib 240 mg/day or placebo. The primary endpoint was iDFS. Descriptive analyses were performed in patients with HR+ eBC who initiated treatment ≤ 1 year (HR+/≤ 1-year) and > 1 year (HR+/> 1-year) post-trastuzumab.

      Results

      HR+/≤ 1-year and HR+/> 1-year populations comprised 1334 (neratinib, n = 670; placebo, n = 664) and 297 (neratinib, n = 146; placebo, n = 151) patients, respectively. Absolute iDFS benefits at 5 years were 5.1% in HR+/≤ 1-year (hazard ratio, 0.58; 95% confidence interval [CI], 0.41-0.82) and 1.3% in HR+/>1-year (hazard ratio, 0.74; 95% CI, 0.29-1.84). In HR+/≤ 1-year, neratinib was associated with a numerical improvement in overall survival (OS) at 8 years (absolute benefit, 2.1%; hazard ratio, 0.79; 95% CI, 0.55-1.13). Of 354 patients in the HR+/≤ 1-year group who received neoadjuvant therapy, 295 had residual disease, and results showed absolute benefits of 7.4% at 5-year iDFS (hazard ratio, 0.60; 95% CI, 0.33-1.07) and 9.1% at 8-year OS (hazard ratio, 0.47; 95% CI, 0.23-0.92). There were fewer central nervous system events with neratinib. Adverse events were similar to those previously reported.

      Conclusion

      Neratinib significantly improved iDFS in the HER2+/HR+/≤ 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in central nervous system events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population.

      Graphical abstract

      Keywords

      Introduction

      Trastuzumab, the first monoclonal antibody to target the human epidermal growth factor receptor 2 (HER2), markedly reduces the risk of disease recurrences and death among patients with HER2-positive (HER2+) early breast cancer (eBC) when added to adjuvant chemotherapy.
      • Piccart-Gebhart M.J.
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      Herceptin Adjuvant (HERA) Trial Study Team
      Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.
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      Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.
      • Slamon D.
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      Breast Cancer International Research Group
      Adjuvant trastuzumab in HER2-positive breast cancer.
      After the initial trials of trastuzumab, several subsequent adjuvant strategies designed to further improve outcomes were unsuccessful (ie, extending the duration of adjuvant trastuzumab from 1 to 2 years,
      • Goldhirsch A.
      • Gelber R.D.
      • Piccart-Gebhart M.J.
      • et al.
      Herceptin Adjuvant (HERA) Trial Study Team
      2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial.
      concurrent or sequential use of lapatinib with trastuzumab,
      • Piccart-Gebhart M.
      • Holmes E.
      • Baselga J.
      • et al.
      Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial.
      or by adding bevacizumab to trastuzumab
      • Slamon D.L.
      • Swain S.M.
      • Buyse M.
      • et al.
      Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive, or high-risk node-negative breast cancer. Thirty-Sixth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2013 Dec 10-14; San Antonio, TX.
      ). However, significant disease-free survival gains compared with 1 year of trastuzumab have since been reported with other approaches. These include the addition of pertuzumab to trastuzumab,
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • et al.
      APHINITY Steering Committee and Investigators
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      ,
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      • et al.
      GS1–04. Interim overall survival analysis of APHINITY (BIG 4-11): a randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR.
      targeted use of the anti-HER2 antibody-drug conjugate trastuzumab emtansine in patients with residual disease after neoadjuvant therapy,
      • von Minckwitz G.
      • Huang C.S.
      • Mano M.S.
      • et al.
      KATHERINE Investigators
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      and extending the duration of adjuvant HER2-based therapy with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, given for 1 year after completion of trastuzumab.
      • Chan A.
      • Delaloge S.
      • Holmes F.A.
      • et al.
      ExteNET Study Group
      Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Martin M.
      • Holmes F.A.
      • Ejlertsen B.
      • et al.
      ExteNET Study Group
      Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.
      Extended adjuvant therapy with neratinib after trastuzumab-based therapy was investigated in the phase III ExteNET trial, in which 1 year of neratinib was shown to significantly improve invasive disease-free survival (iDFS) compared with placebo at the planned primary analysis time point of 2 years (hazard ratio, 0.66; 95% confidence interval [CI], 0.49-0.90; P = .008).
      The efficacy of neratinib was confirmed at the 5-year analysis (hazard ratio, 0.73; 95% CI, 0.57-0.92; P = .008).
      • Martin M.
      • Holmes F.A.
      • Ejlertsen B.
      • et al.
      ExteNET Study Group
      Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.
      A consistent finding at both time points was that the benefit of neratinib was more marked in predefined subgroups, including patients who initiated treatment within 1 year of completing prior trastuzumab compared with those who started treatment later, and among patients with hormone receptor-positive (HR+) versus hormone receptor-negative (HR) disease.
      • Chan A.
      • Delaloge S.
      • Holmes F.A.
      • et al.
      ExteNET Study Group
      Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Martin M.
      • Holmes F.A.
      • Ejlertsen B.
      • et al.
      ExteNET Study Group
      Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.
      The greater efficacy of neratinib in the ExteNET HR+ population (most of whom were receiving concurrent endocrine therapy) may be attributed to the effective inhibition of cross-talk between HER2 and estrogen receptors, a known mechanism of resistance in HER2+/HR+ tumors.
      • Johnston S.R.D.
      New strategies in estrogen receptor-positive breast cancer.
      Patients with HR+/HER2+ cancers, as for HR+/HER2-negative cancers, are at continuous risk of late recurrences,
      • Pan H.
      • Gray R.
      • Braybrooke J.
      • et al.
      EBCTCG
      20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years.
      and the benefit of neratinib as extended adjuvant therapy in this population is biologically sound.
      Based on the findings from ExteNET, neratinib was approved by the United States Food and Drug Administration as extended adjuvant therapy in the intention-to-treat (ITT) patient population, which included patients with HR+ and HR tumors.
      The European Medicines Agency approved neratinib in patients with HER2+/HR+ eBC who initiate treatment within 1 year of completing trastuzumab-based therapy.
      We describe clinically relevant breast cancer events in patients with HER2+/HR+ breast cancer from ExteNET. As the magnitude and durability of iDFS benefit with neratinib was notable in patients with HR+ tumors who initiated treatment within a year of completing trastuzumab, referred to hereafter as the HR+/≤ 1-year population, we report additional descriptive analyses for this population, including estimates of overall survival (OS). We also report iDFS and OS in a subset of patients considered to be at higher risk of relapse – patients with HR+ tumors with residual disease after neoadjuvant therapy (non-pathologic complete response [non-pCR] subgroup).

