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Breast cancer, early stage

3959 - Neratinib after trastuzumab (T)-based adjuvant therapy in early-stage HER2+ breast cancer (BC): 5‑year analysis of the phase III ExteNET trial


08 Sep 2017


Breast cancer, early stage


Cytotoxic Therapy;  Breast Cancer;  Prostate Cancer


Miguel Martin Jimenez


Annals of Oncology (2017) 28 (suppl_5): v43-v67. 10.1093/annonc/mdx362


M. Martin Jimenez1, F.A. Holmes2, B. Ejlertsen3, S. Delaloge4, B. Moy5, H. Iwata6, G. von Minckwitz7, S. Chia8, J. Mansi9, C. Barrios10, M. Gnant11, Z. Tomasevic12, N. Denduluri13, R. Separovic14, S. Kim15, E.H. Jakobsen16, R.P. Bryce17, F. Xu18, M. Buyse119, A. Chan20

Author affiliations

  • 1 Medical Oncology, Hospital General Universitario Gregorio Marañón, 28007 - Madrid/ES
  • 2 Medical Oncology, Texas Oncology, Houston/US
  • 3 Clinical Oncology, Rigshospitalet, Copenhagen/DK
  • 4 Medical Oncology, Institut Gustave Roussy, Villejuif/FR
  • 5 Medical Oncology, Massachusetts General Hospital Cancer Center, Boston/US
  • 6 Medical Oncology, Aichi Cancer Center Hospital, Chikusa-ku, Nagoya/JP
  • 7 Medical Oncology, German Breast Group, 63263 - Neu-Isenburg/DE
  • 8 Medical Oncology, British Columbia Cancer Agency, Vancouver/CA
  • 9 Medical Oncology, Guy’s and St Thomas’ NHS Foundation Trust and Biomedical Research Centre, King’s College London, London/GB
  • 10 Medical Oncology, Pontifical Catholic University of Rio Grande do Sul School of Medicine, Porto Alegre/BR
  • 11 Surgical Oncology, Comprehensive Cancer Centre, Medical University of Vienna, Vienna/AT
  • 12 Medical Oncology, Institute for Oncology and Radiology of Serbia, Belgrade/RS
  • 13 Virginia Cancer Specialists, US Oncology Research, 22205 - Arlington/US
  • 14 Medical Oncology, Sestre milosrdnice University Hospital Center; University Hospital for Tumors, 10000 - Zagreb/HR
  • 15 Oncology, Asan Medical Centre, Seoul/KR
  • 16 Department Of Oncology, Sygehus Lillebaelt, Vejle/DK
  • 17 Clinical Research And Development, Puma Biotechnology Inc., Los Angeles/US
  • 18 Statistics, Puma Biotechnology Inc., Los Angeles/US
  • 19 Drug Development, International Drug Development Institute (IDDI), San Francisco/US
  • 20 Medical Oncology, Breast Cancer Research Centre-Western Australia and Curtin University, Perth/AU


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Abstract 3959


In the Herceptin Adjuvant (HERA) trial, 24% of patients (pts) who received T for 1 year (y) had a disease recurrence at 11 y follow-up. The primary analysis of the ExteNET trial, performed after 2 y follow-up, showed that a 1-y course of neratinib after T-based adjuvant therapy significantly improved invasive disease-free survival (iDFS) vs placebo in early-stage HER2+ BC (HR 0.67; 95% CI 0.50–0.91; p = 0.0091) [Chan et al. Lancet Oncol 2016]. We now report updated 5-y efficacy findings.


ExteNET is an international, multicenter, randomized, double-blind, placebo-controlled phase III trial. Pts received oral neratinib 240 mg/d or placebo for 1 y. After 2 y, randomized pts were asked to re-consent to collection of data concerning disease recurrences and survival from medical records for a further 3 y. The preplanned 5-y analysis was by intention-to-treat (ITT). Non-consenting pts were censored at their last physical examination. Primary endpoint: iDFS. HR (95% CI) were estimated using Cox proportional-hazards models. Data cut-off: March 2017. Clinicaltrials.gov: NCT00878709.


ITT population comprised 2840 pts (neratinib, n = 1420; placebo, n = 1420); 53 pts died during the initial 2-y follow-up. Among 2787 available pts, 2117 (76%) re-consented to additional follow-up (neratinib, n = 1028; placebo, n = 1089). Updated results after a median follow-up of 5.2 y are shown below. Secondary efficacy endpoints were supportive of the primary analysis.Table:


Estimated 5-y iDFS rate, %
nNeratinibPlaceboHR (95% CI)P value
ITT284090.287.70.73 (0.57–0.92)a0.008
Centrally confirmed HER2+179690.488.20.74 (0.55–1.00)0.047
HR + b163191.286.80.60 (0.43–0.83)0.002
HR–b120988.888.90.95 (0.66–1.35)0.762
Completed T ≤ 1 y of randomization229789.786.50.70 (0.54–0.90)0.006

HR, hormone receptor; aStratified analysis; bStratification factor.


1 y of neratinib after T-based adjuvant therapy significantly improves iDFS at 5 y in pts with early-stage HER2+ BC, with a long-term sustained effect. A protocol-specified subgroup analysis suggested greater benefit in HR+ pts. Overall survival data are not yet mature.

Clinical trial identification


Legal entity responsible for the study

Wyeth, Pfizer and Puma Biotechnology


Puma Biotechnology


B. Ejlertsen: Grants to institution from NanoString, Novartis, and Roche, outside the submitted work. Travel support for educational meetings from AstraZeneca and Celgene. S. Delaloge: Grants and personal fees from Roche and GSK. G. von Minckwitz: Research funding to the institution from Amgen, Roche, Novartis, Celgene, Teva, AstraZeneca, Myriad Genetics, AbbVie and Vifor Pharma. C. Barrios: Grants from Amgen, AstraZeneca, Boehringer, Novartis, Pfizer, Roche, Celgene, Sanofi, Lilly, Puma. Personal fees from GSK, Novartis, Pfizer, Roche, Eisai. M. Gnant: Grants from Sanofi-Aventis, Novartis, Roche, GSK, Pfizer, Smith Medical. Personal fees from Novartis, AstraZeneca, Accelsiors, Esai. S-B. Kim: Research funding to the institution from Novartis, Sanofi-Aventis, Kyowa-Kirin Inc, and Dongkook Pharma Co., Ltd. R.P. Bryce: Emplyee and stock options: Puma Biotechnology Inc. F. Xu: Emplyee: Puma Biotechnology Inc. M. Buyse: Emplyee and shareholder: IDDI. A. Chan: Personal fees for educational meetings from Pfizer, Amgen. All other authors have declared no conflicts of interest.

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