149O - Neratinib after trastuzumab (T)-based adjuvant therapy in early-stage HER2+ breast cancer (BC): 5‑year analysis of the phase III ExteNET trial

Date 08 September 2017
Event ESMO 2017 Congress
Session Breast cancer, early stage
Topics Anticancer Agents
Breast Cancer
Prostate Cancer
Biological Therapy
Presenter Miguel Martin Jimenez
Citation Annals of Oncology (2017) 28 (suppl_5): v43-v67. 10.1093/annonc/mdx362
Authors 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
  • 1Medical Oncology, Hospital General Universitario Gregorio Marañón, 28007 - Madrid/ES
  • 2Medical Oncology, Texas Oncology, Houston/US
  • 3Clinical Oncology, Rigshospitalet, Copenhagen/DK
  • 4Medical Oncology, Institut Gustave Roussy, Villejuif/FR
  • 5Medical Oncology, Massachusetts General Hospital Cancer Center, Boston/US
  • 6Medical Oncology, Aichi Cancer Center Hospital, Chikusa-ku, Nagoya/JP
  • 7Medical Oncology, German Breast Group, 63263 - Neu-Isenburg/DE
  • 8Medical Oncology, British Columbia Cancer Agency, Vancouver/CA
  • 9Medical Oncology, Guy’s and St Thomas’ NHS Foundation Trust and Biomedical Research Centre, King’s College London, London/GB
  • 10Medical Oncology, Pontifical Catholic University of Rio Grande do Sul School of Medicine, Porto Alegre/BR
  • 11Surgical Oncology, Comprehensive Cancer Centre, Medical University of Vienna, Vienna/AT
  • 12Medical Oncology, Institute for Oncology and Radiology of Serbia, Belgrade/RS
  • 13Virginia Cancer Specialists, US Oncology Research, 22205 - Arlington/US
  • 14Medical Oncology, Sestre milosrdnice University Hospital Center; University Hospital for Tumors, 10000 - Zagreb/HR
  • 15Oncology, Asan Medical Centre, Seoul/KR
  • 16Department Of Oncology, Sygehus Lillebaelt, Vejle/DK
  • 17Clinical Research And Development, Puma Biotechnology Inc., Los Angeles/US
  • 18Statistics, Puma Biotechnology Inc., Los Angeles/US
  • 19Drug Development, International Drug Development Institute (IDDI), San Francisco/US
  • 20Medical Oncology, Breast Cancer Research Centre-Western Australia and Curtin University, Perth/AU



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.