      Patients and Methods

      Study Design and Patients

      ExteNET was a multicenter, randomized, double-blind, placebo-controlled phase III trial designed to investigate extended adjuvant therapy with 1 year of neratinib or placebo after standard locoregional treatment, and adjuvant ± neoadjuvant therapy with chemotherapy and trastuzumab (n = 2840).
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • et al.
      APHINITY Steering Committee and Investigators
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      The study was initiated in April 2009 and conducted in 40 countries worldwide. The study design comprised 3 parts: Part A, the primary efficacy analysis at 2 years
      • Chan A.
      • Delaloge S.
      • Holmes F.A.
      • et al.
      ExteNET Study Group
      Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
      ; Part B, a sensitivity analysis of efficacy at 5 years
      • Martin M.
      • Holmes F.A.
      • Ejlertsen B.
      • et al.
      ExteNET Study Group
      Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.
      ; and Part C, a definitive analysis of OS when 248 deaths had occurred in the ITT population.
      Randomization was stratified by locally determined HR status, schedule of trastuzumab administration (sequential vs. concurrent administration with chemotherapy), and nodal status (0, 1-3, or 4+ positive nodes). A detailed description of the study design is provided by Chan et al.
      • Chan A.
      • Delaloge S.
      • Holmes F.A.
      • et al.
      ExteNET Study Group
      Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
      Women aged 18 years or older with stage 1 to 3c HER2+ primary breast cancer who received standard locoregional treatment and completed neoadjuvant or adjuvant chemotherapy (anthracycline and/or a taxane or non-taxane regimen) plus trastuzumab within 2 years of randomization were eligible. Clinical and radiologic assessments were required to be negative for recurrences or metastatic disease at study entry. Initially, all patients who completed neoadjuvant therapy were eligible irrespective of outcome at surgery (pCR and non-pCR patients). Recruitment was restricted in February 2010 (protocol amendment 3) to higher risk patients with stage 2 to 3c disease and completion of trastuzumab within 1 year of randomization. With this amendment, patients who completed neoadjuvant therapy were eligible only if residual invasive cancer in the breast and/or axilla was present after completing a year of adjuvant trastuzumab. Patients were excluded if they achieved a pCR in breast and/or axilla (if axillary status was known), or if they had only residual in situ disease in breast and/or axilla (if axillary status was known).
      The study protocol and subsequent amendments were approved by institutional ethics committees at participating sites. Patients provided written informed consent.

      Treatment

      Patients were randomized (1:1 ratio) to neratinib 240 mg orally once daily or matching placebo for 1 year or until disease recurrence, new breast cancer, intolerable adverse events, or consent withdrawal. Adjuvant endocrine therapy for women with HR+ disease was recommended according to local guidelines. Primary prophylaxis for diarrhea was not protocol-specified, but treatment for diarrhea with loperamide was recommended once symptoms became apparent. Neratinib dose reductions (200, 160, and 120 mg/day) or dose interruptions were allowed to manage treatment-emergent toxicities; treatment was stopped if neratinib 120 mg was not tolerated or if treatment was interrupted for more than 3 weeks.

      Endpoints

      The primary endpoint was iDFS, defined as the time from randomization to first occurrence of invasive ipsilateral tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence, or death from any cause. Secondary endpoints were disease-free survival including ductal carcinoma in situ (DFS-DCIS), distant disease-free survival (DDFS), time to distant recurrence (TDR), cumulative incidence of first occurrence of central nervous system (CNS) recurrences, OS, and safety. Definitions for efficacy endpoints are provided in Supplemental Table 1 (in the online version). The composite endpoint of CNS disease-free survival (CNS-DFS), defined as time from randomization to any CNS recurrence or death from any cause, was also evaluated on an ad hoc basis. Treatment-emergent adverse events (TEAE) were monitored until 28 days after the last dose of study drug and graded according to National Cancer Institute Common Terminology Criteria, version 3.0.

      Statistical Analysis

      Analyses of protocol-defined 2-year (cutoff date, July 2014), 5-year (cutoff date, March 2017), and OS (cutoff date, July 2019) datasets were performed. Time-to-event endpoints were tested with a 2-sided log-rank test, and hazard ratios with 95% CIs were estimated using a Cox proportional hazards model. Kaplan-Meier methods were used to estimate event-free survival rates. Cumulative incidence of CNS recurrence was analyzed by competing risks analysis and tested via Gray’s method. All analyses are descriptive, and P-values presented are without multiplicity adjustments. Safety analyses included all patients who received at least 1 dose of study treatment. SAS statistical software (version 9.2 or later) was used for all analyses.

      Results

      Patients

      Between July 2009 and October 2011, 2840 patients were randomly assigned to study treatment and constituted the ITT population (1420 per group), of whom 1631 (57%) patients had HR+ disease (neratinib, n = 816; placebo, n = 815). Among patients with HR+ tumors, 1334 (82%) patients had initiated study treatment within 1 year of prior trastuzumab – HR+/≤ 1-year population (neratinib, n = 670; placebo, n = 664) – and 297 (18%) patients had initiated study treatment 1 year or more after prior trastuzumab – HR+/> 1-year population (neratinib, n = 146; placebo, n = 151) (see Supplemental Figure 1 in the online version for Consolidated Standards of Reporting Trials [CONSORT] flowchart). Baseline characteristics in the HR+/≤ 1-year population, the focus of this article, were balanced between treatment groups and were similar to the ITT population (see Supplemental Table 2 in the online version). In the HR+/≤ 1-year population, the median interval from last dose of trastuzumab to randomization was 3.1 months (range, 0.2-12.0 months) in the neratinib group and 3.3 months (range, 0.3-12.0 months) in the placebo group, and the median duration of trastuzumab therapy was 11.4 months (range, 1.4-29.1 months) and 11.4 months (range, 1.4-24.0 months), respectively.
      Within the HR+/≤ 1-year population, 354 (27%) patients had received neoadjuvant therapy, of whom 295 patients had residual invasive disease (non-pCR) at study entry. The baseline characteristics of this patient subgroup are presented in Supplemental Table 2 (in the online version).

      Treatment Exposure

      In the HR+/≤ 1-year population, the median duration of study treatment was 11.5 months (range, 0.0-13.3 months) in the neratinib group and 11.9 months (range, 0.1-12.9 months) in the placebo group, with mean actual dose intensities of 210.4 mg/day (SD, 43.9) and 235.9 mg/day (SD, 11.0), respectively. Most (neratinib, 93%; placebo, 95%) patients were receiving concomitant endocrine therapy at baseline; the most frequently used therapies were an anti-estrogen only, which was largely tamoxifen (neratinib, 52%; placebo, 47%), or aromatase inhibitor only (44% and 48%, respectively) (see Supplemental Table 3 in the online version).

