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.

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Acknowledgements

We thank patients and their families for participating in this study. Editorial support, not including writing, was provided by L. Miller. This work was funded by Puma Biotechnology, and supported by grants from the National Institutes of Health (grants P30 CA008748, P30 CA016672, P30 CA014089, R01 CA204749, R01 CA80195, T32 CA009207, 1U01 CA180964 and UL1 TR000371), the National Institutes of Health/National Cancer Institute (Breast SPORE grant P50 CA098131), Cycle for Survival, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, The Cancer Prevention and Research Institute of Texas (RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, Nellie B. Connally Breast Cancer Research Endowment, and the Breast Cancer Research Foundation.

Author information

Affiliations

  1. Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • David M. Hyman
    • , Helen Won
    • , 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
    • , José Baselga
    •  & David B. Solit
  2. University of Texas, MD Anderson Cancer Center, Houston, Texas, USA

    • Sarina A. Piha-Paul
    •  & Funda Meric-Bernstam
  3. Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

    • Jordi Rodon
    •  & Cristina Saura
  4. Dana-Faber Cancer Institute, Boston, Massachusetts, USA

    • Geoffrey I. Shapiro
  5. Massachusetts Hospital Cancer Center, Boston, Massachusetts, USA

    • Dejan Juric
  6. USC Norris Comprehensive Cancer Center, Los Angeles, California, USA

    • David I. Quinn
  7. START Madrid Fundación Jímenez Díaz, Madrid, Spain

    • Victor Moreno
    •  & Bernard Doger
  8. Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA

    • Ingrid A. Mayer
    •  & Carlos L. Arteaga
  9. START Madrid, Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain

    • Valentina Boni
    •  & Emiliano Calvo
  10. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    • Sherene Loi
  11. Washington University in St. Louis School of Medicine, St Louis, Missouri, USA

    • Albert C. Lockhart
  12. Puma Biotechnology Inc., Los Angeles, California, USA

    • Richard E. Cutler Jr
    • , Feng Xu
    • , Anna Butturini
    • , Lisa D. Eli
    • , Grace Mann
    • , Cynthia Farrell
    • , Alshad S. Lalani
    •  & Richard P. Bryce

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Contributions

D.M.H., H.W., M.F.B., R.E.C, F.X., A.B., L.D.E., G.M., C.F., A.S.L., R.P.B., J.B. and D.B.S. designed the study and supervised the analyses. R.E.C., F.X., L.D.E., G.M., C.F., A.S.L. and R.P.B. helped to collect and monitor the clinical outcome data. D.M.H., S.A.P., J.R., C.S., G.I.S., D.J., D.I.Q., V.M., B.D., I.A.M., V.B., E.C., S.L., A.C.L., J.P.E., B.T.L., A.J.H., R.M., A.M.S., A.D., L.M.S., K.J., G.I., J.J.H., C.L.A., F.M.B., J.B. and D.B.D. enrolled patients and provided patient samples. G.U. developed the PET response criteria and performed radiographic response assessments. B.S.T., J.P., J.T., S.D.S., N.B., M.M., M.F.B., J.B. and D.B.S. performed the tumour and plasma sequencing, provided computational infrastructure, and made final variant calls. D.M.H., H.W., M.S., B.S.T., J.P., J.T., H.B., M.F.B. and D.B.S. analysed clinical and genomic data and performed the integrated efficacy analyses. F.X. performed biostatistical analyses of the clinical efficacy data. D.M.H., H.W., B.S.T., C.L.A., F.M.B. and D.B.S. wrote the manuscript with input from all authors.

Competing interests

R.E.C., F.X., L.D.E., G.M., C.F., A.S.L. and R.P.B. are employees of Puma Biotechnology. D.M.H., M.S. and J.B. receive research support from Puma Biotechnology, B.T.L. and M.S. receive research funding from Diachi, A.D. receives personal fees from Roche, and D.S. received personal fees from Loxo Oncology and Pfizer.

Corresponding author

Correspondence to David M. Hyman.

Reviewer Information Nature thanks E. Mardis and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

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  1. 1.

    Life Sciences Reporting Summary

  2. 2.

    Supplementary Information

    This file contains: 1 - list of genes covered in the MSK-IMPACT panel along with the HGNC ID, short gene description, chromosomal location, and panel version, 2 - list of all somatic mutations within the MSK-IMPACT genes for patient tumour samples with sequencing data and 3 - list of all somatic copy number alterations within the MSK-IMPACT genes for patient tumour samples with sequencing data.

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DOI

https://doi.org/10.1038/nature25475

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