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Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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  • Lillian M Smyth
  • Sarina A Piha-Paul
  • Helen H Won
  • Alison M Schram
  • Cristina Saura
  • Sherene Loi
  • Janice Lu
  • Geoffrey I Shapiro
  • Dejan Juric
  • Ingrid A Mayer
  • Carlos L Arteaga
  • Macarena I de la Fuente
  • Adam M Brufksy
  • Iben Spanggaard
  • Morten Mau-Sorensen
  • Monica Arnedos
  • Victor Moreno
  • Valentina Boni
  • Joohyuk Sohn
  • Lee S Schwartzberg
  • Xavier Gonzalez-Farre
  • Andres Cervantes
  • Francois-Clement Bidard
  • Alexander N Gorelick
  • Richard B Lanman
  • Rebecca J Nagy
  • Gary A Ulaner
  • Sarat Chandarlapaty
  • Komal Jhaveri
  • Elena I Gavrila
  • Catherine Zimel
  • S Duygu Selcuklu
  • Myra Melcer
  • Aliaksandra Samoila
  • Yanyan Cai
  • Maurizio Scaltriti
  • Grace Mann
  • Feng Xu
  • Lisa D Eli
  • Melanie Dujka
  • Alshad S Lalani
  • Richard Bryce
  • Jose Baselga
  • Barry S Taylor
  • David B Solit
  • Funda Meric-Bernstam
  • David M Hyman
Vis graf over relationer

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.This article is highlighted in the In This Issue feature, p. 161.

OriginalsprogEngelsk
TidsskriftCancer Discovery
Vol/bind10
Udgave nummer2
Sider (fra-til)198-213
Antal sider16
ISSN2159-8274
DOI
StatusUdgivet - feb. 2020

Bibliografisk note

Funding Information:
L.M. Smyth is consultant at AstraZeneca, Pfizer, Roche-Genen-tech, and Novartis; reports receiving a commercial research grant from AstraZeneca; reports receiving other commercial research support from Roche-Genentech and Puma Biotechnology Inc.; and reports receiving other remuneration from AstraZeneca, Pfizer, Puma Biotechnology Inc., and Roche-Genentech. S.A. Piha-Paul reports receiving a commercial research grant from NIH/ NCI and other commercial research support from AbbVie, Inc., Aminex Therapeutics, GlaxoSmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals, Co., Ltd., Medimmune, LLC, Medivation, Inc., Merck Sharp and Dohme Corp., NewLink Genetics Corporation/Blue Link Pharmaceuticals, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., BioMarin Pharmaceutical, Inc., Pfizer, Merck & Co., Inc., Principia Biopharma, Inc., Puma Biotechnology, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Taiho Oncology, Tessaro, Inc., TransThera Bio, Xuan Zhu Biopharma, Boehringer Ingelheim, Bristol-Myers Squibb, Cerulean Pharma Inc., Chugai Pharmaceuticals Co., Ltd., Curis, Inc., Five Prime Therapeutics, and Genmab A/S. C. Saura is a consultant at AstraZeneca, Celgene, Synthon, Roche, Daiichi Sankyo, Eisai, Genomic Health, Novartis, Pfizer, Philips Health-work, Pierre Fabre, and Puma. S. Loi reports receiving research funding to her institution from Novartis, Bristol-Myers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer, and Eli Lilly; has been an unpaid consultant for Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca, and Roche-Genentech; and has acted as a consultant (paid to her institution) for Aduro Biotech. J. Lu is consultant at Pfizer, Daiichi, Novartis, Syn-dex, and Puma. G.I. Shapiro is an advisory board member for Lilly, Merck-EMD Serono, Almac, Ipsen, Boehringer Ingelheim, Immunomet, Angiex, Daiichi Sankyo, Sierra Oncology, Pfizer, G1 Therapeutics, Bicycle Therapeutics, Fusion Pharmaceuticals, Bayer, Cybrexa Therapeutics, and Astex; reports receiving com- mercial research grants from Lilly, Sierra Oncology, Merck-EMD Serono, and Merck & Co.; and reports receiving other commercial research support from Pfizer and Array Biopharma. D. Juric is scientific advisory board member for Novartis, Genentech, Eisai, Guardant, EMD Serono, Ipsen, and Syros, and reports receiving commercial research grants from Novartis, Genentech, Eisai, EMD Serono, Celgene, Placon Therapeutics, Syros, Amgen, and Takeda. I.A. Mayer is an advisory board member for Genentech, Novartis, GSK, Lilly, Macrogenics, Immunogenics, Seattle Genetics, and AstraZeneca, and reports receiving commercial research grants from Pfizer and Genentech. C.L. Arteaga reports receiving commercial research grants from Pfizer, Lilly, Takeda, and Bayer; has ownership interest (including patents) in Provista and Y-TRAP; has a consultant/advisory board relationship with Novartis, Merck, Immunomedics, Petra Pharma, G1 Therapeutics, Athenex, Lilly, Symphogen, Daiichi Sankyo, Radius, Taiho Oncology, Puma Biotechnology, Sanofi, and H3 Biomedicine; and has received other remuneration from the Komen Foundation. M.I. de la Fuente is an advisory board member for Puma Biotechnology. A.M. Brufksy is a consultant at Puma. I. Spanggaard reports receiving a commercial research grant from Puma Biotechnology. M. Arnedos reports receiving a commercial research grant from Eli Lilly and has received honoraria from the speakers’ bureaus of Seattle Genetics, AstraZeneca, Novartis, and AbbVie. V. Boni has a consultant/advisory board relationship with Ideaya and Loxo Therapeutics. J. Sohn reports receiving commercial research grants from MSD, Roche, Novartis, AstraZeneca, Lilly, Pfizer, Bayer, GSK, Contessa, and Daiichi Sankyo. L.S. Schwartzberg is a consultant at Pfizer, Amgen, Genentech, Bristol-Myers Squibb, Genomic Health, Myriad, and AstraZeneca, and has received honoraria from the speakers’ bureau of Puma. R.B. Lanman is Global Chief Medical Officer at Guardant Health, Inc., is on the Board of Directors at Biolase, Inc., is an advisory board member for Forward Medical, Inc., and has ownership interest (including patents) in Guardant Health, Inc., Biolase, Inc., and Forward Medical, Inc. R.J. Nagy is Sr. Director, medical affairs, at Guardant Health, Inc., and has ownership interest (including patents) in the same. S. Chandarlapaty is a consultant at Novartis, Eli Lilly, Sermonix, Revolution Medicine, Context Therapeutics, BMS, and Paige AI, and reports receiving a commercial research grant from Daiichi Sankyo. K. Jhaveri is an advisory board member for Astra-Zeneca, Pfizer, Novartis, Taiho Oncology, Juno Therapeutics, ADC Therapeutics, and Genentech; is a consultant at Synthon; and is a speaker at Intellisphere. M. Scaltriti is an advisory board member for Menarini Ricerche and Bioscience Institute; reports receiving commercial research grants from Puma Biotechnology, Menarini Ricerche, Immunomedics, Daiichi Sankyo, and Targimmune; and has ownership interest (including patents) in Medendi.org. F. Xu is Sr. Director at Puma Biotechnology. L.D. Eli is Sr. Director, Translational Medicine, at Puma Biotechnology. M. Dujka is Clinical Scientist at Puma Biotechnology, and has ownership interest (including patents) in the same. A.S. Lalani is SVP, Translational Medicine, at Puma Biotechnology and has ownership interest (including patents) in the same. R. Bryce is CMO/CSO at Puma Biotechnology and has an ownership interest (including patents) in the same. J. Baselga is EVP, Oncology R&D, at Astra-Zeneca; is a board member at Bristol-Myers Squibb, Grail, Varian Medical Systems, Foghorn, Aura Biosciences, and Infinity Pharmaceuticals; is an advisor at Seragon, Novartis, Apogen, and Lilly; is founder-advisor at Northern Biologicals; is founder at Tango and Venthera; is a consultant at PMV; has received honoraria from the speakers’ bureau of Roche; and has ownership interest (including patents) in PMV, Grail, Juno, Varian Medical Systems, Aura Biosciences, Infinity, Apogen, Tango, Foghorn, and Venthera. B.S. Taylor reports receiving a commercial research grant from Genentech; has received honoraria from the speakers’ bureau of