      Efficacy

      The iDFS benefits at 2 and 5 years were evaluated in both the HR+/≤ 1-year and HR+/> 1-year populations.
      In the 2-year analysis of the HR+/≤ 1-year population, iDFS rates were 95.3% (95% CI, 93.1%-96.7%) with neratinib and 90.8% (95% CI, 88.2%-92.9%) with placebo, corresponding to an absolute benefit of 4.5% with neratinib (hazard ratio, 0.49; 95% CI, 0.30-0.78) (Figure 1A). In the HR+/> 1-year population, 2-year iDFS rates were 97.4% (95% CI, 92.1%-99.2%) with neratinib and 94.4% (95% CI, 89.0%-97.1%) with placebo, corresponding to an absolute benefit of 3.0% with neratinib (hazard ratio, 0.43; 95% CI, 0.09-1.47) (see Supplemental Figure 2A in the online version).
      Figure thumbnail gr1
      Figure 1Invasive Disease-free Survival at 2 years (A) and 5 years (B), Distant Disease-free Survival at 5 years (C), and Overall Survival (D) in the HR+/≤ 1-Year Population (n = 1334)
      Abbreviations: CI = confidence interval; HR+ = hormone receptor-positive.
      In the 5-year analysis of the HR+/≤ 1-year population, iDFS rates were 90.8% (95% CI, 88.1%-93.0%) in the neratinib group and 85.7% (95% CI, 82.6%-88.3%) in the placebo group, corresponding to a durable absolute benefit of 5.1% (hazard ratio, 0.58; 95% CI, 0.41-0.82) (Figure 1B). In the HR+/> 1-year population, 5-year iDFS rates were 93.0% (95% CI, 86.5%-96.5%) in the neratinib group and 91.7% (95% CI, 85.4%-95.4%) in the placebo group, corresponding to an absolute benefit of 1.3% (hazard ratio, 0.74; 95% CI, 0.29-1.84) (see Supplemental Figure 2B in the online version).
      Evaluation of the Kaplan-Meier curves for iDFS in the HR+/≤ 1-year group revealed that they separated early (3 months) and continued to separate for the duration of follow-up (Figure 1); this was in contrast to the HR+/> 1-year group where an early benefit for the neratinib group was not maintained (see Supplemental Figure 2 in the online version).
      Most of the reduction in invasive recurrent events seen in patients who received neratinib was at distant sites. The 5-year DDFS rates were 92.4% (95% CI, 89.9%-94.4%) with neratinib and 87.7% (95% CI, 84.8%-90.1%) with placebo, corresponding with an absolute benefit of 4.7% (hazard ratio, 0.57; 95% CI, 0.39-0.83) (Figure 1C), and confirmed the results from the primary 2-year analysis (Figure 2; Supplemental Figure 3 in the online version). The cumulative incidence of first CNS recurrences at 5 years was 0.7% with neratinib and 2.1% with placebo (Table 1). At 5 years, 98.4% (95% CI, 96.8%-99.1%) of patients in the neratinib group and 95.7% (95% CI, 93.6%-97.2%) of patients in the placebo group were alive and did not report a CNS recurrence (hazard ratio for CNS-DFS, 0.41; 95% CI, 0.18-0.85) (Table 2). In the OS analysis after a median follow-up of 8.0 years (range, 0-9.8 years), 53 (7.9%) of 670 patients in the neratinib group and 68 (10.2%) of 664 patients in the placebo group of the HR+/≤ 1-year population had died. The hazard ratio of OS was 0.79 (95% CI, 0.55-1.13), and the estimated 8-year OS rates were 91.5% (95% CI, 88.9%-93.5%) in the neratinib group and 89.4% (95% CI, 86.6%-91.6%) in the placebo group of the HR+/≤ 1-year population, giving an absolute between-group difference of 2.1% (Figure 1D).
      Figure thumbnail gr2
      Figure 2Two-Year, 5-Year, and Overall Survival Analyses in the HR+/≤ 1-Year Population (n = 1334)
      Note: Definitions for efficacy endpoints provided in (in the Online Version).Abbreviations: CI = confidence interval; disease-free survival-DCIS = disease-free survival including ductal carcinoma in situ; HR+ = hormone receptor-positive.
      Table 1Cumulative Incidence of CNS Recurrences as First Site of Metastases at 5 Years in the HR+/≤ 1-year Population (n = 1334) and Subgroups
      Population or SubgroupCNS Events (No. Patients)Cumulative Incidence of CNS Recurrences at 5 Years, % (95% CI)
      NeratinibPlaceboNeratinibPlacebo
      HR+/≤ 1-year population4 (670)12 (664)0.7 (0.2–1.7)2.1 (1.1–3.5)
      Nodal status
       Positive4 (540)10 (539)0.8 (0.3-2.0)2.2 (1.1-3.8)
       Negative0 (130)2 (125)0 (NE)1.9 (0.4-6.0)
      Prior trastuzumab regimen
       Concurrent2 (411)8 (415)0.6 (0.1-1.9)2.3 (1.1-4.3)
       Sequential2 (259)4 (249)0.9 (0.2-3.0)1.8 (0.6-4.3)
      Adjuvant or neoadjuvant therapy
       Adjuvant3 (508)6 (472)0.7 (0.2-2.0)1.5 (0.6-3.0)
       Neoadjuvant1 (162)6 (192)0.7 (0.1-3.3)3.7 (1.5-7.4)
      pCR status
      Among the 354 patients who had received neoadjuvant therapy, 295 patients had no pCR, 38 patients achieved a pCR, and 21 patients had no outcome reported.
       No1 (131)5 (164)0.8 (0.1-4.0)3.6 (1.3-7.8)
       Yes0 (17)1 (21)0 (NE)5.0 (0.3-21.2)
      Abbreviations: CI = confidence interval; CNS = central nervous system; HR+ = hormone receptor-positive; NE = not estimable; pCR = pathologic complete response.
      a Among the 354 patients who had received neoadjuvant therapy, 295 patients had no pCR, 38 patients achieved a pCR, and 21 patients had no outcome reported.
      Table 2CNS Disease-free Survival at 5 Years in the HR+/≤ 1-year Population (n = 1334) and Subgroups
      Population or SubgroupEvents (No. Patients)Kaplan-Meier Estimate at 5 Years, % (95% CI)Hazard Ratio (95% CI)
      NeratinibPlaceboNeratinibPlacebo
      HR+/≤ 1-year population9 (670)23 (664)98.4 (96.8-99.1)95.7 (93.6-97.2)0.41 (0.18-0.85)
      Nodal status
       Positive8 (540)20 (539)98.2 (96.4-99.1)95.4 (92.9-97.0)0.41 (0.17-0.89)
       Negative1 (130)3 (125)99.1 (93.9-99.9)97.2 (91.4-99.1)0.37 (0.02-2.87)
      Prior trastuzumab regimen
       Concurrent6 (411)16 (415)98.1 (95.8-99.2)95.3 (92.3-97.1)0.40 (0.15-0.98)
       Sequential3 (259)7 (249)98.7 (95.9-99.6)96.5 (92.8-98.4)0.42 (0.09-1.50)
      Adjuvant or neoadjuvant therapy
       Adjuvant7 (508)10 (472)98.2 (96.3-99.2)97.5 (95.3-98.6)0.70 (0.25-1.82)
       Neoadjuvant2 (162)13 (192)98.7 (94.8-99.7)91.2 (85.1-94.8)0.18 (0.03-0.63)
      pCR status
      Among the 354 patients who had received neoadjuvant therapy, 295 patients had no pCR, 38 patients achieved a pCR, and 21 patients had no outcome reported.
       No2 (131)10 (164)98.4 (93.6-99.6)92.0 (85.6-95.7)0.24 (0.04-0.92)
       Yes0 (17)3 (21)100.0 (100.0-100.0)81.9 (53.1-93.9)0 (NE-1.08)
      Abbreviations: CI = confidence interval; CNS = central nervous system; HR+ = hormone receptor-positive; NE = not estimable; pCR = pathologic complete response.
      a Among the 354 patients who had received neoadjuvant therapy, 295 patients had no pCR, 38 patients achieved a pCR, and 21 patients had no outcome reported.

      Subgroup Analyses in the HR+/≤ 1-year Population Including Subgroups of Clinical Interest

