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

David M. Hyman, Sarina A. Piha-Paul, Helen Won, Jordi Rodon, Cristina Saura, Geoffrey I. Shapiro, Dejan Juric, David I. Quinn, Victor Moreno, Bernard Doger, Ingrid A. Mayer, Valentina Boni, Emiliano Calvo, Sherene Loi, Albert Lockhart, Joseph P. Erinjeri, Maurizio Scaltriti, Gary A. Ulaner, Juber Patel, Jiabin TangHannah Beer, S. Duygu Selcuklu, Aphrothiti J. Hanrahan, Nancy Bouvier, Myra Melcer, Rajmohan Murali, Alison M. Schram, Lillian M. Smyth, Komal Jhaveri, Bob T. Li, Alexander Drilon, James J. Harding, Gopa Iyer, Barry S. Taylor, Michael F. Berger, Richard E. Cutler, Feng Xu, Anna Butturini, Lisa D. Eli, Grace Mann, Cynthia Farrell, Alshad S. Lalani, Richard P. Bryce, Carlos L. Arteaga, Funda Meric-Bernstam, José Baselga, David B. Solit

Research output: Contribution to journalArticle

173 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)189-194
Number of pages6
JournalNature
Volume554
Issue number7691
DOIs
StatePublished - Feb 8 2018
Externally publishedYes

ASJC Scopus subject areas

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    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., Erinjeri, J. P., Scaltriti, M., Ulaner, G. A., Patel, J., ... Solit, D. B. (2018). HER kinase inhibition in patients with HER2-and HER3-mutant cancers. Nature, 554(7691), 189-194. https://doi.org/10.1038/nature25475