HER kinase inhibition in patients with HER2-and HER3-mutant cancers Journal Article


Authors: Hyman, D. M.; Piha-Paul, S. A.; Won, H.; Rodon, J.; Saura, C.; Shapiro, G. I.; Juric, D.; Quinn, D. I.; Moreno, V.; Doger, B.; Mayer, I. A.; Boni, V.; Calvo, E.; Loi, S.; Lockhart, A. C.; Erinjeri, J. P.; Scaltriti, M.; Ulaner, G. A.; Patel, J.; Tang, J.; Beer, H.; Selcuklu, S. D.; Hanrahan, A. J.; Bouvier, N.; Melcer, M.; Murali, R.; Schram, A. M.; Smyth, L. M.; Jhaveri, K.; Li, B. T.; Drilon, A.; Harding, J. J.; Iyer, G.; Taylor, B. S.; Berger, M. F.; Cutler, R. E. Jr; Xu, F.; Butturini, A.; Eli, L. D.; Mann, G.; Farrell, C.; Lalani, A. S.; Bryce, R. P.; Arteaga, C. L.; Meric-Bernstam, F.; Baselga, J.; Solit, D. B.
Article Title: HER kinase inhibition in patients with HER2-and HER3-mutant cancers
Abstract: Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, â €basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Keywords: adult; aged; gene mutation; major clinical study; missense mutation; mutation; diarrhea; drug dose reduction; drug efficacy; drug withdrawal; endometrium cancer; colorectal cancer; allele; progression free survival; ovary cancer; breast cancer; epidermal growth factor receptor 2; lung cancer; inhibitor; bladder cancer; histology; uterine cervix cancer; genomics; stomach cancer; genome; salivary gland cancer; epidermal growth factor receptor 3; esophagus cancer; biliary tract cancer; neratinib; small intestine cancer; enzyme; oncogene neu; non small cell lung cancer; inhibition; vagina cancer; paget skin disease; response evaluation criteria in solid tumors; cancer; human; male; female; priority journal; article; her3 gene
Journal Title: Nature
Volume: 554
Issue: 7691
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2018-02-08
Start Page: 189
End Page: 194
Language: English
DOI: 10.1038/nature25475
PROVIDER: scopus
PMCID: PMC5808581
PUBMED: 29420467
DOI/URL:
Notes: Article -- Author correction has been issued, see DOI 10.1038/s41586-019-0974-0 -- Export Date: 1 March 2018 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Gary Ulaner
    87 Ulaner
  2. David Solit
    435 Solit
  3. James Joseph Harding
    66 Harding
  4. Gopakumar Vasudeva Iyer
    126 Iyer
  5. David Hyman
    187 Hyman
  6. Komal Lachhman Jhaveri
    46 Jhaveri
  7. Rajmohan Murali
    156 Murali
  8. Nancy Bouvier
    30 Bouvier
  9. Michael Forman Berger
    386 Berger
  10. Alexander Edward Drilon
    141 Drilon
  11. Barry Stephen Taylor
    141 Taylor
  12. Alison Michele Schram
    22 Schram
  13. Helen Hyeong-Eun Won
    79 Won
  14. Jose T Baselga
    404 Baselga
  15. Bob Tingkan Li
    59 Li
  16. Lillian   Smyth
    20 Smyth
  17. Jiabin   Tang
    3 Tang
  18. Hannah Marie Beer
    2 Beer
  19. Myra Beth Melcer
    1 Melcer
  20. Juber Ahamad Abdul Bari Patel
    2 Patel