      A subgroup analysis of the HR+/≤ 1-year population according to randomization stratification factors showed that iDFS, DDFS, and CNS endpoints at 5 years for neratinib compared with placebo were consistent when analyzed by nodal status and schedule of administration of prior trastuzumab with chemotherapy, and that OS showed a small but consistent numerical benefit with neratinib across patient subgroups (Figure 3; Tables 1 and 2).
      Figure thumbnail gr3
      Figure 3Subgroup Analyses of Invasive Disease-free Survival and Disease-free Survival at 5 Years, and Overall Survival according to Randomization Stratification Factors in the HR+/≤ 1-Year Population (n = 1334)
      Abbreviations: CI = confidence interval; HR+ = hormone receptor-positive.
      Of the 354 (27%) patients in the HR+/≤ 1-year population who had received neoadjuvant therapy, 295 (83%) patients had residual invasive disease (non-pCR), 38 (11%) patients achieved a pCR, and 21 (6%) patients had no outcome reported. Analyses of these subgroups of clinical interest are presented in Figure 4, and their baseline characteristics are shown in Supplemental Table 2 (in the online version). In patients with no pCR (n = 295), 5-year iDFS rates were 85.0% (95% CI 77.0-90.4) in the neratinib group and 77.6% (95% CI 69.8-83.6) in the placebo group, corresponding to an absolute benefit of 7.4% (hazard ratio 0.60; 95% CI 0.33‒1.07); 5-year DDFS rates were 86.8% (95% CI 79.0-91.9) in the neratinib group and 79.8% (95% CI 72.1-85.6) in the placebo group, corresponding to a 7.0% absolute benefit (hazard ratio 0.61; 95% CI 0.32‒1.11); and 8-year OS rates were 91.3% (95% CI 84.4-95.2) in the neratinib group and 82.2% (95% CI 75.1-87.4) in the placebo group, corresponding to a 9.1% absolute benefit (hazard ratio 0.47; 95% CI 0.23-0.92) (Figure 4). Kaplan-Meier curves for iDFS, DDFS, and OS in this subgroup are shown in Figure 5. In patients with no evidence of invasive residual disease (pCR) after neoadjuvant therapy (n = 38), 5-year iDFS rates were 84.0% (95% CI 48.7-95.9) in the neratinib group and 74.2% (95% CI 48.4-88.5) in the placebo group, corresponding to an absolute benefit of 9.8% (hazard ratio 0.44; 95% CI 0.06‒1.89), and 8-year OS rates were 93.3% (95% CI 61.3-99.0) in the neratinib group and 73.7% (95% CI 47.4-88.2) in the placebo group, corresponding to an absolute benefit of 19.6% (hazard ratio 0.40; 95% CI 0.06-1.88) (Figure 4). In both subgroups, the cumulative incidence of CNS recurrences and CNS-DFS at 5 years were improved with neratinib versus placebo (Tables 1 and 2).
      Figure thumbnail gr4
      Figure 4Subgroup Analyses of Invasive Disease-free and Distant Disease-free Survival at 5 Years, and Overall Survival in Subgroups of Clinical Interest in the HR+/≤ 1-Year Population (n = 1334)
      Note: Among 354 patients who had received neoadjuvant therapy, 295 patients had no pCR, 38 patients achieved a pCR, and 21 patients had no outcome reported. aDistant disease-free survival results for the pCR (Yes) subgroup are not displayed because there were no events in the neratinib group, and it was therefore not possible to estimate the confidence boundary for the hazard ratio.Abbreviations: CI = confidence interval; HR+ = hormone receptor-positive; NE, not estimable; pCR = pathologic complete response.
      Figure thumbnail gr5
      Figure 5Invasive Disease-free Survival (A) and Distant Disease-free Survival at 5 years (B), and Overall Survival (C) in the HR+/≤ 1-Year Population With No pCR after Neoadjuvant Therapy (n = 295)
      Abbreviations: CI = confidence interval; HR+ = hormone receptor-positive.

      Safety

      A total of 1319 patients in the HR+/≤ 1-year population were included in the safety analysis (neratinib, n = 662; placebo, n = 657). The most common TEAE with neratinib in the HR+/≤ 1-year population was diarrhea (no mandatory anti-diarrheal prophylaxis given); grade 1, 2, and 3 events were reported in 23%, 32%, and 39% of patients in the neratinib group, respectively, and in 26%, 7%, and 1% of patients in the placebo group, respectively; no grade 4 diarrhea was reported (see Supplemental Table 4 in the online version). In cases of grade 3 diarrhea, most episodes with neratinib occurred in the first month of treatment, with a median time to onset of 8 days versus 240 days in the placebo group. The median cumulative duration of grade 3 diarrhea, defined as the sum of the durations of all grade 3 episodes, was 5 days with neratinib versus 1 day with placebo.
      All other grade 3 adverse events in the neratinib group were each reported in 4% of patients or less. Grade 4 or greater TEAE occurred in 8 (1%) patients in the neratinib group (neutropenia, n = 1; elevated aminotransferases, n = 1; anemia, n = 1; rectal cancer, n = 1; increased blood creatinine and hypokalemia, n = 1; increased blood creatine, n = 1; dehydration, n = 1; glioma, n = 1), and 2 (< 1%) patients in the placebo group (vertigo, n = 1; septic shock, n = 1). One fatal (grade 5) TEAE occurred with neratinib (acute myeloid leukemia). There was no evidence of hematopoietic, pulmonary, or cardiac toxicity with neratinib, and no evidence of increased risk for second malignancies. TEAEs led to dose reductions, dose interruptions, and hospitalization in 203 (31%), 280 (42%), and 41 (6%) patients in the neratinib group, respectively, and in 13 (2%), 75 (11%), and 35 (5%) patients in the placebo group (see Supplemental Table 5 in the online version).

