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 C. Lockhart, Joseph P. Erinjeri, Maurizio Scaltriti, Gary A. Ulaner, Juber Patel, Jiabin Tang, Hannah 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 and David B. Solit
Additional contact information
David M. Hyman: Memorial Sloan Kettering Cancer Center
Sarina A. Piha-Paul: University of Texas, MD Anderson Cancer Center
Helen Won: Memorial Sloan Kettering Cancer Center
Jordi Rodon: Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO)
Cristina Saura: Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO)
Geoffrey I. Shapiro: Dana-Faber Cancer Institute
Dejan Juric: Massachusetts Hospital Cancer Center
David I. Quinn: USC Norris Comprehensive Cancer Center
Victor Moreno: START Madrid Fundación Jímenez Díaz
Bernard Doger: START Madrid Fundación Jímenez Díaz
Ingrid A. Mayer: Vanderbilt-Ingram Cancer Center
Valentina Boni: START Madrid, Centro Integral Oncológico Clara Campal (CIOCC)
Emiliano Calvo: START Madrid, Centro Integral Oncológico Clara Campal (CIOCC)
Sherene Loi: Peter MacCallum Cancer Centre
Albert C. Lockhart: Washington University in St. Louis School of Medicine
Joseph P. Erinjeri: Memorial Sloan Kettering Cancer Center
Maurizio Scaltriti: Memorial Sloan Kettering Cancer Center
Gary A. Ulaner: Memorial Sloan Kettering Cancer Center
Juber Patel: Memorial Sloan Kettering Cancer Center
Jiabin Tang: Memorial Sloan Kettering Cancer Center
Hannah Beer: Memorial Sloan Kettering Cancer Center
S. Duygu Selcuklu: Memorial Sloan Kettering Cancer Center
Aphrothiti J. Hanrahan: Memorial Sloan Kettering Cancer Center
Nancy Bouvier: Memorial Sloan Kettering Cancer Center
Myra Melcer: Memorial Sloan Kettering Cancer Center
Rajmohan Murali: Memorial Sloan Kettering Cancer Center
Alison M. Schram: Memorial Sloan Kettering Cancer Center
Lillian M. Smyth: Memorial Sloan Kettering Cancer Center
Komal Jhaveri: Memorial Sloan Kettering Cancer Center
Bob T. Li: Memorial Sloan Kettering Cancer Center
Alexander Drilon: Memorial Sloan Kettering Cancer Center
James J. Harding: Memorial Sloan Kettering Cancer Center
Gopa Iyer: Memorial Sloan Kettering Cancer Center
Barry S. Taylor: Memorial Sloan Kettering Cancer Center
Michael F. Berger: Memorial Sloan Kettering Cancer Center
Richard E. Cutler: Puma Biotechnology Inc.
Feng Xu: Puma Biotechnology Inc.
Anna Butturini: Puma Biotechnology Inc.
Lisa D. Eli: Puma Biotechnology Inc.
Grace Mann: Puma Biotechnology Inc.
Cynthia Farrell: Puma Biotechnology Inc.
Alshad S. Lalani: Puma Biotechnology Inc.
Richard P. Bryce: Puma Biotechnology Inc.
Carlos L. Arteaga: Vanderbilt-Ingram Cancer Center
Funda Meric-Bernstam: University of Texas, MD Anderson Cancer Center
José Baselga: Memorial Sloan Kettering Cancer Center
David B. Solit: Memorial Sloan Kettering Cancer Center

Nature, 2018, vol. 554, issue 7691, 189-194

Abstract: 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.

Date: 2018
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DOI: 10.1038/nature25475

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