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

被引：656

作者：

Hyman, David M. ^{[1
]}

Piha-Paul, Sarina A. ^{[2
]}

Won, Helen ^{[1
]}

Rodon, Jordi ^{[3
]}

Saura, Cristina ^{[3
]}

Shapiro, Geoffrey I. ^{[4
]}

Juric, Dejan ^{[5
]}

Quinn, David I. ^{[6
]}

Moreno, Victor ^{[7
]}

Doger, Bernard ^{[7
]}

Mayer, Ingrid A. ^{[8
]}

Boni, Valentina ^{[9
]}

Calvo, Emiliano ^{[9
]}

Loi, Sherene ^{[10
]}

Lockhart, Albert C. ^{[11
]}

Erinjeri, Joseph P. ^{[1
]}

Scaltriti, Maurizio ^{[1
]}

Ulaner, Gary A. ^{[1
]}

Patel, Juber ^{[1
]}

Tang, Jiabin ^{[1
]}

Beer, Hannah ^{[1
]}

Selcuklu, S. Duygu ^{[1
]}

Hanrahan, Aphrothiti J. ^{[1
]}

Bouvier, Nancy ^{[1
]}

Melcer, Myra ^{[1
]}

Murali, Rajmohan ^{[1
]}

Schram, Alison M. ^{[1
]}

Smyth, Lillian M. ^{[1
]}

Jhaveri, Komal ^{[1
]}

Li, Bob T. ^{[1
]}

Drilon, Alexander ^{[1
]}

Harding, James J. ^{[1
]}

Iyer, Gopa ^{[1
]}

Taylor, Barry S. ^{[1
]}

Berger, Michael F. ^{[1
]}

Cutler, Richard E., Jr. ^{[12
]}

Xu, Feng ^{[12
]}

Butturini, Anna ^{[12
]}

Eli, Lisa D. ^{[12
]}

Mann, Grace ^{[12
]}

Farrell, Cynthia ^{[12
]}

Lalani, Alshad S. ^{[12
]}

Bryce, Richard P. ^{[12
]}

Arteaga, Carlos L. ^{[8
]}

Meric-Bernstam, Funda ^{[2
]}

Baselga, Jose ^{[1
]}

Solit, David B. ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[2] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[3] Vall Hebron Univ Hosp, VHIO, Barcelona, Spain

[4] Dana Faber Canc Inst, Boston, MA USA

[5] Massachusetts Hosp, Canc Ctr, Boston, MA USA

[6] USC Norris Comprehens Canc Ctr, Los Angeles, CA USA

[7] START Madrid Fdn Jimenez Diaz, Madrid, Spain

[8] Vanderbilt Ingram Canc Ctr, Nashville, TN USA

[9] CIOCC, START Madrid, Madrid, Spain

[10] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[11] Washington Univ, Sch Med, St Louis, MO USA

[12] Puma Biotechnol Inc, Los Angeles, CA USA

来源：

NATURE | 2018年 / 554卷 / 7691期

基金：

美国国家卫生研究院;

关键词：

BREAST-CANCER; MONOCLONAL-ANTIBODY; HIGH-FREQUENCY; SOLID TUMORS; PHASE-II; MUTATIONS; TRASTUZUMAB; LAPATINIB; TARGETS; PERTUZUMAB;

D O I：

10.1038/nature25475

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：189 / 194

页数：6

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