      Discussion

      Approximately 25% of patients with HER2+ breast cancer who receive trastuzumab-based adjuvant therapy will experience disease recurrences within 8 to 10 years of completing therapy,
      • Goldhirsch A.
      • Gelber R.D.
      • Piccart-Gebhart M.J.
      • et al.
      Herceptin Adjuvant (HERA) Trial Study Team
      2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial.
      ,
      • Perez E.A.
      • Romond E.H.
      • Suman V.J.
      • et al.
      Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831.
      ,
      • Slamon D.J.
      • Eiermann W.
      • Robert N.J.
      • et al.
      Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab in HER2-positive early breast cancer. 2015 San Antonio Breast Cancer Symposium.
      highlighting an unmet need for new treatment options beyond trastuzumab-based adjuvant treatment alone. The ExteNET trial demonstrated that neratinib given for 1 year following trastuzumab-based therapy significantly improved iDFS in patients with HER2+ breast cancer, with the greatest efficacy seen in patients who initiated treatment within 1 year of prior trastuzumab and in those with HR+ disease. After 5 years of follow-up, the absolute iDFS benefit with neratinib compared with placebo was 5.1% in the HR+/≤ 1-year population and 1.3% in the HR+/> 1-year population, suggesting a more pronounced and durable response among patients who initiated neratinib shortly after completing trastuzumab-based therapy, consistent with the current use of neratinib in clinical practice. In the HR+/≤ 1-year population, an important clinical endpoint achieved was the 4.7% absolute DDFS benefit. The OS analysis in the HR+/≤ 1-year population confirmed the value of neratinib.
      Patients who do not attain a pCR after neoadjuvant treatment experience significantly worse outcomes.
      • Broglio K.R.
      • Quintana M.
      • Foster M.
      • et al.
      Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes: a meta-analysis.
      Although trastuzumab emtansine is now used in clinical practice in patients with residual invasive disease after neoadjuvant therapy based on findings from the KATHERINE trial,
      • von Minckwitz G.
      • Huang C.S.
      • Mano M.S.
      • et al.
      KATHERINE Investigators
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      the study further reinforced the poor prognosis of this patient population despite a hazard ratio for iDFS of 0.50.
      • von Minckwitz G.
      • Huang C.S.
      • Mano M.S.
      • et al.
      KATHERINE Investigators
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      In an exploratory subset analysis, we were able to show that patients with residual invasive disease after neoadjuvant therapy showed clinically meaningful improvements with neratinib, with absolute benefits at 5-year iDFS of 7.4% and 8-year OS of 9.1%. Clinically meaningful improvements were also evident with neratinib in those attaining a pCR (absolute benefits at 5-year iDFS of 9.8% and 8-year OS of 19.6%). The prognosis of patients who are HER2+/HR+ and who achieve a pCR has been unclear, with several studies suggesting that clinical outcomes in these patients may not be appreciably better than patients without a pCR.
      • Cortazar P.
      • Zhang L.
      • Untch M.
      • et al.
      Pathological complete response and long-term clinical benefit in breast cancer: the CTNEOBC pooled analysis.
      • Huober J.
      • Holmes E.
      • Baselga J.
      • et al.
      Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer.
      • Loibl S.
      • Untch M.
      • Buyse M.
      • et al.
      Pathologic complete response (pCR) and prognosis following neoadjuvant chemotherapy plus anti-HER2 therapy of HER2-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10–14; San Antonio, TX. Philadelphia (PA): AACR.
      Similarly in ExteNET, 5-year iDFS rates in patients with or without a pCR were similar (ie, 84% and 85% in the neratinib arm, respectively, and 74% and 78% in the placebo arm, respectively). This highlights an unmet need in patients with HER2+/HR+ breast cancer who receive neoadjuvant therapy, and evaluation of additional treatment strategies in this patient group is needed.
      Between 35% and 55% of first distant recurrences after HER2-directed adjuvant therapies occur in the CNS,
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • et al.
      APHINITY Steering Committee and Investigators
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      • Piccart M.
      • Procter M.
      • Fumagalli D.
      • et al.
      GS1–04. Interim overall survival analysis of APHINITY (BIG 4-11): a randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR.
      • von Minckwitz G.
      • Huang C.S.
      • Mano M.S.
      • et al.
      KATHERINE Investigators
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      and our results suggest that neratinib may be effective in controlling CNS events in the HR+/≤ 1-year population as well as in patients who received neratinib following neoadjuvant therapy. Benefits of neratinib in the prevention
      • Awada A.
      • Colomer R.
      • Inoue K.
      • et al.
      Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: the NEfERT-T randomized clinical trial.
      ,
      • Saura C.
      • Oliveira M.
      • Feng Y.-H.
      • et al.
      NALA Investigators
      Neratinib + capecitabine vs lapatinib + capecitabine in HER2+ metastatic breast cancer previously treated with two or more HER2-directed regimens: phase III NALA trial.
      and treatment
      • Freedman R.A.
      • Gelman R.S.
      • Anders C.K.
      • et al.
      Translational Breast Cancer Research Consortium
      TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases.
      of CNS metastases in HER2+ breast cancer have been reported in other phase II and III studies, supporting a recommendation in current treatment guidelines for the use of neratinib-based therapy in brain metastases.
      National Comprehensive Cancer Network
      (NCCN) Clinical Practice Guidelines in Oncology. Central nervous system cancer, version 3, 2020.
      In the randomized NEfERT-T trial of patients with metastatic HER2+ breast cancer treated in the first-line setting, the incidence of symptomatic or progressive CNS events was significantly reduced with neratinib plus paclitaxel versus trastuzumab plus paclitaxel (P = .002).
      • Awada A.
      • Colomer R.
      • Inoue K.
      • et al.
      Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: the NEfERT-T randomized clinical trial.
      Further support for the role of neratinib in CNS disease was shown in the phase III NALA trial.
      • Saura C.
      • Oliveira M.
      • Feng Y.-H.
      • et al.
      NALA Investigators
      Neratinib + capecitabine vs lapatinib + capecitabine in HER2+ metastatic breast cancer previously treated with two or more HER2-directed regimens: phase III NALA trial.
      In this trial of 621 patients, neratinib plus capecitabine significantly reduced the cumulative incidence of therapeutic interventions for CNS disease compared with lapatinib plus capecitabine after 2 or more HER2-directed therapies for metastatic disease (P = .043).
      • Saura C.
      • Oliveira M.
      • Feng Y.-H.
      • et al.
      NALA Investigators
      Neratinib + capecitabine vs lapatinib + capecitabine in HER2+ metastatic breast cancer previously treated with two or more HER2-directed regimens: phase III NALA trial.
      In the HR+/≤ 1-year population, adverse events associated with neratinib were generally transient and manageable with dose modifications and/or conventional treatment, as has been reported for the ITT population. Diarrhea, a known class effect of tyrosine kinase inhibitors,
      • Rugo H.S.
      • Di Palma J.A.
      • Tripathy D.
      • et al.
      The characterization, management, and future considerations for ErbB-family TKI-associated diarrhea.
      was common with neratinib in the absence of proactive antidiarrheal prophylaxis (grade 3, 39%), although most grade 3 events occurred in the first month of treatment (median time to onset, 8 days) and had a short cumulative duration (median, 5 days). Antidiarrheal prophylaxis or neratinib dose escalation (escalating from 120 mg to 240 mg over 2 weeks) has since been shown to reduce the incidence, severity, and duration of neratinib-associated grade ≥ 3 diarrhea in the phase II CONTROL study as compared with ExteNET.
      • Barcenas C.H.
      • Hurvitz S.A.
      • Di Palma J.A.
      • et al.
      CONTROL Study Investigators
      Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: diarrheal toxicity in the CONTROL trial.
      The greatest benefits were seen in the dose-escalation cohort of CONTROL, where the rate of grade 3 diarrhea was 15% (vs. 40% in ExteNET), the median cumulative duration of grade 3 diarrhea was 2 days (vs. 5 days in ExteNET), and the rate of discontinuation owing to diarrhea was 3% (vs. 17% in ExteNET).
      • Barcenas C.H.
      • Hurvitz S.A.
      • Di Palma J.A.
      • et al.
      CONTROL Study Investigators
      Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: diarrheal toxicity in the CONTROL trial.
      Tolerability is also improved with preemptive prophylaxis or dose escalation,
      • Barcenas C.H.
      • Hurvitz S.A.
      • Di Palma J.A.
      • et al.
      CONTROL Study Investigators
      Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: diarrheal toxicity in the CONTROL trial.
      allowing many patients to complete the full year of neratinib treatment.
      Current clinical practice in some countries may involve the use of 2 additional HER2-directed agents (pertuzumab
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • et al.
      APHINITY Steering Committee and Investigators
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      and trastuzumab emtansine
      • von Minckwitz G.
      • Huang C.S.
      • Mano M.S.
      • et al.
      KATHERINE Investigators
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      ) prior to receiving extended adjuvant therapy with neratinib, which differs from the patient population in ExteNET. Although the precise implications of changing clinical practice on the findings from ExteNET are not known, several studies have demonstrated the efficacy and safety of neratinib-based regimens after pertuzumab and/or trastuzumab emtansine
      • Saura C.
      • Oliveira M.
      • Feng Y.-H.
      • et al.
      NALA Investigators
      Neratinib + capecitabine vs lapatinib + capecitabine in HER2+ metastatic breast cancer previously treated with two or more HER2-directed regimens: phase III NALA trial.
      ,
      • Freedman R.A.
      • Gelman R.S.
      • Anders C.K.
      • et al.
      Translational Breast Cancer Research Consortium
      TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases.
      ,
      • Barcenas C.H.
      • Hurvitz S.A.
      • Di Palma J.A.
      • et al.
      CONTROL Study Investigators
      Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: diarrheal toxicity in the CONTROL trial.
      or neratinib in combination with trastuzumab emtansine.
      • Abraham J.
      • Montero A.J.
      • Jankowitz R.C.
      • et al.
      Safety and efficacy of T-DM1 plus neratinib in patients with metastatic HER2-positive breast cancer: NSABP Foundation Trial FB-10.
      Moreover, owing to the mechanism of action of neratinib, which differs from the above therapies — namely inhibition of the intracellular component of the HER2 pathway — neratinib represents a potentially non-cross–resistant therapy. Furthermore, the demonstrated synergy of concurrent anti-estrogen receptor therapy and HER2 inhibition is an additional benefit.
      • Smyth L.M.
      • Piha-Paul S.A.
      • Won H.H.
      • et al.
      Efficacy and determinants of response to HER kinase inhibition in HER2-mutant metastatic breast cancer.
      ,
      • Sudhan D.R.
      • Schwarz L.J.
      • Guerrero-Zotano A.
      • et al.
      Extended adjuvant therapy with neratinib plus fulvestrant blocks ER/HER2 crosstalk and maintains complete responses of ER+/HER2+ breast cancers: implications to the ExteNET trial.
      These factors suggest that extended adjuvant use of neratinib remains an appropriate agent for managing patients with HER2+/HR+ eBC.
      Although subgroup analyses based on HR status and the interval between completion of prior trastuzumab and randomization were defined by 2 prespecified factors and were the basis for the European Medicines Agency approval of neratinib, the analyses described herein are exploratory. We provided conventional 95% CIs to help quantify the variability associated with effect estimates. Some CIs for the hazard ratios crossed 1 and some did not. However, the study was not powered for subgroup findings, and no multiplicity adjustments were performed. The patient numbers in some subgroups, notably those with a pCR after neoadjuvant therapy, were small. The CNS-DFS endpoint was not pre-specified, and disease recurrences beyond the first recurrence might not have been collected consistently during the study. These limitations should be considered when evaluating our findings. The present analyses focus on the HR+ population from ExteNET; although greater benefits with neratinib were also documented in the HR population when treatment was initiated within 6 months of prior trastuzumab rather than later,
      • Ejlertsen B.
      • Chan A.
      • Gnant M.
      • et al.
      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. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5–9; San Antonio, TX.
      the conclusions described here for the HR+ group cannot be extended to the HR population.

