HER kinase inhibition in patients with HER2- and HER3-mutant cancers (original) (raw)

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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

Authors and 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

Authors

1. David M. Hyman
2. Sarina A. Piha-Paul
3. Helen Won
4. Jordi Rodon
5. Cristina Saura
6. Geoffrey I. Shapiro
7. Dejan Juric
8. David I. Quinn
9. Victor Moreno
10. Bernard Doger
11. Ingrid A. Mayer
12. Valentina Boni
13. Emiliano Calvo
14. Sherene Loi
15. Albert C. Lockhart
16. Joseph P. Erinjeri
17. Maurizio Scaltriti
18. Gary A. Ulaner
19. Juber Patel
20. Jiabin Tang
21. Hannah Beer
22. S. Duygu Selcuklu
23. Aphrothiti J. Hanrahan
24. Nancy Bouvier
25. Myra Melcer
26. Rajmohan Murali
27. Alison M. Schram
28. Lillian M. Smyth
29. Komal Jhaveri
30. Bob T. Li
31. Alexander Drilon
32. James J. Harding
33. Gopa Iyer
34. Barry S. Taylor
35. Michael F. Berger
36. Richard E. Cutler Jr
37. Feng Xu
38. Anna Butturini
39. Lisa D. Eli
40. Grace Mann
41. Cynthia Farrell
42. Alshad S. Lalani
43. Richard P. Bryce
44. Carlos L. Arteaga
45. Funda Meric-Bernstam
46. José Baselga
47. David B. Solit

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.

Corresponding author

Correspondence toDavid M. Hyman.

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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.

Additional information

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 figures and tables

Extended Data Figure 1 Design of SUMMIT study.

Five tumour-specific HER2 (ERBB2)-mutant cohorts were pre-specified (endometrial, gastroesophageal, ovarian, colorectal and bladder/urinary tract). In addition, a sixth ‘solid tumour (not otherwise specified, NOS)’ HER2-mutant cohort allowed for the enrolment of patients with any other cancer types. A sufficient number of patients with breast, cervical, biliary and lung cancer were enrolled in the solid tumours (NOS) cohort to permit independent efficacy analysis using the same design as the pre-specified cohorts. Patients with HER3 (ERBB3)-mutant tumours were enrolled in a HER3-specific cohort regardless of tumour type. CBR, clinical benefit rate; cfDNA, cell-free (tumour) DNA; CI, confidence interval.

Extended Data Figure 2 Distribution of HER2 and HER3 mutations positioned by their amino acid coordinates across the respective protein domains.

a, b, HER2 (a) and HER3 (b) mutations (125 and 16 mutations, respectively). Each unique mutation is represented by a circle, with the circle size and number representing the frequency, and coloured to show the mutation class as indicated in the legend. The corresponding amino acid change and common hotspot mutations (shown in pink) are labelled next to the circles.

Source data

Extended Data Figure 3 Spectrum of HER2 and HER3 mutations observed in the neratinib study versus TCGA, ICGC and other public datasets.

a, b, Distribution of HER2 (a) and HER3 (b) mutations observed across our cohort in comparison to the spectrum of HER2 and HER3 mutations (reflected lollipop) from publically available datasets (TCGA, ICGC and other published studies).

Source data

Extended Data Figure 4 Distribution and outcome of 28 HER2 exon 20 insertions.

a, Percentage best change and PFS plots corresponding to each type of exon 20 insertion (colour coded by synonymous amino acid change). Three cases with no change are indicated in colour-coded circles above the x axis. b, Zoomed-in schematic of all exon 20 insertions positioned by their amino acid coordinates and frequencies. c, Five unique types of exon 20 insertions observed in the study with the resulting full amino acid sequences (insertion indicated in red).

Source data

Extended Data Figure 5 Genomic modifiers of response and outcome by treatment duration.

a, Cancer cell fractions with 95% confidence intervals and clonality status of all HER2 mutations in 74 patients with sufficient sequencing data ordered by increasing clinical benefit (weeks on therapy). b, Comparison of the percentage activation of known oncogenic alterations in the three pathways between the patients of clinical benefit (n = 20, biologically independent samples) and no benefit (n = 66, biologically independent samples). Nominal Fisher’s P values are shown.

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Extended Data Figure 6 SUMMIT CONSORT diagram.

Extended Data Table 1 Patient demographics and efficacy by cohort

Full size table

Extended Data Table 2 Treatment-emergent adverse events (occurring in ≥ 10% of patients)

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Extended Data Table 3 PET response criteria

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Extended Data Table 4 Patient disposition by cohort

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Supplementary information

Life Sciences Reporting Summary (PDF 72 kb) (download PDF )

Supplementary Information (download PDF )

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. (PDF 745 kb)

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Hyman, D., Piha-Paul, S., Won, H. et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers.Nature 554, 189–194 (2018). https://doi.org/10.1038/nature25475

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• Received: 04 August 2017
• Accepted: 22 December 2017
• Published: 31 January 2018
• Version of record: 31 January 2018
• Issue date: 08 February 2018
• DOI: https://doi.org/10.1038/nature25475