Format

Send to

Choose Destination
Nature. 2018 Feb 8;554(7691):189-194. doi: 10.1038/nature25475. Epub 2018 Jan 31.

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

Author information

1
Memorial Sloan Kettering Cancer Center, New York, New York, USA.
2
University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
3
Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
4
Dana-Faber Cancer Institute, Boston, Massachusetts, USA.
5
Massachusetts Hospital Cancer Center, Boston, Massachusetts, USA.
6
USC Norris Comprehensive Cancer Center, Los Angeles, California, USA.
7
START Madrid Fundación Jímenez Díaz, Madrid, Spain.
8
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
9
START Madrid, Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain.
10
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
11
Washington University in St. Louis School of Medicine, St Louis, Missouri, USA.
12
Puma Biotechnology Inc., Los Angeles, California, USA.

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, '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.

PMID:
29420467
PMCID:
PMC5808581
DOI:
10.1038/nature25475
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center