      Conclusion

      Extended adjuvant treatment with neratinib after trastuzumab-based therapy significantly reduces the risk of invasive recurrence and prolongs DDFS. Our descriptive analyses demonstrate consistent benefit in patients with HR+ disease who initiate neratinib within 1 year of trastuzumab-based therapy. In particular, there was consistent numerical benefit seen in iDFS, OS, and CNS events in patients with residual disease following neoadjuvant treatment, who would be considered at heightened risk of disease recurrence. The rate and severity of diarrhea seen in the HR+ population was identical to that of the entire ExteNET population, although recent data show that the tolerability of neratinib can be improved by various treatment modalities, including anti-diarrheal prophylaxis or neratinib dose escalation.

      Clinical Practice Points

      • Approximately 25% of patients with HER2+ breast cancer who receive trastuzumab-based adjuvant therapy experience disease recurrences within 8 to 10 years of completing therapy, highlighting a need for improved treatment options in the extended adjuvant setting.
      • Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is the first HER2-targeted agent approved for extended adjuvant therapy in patients with HER2+ eBC after trastuzumab-based therapy based on the phase III ExteNET trial.
      • In the ExteNET trial, greater and more durable efficacy was observed in the subgroup with HR+ disease who initiated treatment within 1 year of completing trastuzumab, referred to as the HR+/≤ 1-year population.
      • In analyses of the HR+/≤ 1-year population from ExteNET, the absolute iDFS benefit of neratinib versus placebo at 5 years was 5.1%, and the absolute OS benefit at 8 years was 2.1%.
      • Greater benefits were apparent in subgroups of clinical interest, including patients with residual disease after neoadjuvant therapy (absolute benefits: 5-year iDFS, 7.4%; 8-year OS, 9.1%).
      • Notably, 5-year iDFS rates were similar in patients with and without residual disease (neratinib, 85.0% vs. 84.0%; placebo, 77.6% vs. 74.2%, respectively), supporting continued HER2 suppression after neoadjuvant therapy and the lesser prognostic value of no residual disease in HR+ breast cancer.
      • In the HR+/≤ 1-year population and patient subgroups of clinical interest, there were fewer CNS events with neratinib versus placebo.
      • Neratinib significantly improves iDFS in the HR+/≤ 1-year population. Descriptive analyses suggest benefit with neratinib in patients at higher risk, including patients with residual disease following neoadjuvant treatment.

      Disclosure

      B. Moy reports grants from Puma Biotechnology Inc during the conduct of the study, and personal fees from Motus outside the submitted work. B. Ejlertsen reports grants from NanoString , Roche , Novartis , and Oncology-Venture , and non-financial support from MSD outside the submitted work. F. A. Holmes reports personal fees from Puma Biotechnology Inc during the conduct of the study. Stephen Chia reports grants from AstraZeneca , Genentech , and Roche , grants and personal fees from Genomic Health and Novartis , and personal fees from Pfizer outside the submitted work. H. Iwata reports grants and personal fees from AstraZeneca , Chugai Pharma , Daiichi-Sankyo , Eisai , Kyowa Hakko Kirin , Lilly Japan, Novartis , and Pfizer , and grants from Bayer , GlaxoSmithKline , MSD , and Nihonkayaku outside the submitted work. M. Gnant reports personal fees/travel support from Amgen, AstraZeneca, Daiichi-Sankyo, Eli Lilly, LifeBrain, Nanostring, Novartis, and TLC Biopharmaceuticals all outside the submitted work; an immediate family member is employed by Sandoz. S. Loibl reports grants and non-financial support from Immunomedics during the conduct of the study, grants and other from Abbvie , Amgen , AstraZeneca , Celgene , Daiichi-Sankyo , Novartis , Pfizer , and Roche , other from BMS, Eirgenix, Lilly, MSD, PriME/Medscape, Puma Biotechnology Inc, Samsung, and Seattle Genetics, and personal fees from Chugai, and grants from Teva and Vifor from outside the submitted work. In addition, S. Loibl has a patent (EP14153692.0) pending. C. H. Barrios reports grants from Abbvie , Amgen , Astellas , AstraZeneca , BMS , Celgene , Covance , Lilly , Medivation , MSD , Merck Serono , Novartis , Pfizer , PharmaMar , and Roche , and personal fees from AstraZeneca, Bayer, BMS, Beringer, Eisai, GSK, Lilly, MSD, Novartis, Pfizer, and Roche outside the submitted work. S. Smichkoska reports personal fees from Pfizer and Roche outside the submitted work. I. A. Mayer reports personal fees from Puma Biotechnology Inc during the conduct of the study, grants and personal fees from Genentech , Novartis , and Pfizer , and personal fees from Abbvie, AstraZeneca, Eisai, GSK, Immunomedics, Lilly, Macrogenics, and Seattle Genetics, outside the submitted work. K. Inoue reports a grant from Puma Biotechnology Inc during the conduct of the study, and grants from Chugai Pharma , Lilly , MSD , Novartis , and Pfizer outside the submitted work. R. Hui reports personal fees from AstraZeneca, BMS, Eli Lilly, MSD, Novartis, and Roche outside the submitted work. N. Denduluri reports other from Genentech, Immunomedics, Merck, Novartis, and Seattle Genetics, and personal fees and other from Daiichi outside the submitted work. H. S. Rugo reports personal fees from Puma Biotechnology Inc during the conduct of the study, and grants and personal fees from Daiichi , Macrogenics , Merck , and Pfizer , grants from Eisai , Genentech , Immunomedics , Lilly , Novartis , OBI , Odonate , Seattle Genetics , and Sermonix , and personal fees from AstraZeneca and Samsung outside the submitted work. S. R. D. Johnston reports grants and personal fees from Puma Biotechnology Inc during the conduct of the study, grants and personal fees from AstraZeneca , Eisai , Eli Lilly , Novartis , Pfizer , and Roche /Genentech outside the submitted work. R. Bryce, B. Zhang, F. Xu, and A. Wong are employees of Puma Biotechnology Inc, and own stock in Puma Biotechnology Inc. Miguel Martin reports grants and personal fees from Novartis and Roche /Genentech, and personal fees from Amgen, AstraZeneca, Lilly, Pfizer, Pharmamar, and Puma Biotechnology Inc. outside the submitted work. The remaining authors have stated that they have no conflicts of interest.

