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

2018; Nature Portfolio; Volume: 554; Issue: 7691 Linguagem: Inglês

10.1038/nature25475

1476-4687

David M. Hyman, Sarina A. Piha‐Paul, Helen Won, Jordi Rodón, Cristina Saura, Geoffrey I. Shapiro, Dejan Juric, David I. Quinn, Víctor Moreno, Bernard Doger, Ingrid A. Mayer, Valentina Boni, Emiliano Calvo, Sherene Loi, A. Craig Lockhart, Joseph P. Erinjeri, Maurizio Scaltriti, Gary A. Ulaner, Juber Patel, Jiabin Tang, Hannah Beer, S. Duygu Selçuklu, 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 Bryce, Carlos L. Arteaga, Funda Meric‐Bernstam, José Baselga, David B. Solit,

Monoclonal and Polyclonal Antibodies Research

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. In a basket trial design, the efficacy of the pan-HER kinase inhibitor neratinib is tested in patients with 21 different tumour types, and responses are determined by mutation and tissue type, and are restricted to HER2-mutant cancers. Mutations in, or overexpression of, HER2 and HER3 (members of the epidermal growth factor receptor (EGFR) family) are found in numerous cancer types. Here, the authors conduct a basket trial—a clinical trial whereby patients are given a targeted therapy based on the presence of a molecular marker rather than on their tumour type—to test the efficacy of neratinib, an irreversible inhibitor of all HER kinases. Neratinib was given to 141 patients with one of 21 different tumour types containing mutations in HER2 and HER3, including breast, lung, bladder and colorectal cancer. The results show that responses are determined by mutation and tissue type, and are restricted to HER2-mutant cancers. Clinical benefit is also conditioned by alterations in downstream signalling pathways. The results highlight the potential of basket trials in molecularly driven oncology.