      Acknowledgments

      The authors thank the Independent Data Monitoring Committee, study investigators, research staff, clinical research organizations, and other vendors, as well as the patients who participated in the ExteNET trial. The authors would like to acknowledge statistical programming support provided by Janine Lu, Yan Yan, and Dan DiPrimeo ( Puma Biotechnology ). The authors also thank Deepa Lalla and Bethann Hromatka (Puma Biotechnology) for review and revision of the manuscript, and Lee Miller and Harriet Lamb (Miller Medical Communications Ltd) for writing/editorial support. This work was supported by Puma Biotechnology Inc , Los Angeles, CA. The funders of the study designed the trial, were responsible for data collection, data integrity and analyses, and interpretation of the data with oversight from the authors. The manuscript was written with input from authors, and with review and input from the sponsor. The lead and senior authors were responsible for the final decision regarding manuscript contents and submission. Puma Biotechnology Inc funded the provision of editorial support provided by Miller Medical Communications .

      Supplemental Data

      Figure thumbnail fx1
      Supplemental Figure 1Consolidated Standards of Reporting Trials (CONSORT) Flowchart
      Note: Shaded boxes highlight the HR+/≤ 1-Year Population.Abbreviations: HR = hormone receptor-negative; HR+ = hormone receptor-positive.
      Figure thumbnail fx2
      Supplemental Figure 2Invasive Disease-free Survival at 2 years (Primary Analysis) (A) and 5 years (B) in the HR+/> 1-Year Population (n = 297)
      Abbreviations: CI = confidence interval; HR+ = hormone receptor-positive.
      Figure thumbnail fx3
      Supplemental Figure 3Distant Disease-free Survival at 2 years (Primary Analysis) in the HR+/≤ 1-Year Population (n = 1334)
      Abbreviations: CI = confidence interval; HR+ = hormone receptor-positive.
      Supplemental Table 1Efficacy Endpoint Definitions
      EndpointDefinition
      Primary
       Invasive disease-free survivalTime from randomization to the first occurrence of the following disease-free survival events: (a) Invasive ipsilateral breast tumor recurrence (b) Invasive contralateral breast cancer (c) Local/regional invasive recurrence (d) Distant recurrence (e) Death from any cause. Any patient for whom an event had not been observed by the data cutoff was censored at the date of their last physical examination.
      Secondary
       Disease-free survival including ductal carcinoma in situTime from randomization to the first occurrence of a disease-free survival event or ductal carcinoma in situ event. Disease-free survival including ductal carcinoma in situ events include ductal carcinoma in situ and all disease-free survival events. For subjects who have a ductal carcinoma in situ diagnosis followed by a disease-free survival event, the date of event for disease-free survival including ductal carcinoma in situ is the date of ductal carcinoma in situ. Any patient for whom an event had not been observed by the data cutoff was censored at the date of their last physical examination.
       Time to distant recurrenceTime between randomization and the date of the first distant recurrence or death from breast cancer. Time to distant recurrence events include distant recurrence and death from breast cancer. Any patient for whom an event had not been observed by the cutoff date was censored at the date of their last physical examination.
       Distant disease-free survivalTime from randomization to the first occurrence of distant recurrence or death from any cause. Distant disease-free survival events include distant recurrence and death from any cause. Any patient for whom an event had not been observed by the data cutoff was censored at the date of their last physical examination.
       Central nervous system recurrenceCumulative incidence of central nervous system recurrences (either isolated central nervous system metastases, or diagnosed concurrently with other sites of metastatic disease) defined as time from randomization to central nervous system recurrence as first distant recurrence. Any patient who was alive and for whom distant recurrence had not been observed by the data cutoff was censored at the date of their last physical examination.
       Overall survivalOverall survival is defined as the time from the date of randomization until the date of death, censored at the last date known alive.
      Supplemental Table 2Baseline Characteristics in the Intent-to-treat Population and in the HR+/≤ 1-year Population
      Study PopulationIntention-to-treat, n (%)HR+/≤ 1 Year From Last Dose of Trastuzumab to Randomization, n (%)
      (n = 2840)Total (n = 1334)No pCR After Neoadjuvant Therapy (n = 295)With pCR After Neoadjuvant Therapy (n = 38)
      Neratinib (n = 1420)Placebo (n = 1420)Neratinib (n = 670)Placebo (n = 664)Neratinib (n = 131)Placebo (n = 164)Neratinib (n = 17)Placebo (n = 21)
      Median age, y (range)52 (25-83)52 (23-82)51 (25-83)51 (23-78)49 (25-76)49 (26-76)48 (35‒70)47 (33‒68)
      Gender
       Female1420 (100)1420 (100)670 (100)664 (100)131 (100)164 (100)17 (100)21 (100)
      Menopausal status at diagnosis
       Premenopausal663 (47)664 (47)350 (52)342 (52)75 (57)99 (60)10 (59)12 (57)
       Postmenopausal757 (53)756 (53)320 (48)322 (48)56 (43)65 (40)7 (41)9 (43)
      Region
       North America519 (37)477 (34)237 (35)205 (31)40 (31)54 (33)11 (65)8 (38)
       Western Europe, Australia, and South Africa487 (34)532 (38)236 (35)264 (40)49 (37)64 (39)6 (35)9 (43)
       Asia Pacific, Eastern Europe, and South America414 (29)411 (29)197 (29)195 (29)42 (32)46 (28)04 (19)
      Nodal status
      Stratification factor.
      The number of positive nodes was at the time of initial diagnosis (for patients who received adjuvant therapy) or surgery (for those who received neoadjuvant therapy). Patients with residual invasive disease in the breast, but node-negative disease or unknown nodal status in the axilla, after neoadjuvant therapy were included under 1-3 positive nodes.
       Negative335 (24)336 (24)130 (19)125 (19)15 (12)20 (12)12 (71)10 (48)
       1-3 positive nodes664 (47)664 (47)339 (51)334 (50)85 (65)96 (59)5 (29)9 (43)
       ≥4 nodes421 (30)420 (30)201 (30)205 (31)31 (24)48 (29)02 (10)
      Hormone receptor status
      Stratification factor.
      HR+ defined as estrogen receptor-positive and/or progesterone receptor-positive, and HR− as estrogen receptor-negative and progesterone receptor-negative.
       Positive816 (57)815 (57)670 (100)664 (100)131 (100)164 (100)17 (100)21 (100)
       Negative604 (43)605 (43)
      Prior trastuzumab regimen
      Stratification factor.
       Concurrent884 (62)886 (62)411 (61)415 (63)90 (69)111 (68)14 (82)16 (76)
       Sequential536 (38)534 (38)259 (39)249 (38)41 (31)53 (32)3 (18)5 (24)
      T stage
      For patients who received adjuvant therapy, the pathologic tumor stage at initial diagnosis was recorded. For patients who received neoadjuvant therapy, the pathologic tumor stage at initial diagnosis was recorded if known; otherwise, T-stage was recorded as “unknown”.
       T1440 (31)459 (32)218 (33)209 (31)2 (2)8 (5)1 (6)1 (5)
       T2585 (41)555 (39)270 (40)250 (38)20 (15)17 (10)2 (12)2 (10)
       ≥T3144 (10)117 (8)61 (9)65 (10)15 (12)18 (11)1 (6)6 (29)
       Unknown or missing251 (18)289 (20)121 (18)140 (21)94 (72)121 (74)13 (77)12 (57)
      Previous (neo)adjuvant therapy
       Trastuzumab1420 (100)1420 (100)670 (100)664 (100)131 (100)164 (100)17 (100)21 (100)
       Anthracycline only136 (10)135 (10)67 (10)58 (9)6 (5)4 (2)
       Anthracycline + taxane962 (68)965 (68)435 (65)445 (67)93 (71)129 (79)11 (65)16 (76)
       Taxane only318 (22)316 (22)167 (25)159 (24)32 (24)31 (19)6 (35)5 (24)
       Neither anthracycline nor taxane4 (<1)4 (<1)1 (<1)2 (<1)
      Median duration of adjuvant trastuzumab therapy, mos (range)11.5 (0.7-56.9)11.4 (1.4-38.0)11.4 (1.4-29.1)11.4 (1.4-24.0)8.7 (1.5-23.2)8.9 (3.5-24.0)7.2 (5.3-13.0)8.7 (3.0-22.4)
      Median time from last trastuzumab dose to randomization, mos (range)4.4 (0.2-30.9)4.7 (0.3-40.6)3.1 (0.2-12.0)3.3 (0.3-12.0)3.0 (0.4-12.0)2.8 (0.3-11.9)2.7 (0.6-11.8)4.8 (0.7-11.8)
      Time from last trastuzumab dose to randomization
       ≤1 y1152 (81)1145 (81)670 (100)664 (100)131 (100)164 (100)17 (100)21 (100)
       >1 y268 (19)275 (19)
      Prior neoadjuvant therapy342 (24)379 (27)162 (24)192 (29)131 (100)164 (100)17 (100)21 (100)
       pCR61 (4)65 (5)17 (3)21 (3)17 (100)21 (100)
       No pCR258 (18)298 (21)131 (20)164 (25)131 (100)164 (100)
       Unknown23 (2)16 (1)14 (2)7 (1)
      Note: percentages may not add to 100 owing to rounding.
      Abbreviation: HR+ = hormone receptor-positive; HR = hormone receptor-negative; pCR = pathologic complete response.
      a Stratification factor.
      b The number of positive nodes was at the time of initial diagnosis (for patients who received adjuvant therapy) or surgery (for those who received neoadjuvant therapy). Patients with residual invasive disease in the breast, but node-negative disease or unknown nodal status in the axilla, after neoadjuvant therapy were included under 1-3 positive nodes.
      c HR+ defined as estrogen receptor-positive and/or progesterone receptor-positive, and HR as estrogen receptor-negative and progesterone receptor-negative.
      d For patients who received adjuvant therapy, the pathologic tumor stage at initial diagnosis was recorded. For patients who received neoadjuvant therapy, the pathologic tumor stage at initial diagnosis was recorded if known; otherwise, T-stage was recorded as “unknown”.
      Supplemental Table 3Concomitant Endocrine and GnRH Analogue Therapy in the HR+/≤ 1-year Population (n = 1334)
      Neratinib (n = 670)Placebo (n = 664)
      Receiving concomitant endocrine therapy622 (93)629 (95)
       Anti-estrogen
      Approximately 99% of the anti-estrogen use in ExteNET was tamoxifen, tamoxifen citrate, toremifene, or toremifene citrate.
      only
      325 (52)294 (47)
       Anti-estrogen
      Approximately 99% of the anti-estrogen use in ExteNET was tamoxifen, tamoxifen citrate, toremifene, or toremifene citrate.
      and aromatase inhibitor (sequential)
      20 (3)29 (5)
       Aromatase inhibitor only275 (44)302 (48)
       Neither anti-estrogen
      Approximately 99% of the anti-estrogen use in ExteNET was tamoxifen, tamoxifen citrate, toremifene, or toremifene citrate.
      nor aromatase inhibitor
      2 (<1)4 (<1)
      Receiving concomitant GnRH analogue39 (6)32 (5)
      Data reported as n (%).
      Abbreviations: GnRH = gonadotropin-releasing hormone; HR+ = hormone receptor-positive.
      a Approximately 99% of the anti-estrogen use in ExteNET was tamoxifen, tamoxifen citrate, toremifene, or toremifene citrate.
      Supplemental Table 4Frequently Reported Treatment-emergent Adverse Events in the HR+/≤ 1-year Safety Population (n = 1319)
      Neratinib (n = 662)Placebo (n = 657)
      Grade 1-2Grade 3Grade 1-2Grade 3
      Diarrhea365 (55)261 (39)213 (32)7 (1)
      Nausea280 (42)9 (1)135 (21)2 (<1)
      Fatigue177 (27)13 (2)129 (20)2 (<1)
      Vomiting150 (23)24 (4)41 (6)2 (<1)
      Abdominal pain145 (22)11 (2)58 (9)1 (<1)
      Headache119 (18)6 (<1)125 (19)1 (<1)
      Upper abdominal pain90 (14)6 (<1)35 (5)3 (<1)
      Rash90 (14)3 (<1)40 (6)0 (0)
      Decreased appetite79 (12)1 (<1)13 (2)0 (0)
      Muscle spasms81 (12)0 (0)21 (3)1 (<1)
      Data reported as n (%).
      Events shown are those occurring in ≥ 10% of patients in the neratinib arm of the HR+/≤ 1-year population.
      Abbreviation: HR+ = hormone receptor-positive.
      Supplemental Table 5Summary of Treatment-emergent Adverse Events in the HR+/≤ 1-year Population (n = 1319)
      Neratinib (n = 662)Placebo (n = 657)
      Any TEAE649 (98)567 (86)
      Grade 3 or 4 TEAE327 (49)76 (12)
      Fatal TEAE1 (<1)0 (0)
      Serious TEAE45 (7)36 (6)
      Treatment-related TEAE630 (95)360 (55)
      Serious treatment-related TEAE19 (3)5 (<1)
      TEAE leading to
       Treatment discontinuation178 (27)30 (5)
       Study withdrawal11 (2)2 (<1)
       Dose reduction203 (31)13 (2)
       Hospitalization41 (6)35 (5)
       Dose interruption280 (42)75 (11)
      Data reported as n (%).
      Abbreviations: HR+ = hormone receptor-positive; TEAE = treatment-emergent adverse event.
      Supplemental Table 6Efficacy Outcomes in the HR+/≤ 1-year Population, With Randomization Stratification Factors Taken From Case Report Forms as Requested by the European Medicines Agency (n = 1339)
      Endpoint
      Definitions for efficacy endpoints provided in Supplemental Table 1.
      2-year (Primary) Analysis
      Estimated Event-free Survival Rate,
      Except for CNS recurrence, which is presented as cumulative incidence.
      %
      Hazard Ratio (95% CI)P Value (2-sided)
      Neratinib (n = 671)Placebo (n = 668)Δ, %
      Difference in event-free survival rates between neratinib versus placebo.
      Invasive disease-free survival95.390.9+4.40.50 (0.31-0.78).003
      Disease-free survival including DCIS95.390.1+5.20.45 (0.28-0.71)<.001
      Distant disease-free survival96.193.0+3.10.53 (0.31-0.88).015
      Time to distant recurrence96.393.3+3.00.53 (0.30-0.89).018
      Cumulative incidence of CNS recurrences0.341.01.189
      Overall Survival Analysis
      Estimated Rate, %Δ, %
      Difference in event-free survival rates between neratinib versus placebo.
      Hazard Ratio (95% CI)P Value
      Overall survival
      In the overall survival analysis after a median follow-up of 8.0 years (range, 0-9.8 years), 55 (8.2%) of 671 patients in the neratinib group and 68 (10.2%) of 668 patients in the placebo group had died.
       At 8 years91.189.4+1.70.83 (0.58-1.18).288
      Abbreviations: CI = confidence interval; CNS = central nervous system; DCIS = ductal carcinoma in situ; HR+ = hormone receptor-positive.
      a Definitions for efficacy endpoints provided in Supplemental Table 1.
      b Except for CNS recurrence, which is presented as cumulative incidence.
      c Difference in event-free survival rates between neratinib versus placebo.
      d In the overall survival analysis after a median follow-up of 8.0 years (range, 0-9.8 years), 55 (8.2%) of 671 patients in the neratinib group and 68 (10.2%) of 668 patients in the placebo group had died.

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