Funding Information:
Genentech; and has a consultant/advisory board relationship with Boehringer Ingelheim. D.B. Solit is an advisory board member for Pfizer, Loxo Oncology, Lilly Oncology, Illumina, Vivideon Therapeutics, and QED Therapeutics. F. Meric-Bernstam is consultant at Genentech, Pieris, F. Hoffmann-La Roche, Samsung Bioepis, OrigiMed, Debiopharm Group, Xencor, Jackson Laboratory, Zymeworks, Kolon Life Science, and Parexel International; is an advisory board member for Inflection Biosciences, Darwin Health, Spectrum, Mersana, Seattle Genetics, and Immunomedics; reports receiving commercial research grants from Novartis, AstraZeneca, Zymeworks, Curis, Pfizer, eFFECTOR, AbbVie, Guardant Health, Daiichi Sankyo, GlaxoSmithKline, Seattle Genetics, Royal Philips, Taiho, Genentech, Calithera, Debiopharm, Bayer, Aileron, Puma, and CytoMx; has received honoraria from the speakers’ bureau of Chugai Biopharma; and has a consultant/advisory board relationship with Taiho, Seattle Genetics, and F. Hoffmann-La Roche. D.M. Hyman is a consultant at Chugai, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, and Genentech/Roche; is a scientific advisory board member for Fount Therapeutics/Kinnate; and reports receiving commercial research grants from Loxo Oncology, Bayer, AstraZeneca, and Fount Therapeutics/Kinnate. No potential conflicts of interest were disclosed by the other authors.

Funding Information:
We would like to thank patients and their families for participating in this study. Editorial support, not including writing, was provided by L. Miller and D. Carman (Miller Medical Commu- nications Ltd.). This work was funded by Puma Biotechnology. M. Scaltriti is funded by NIH grant R01 CA190642, the Breast Cancer Research Foundation, Stand Up To Cancer (Cancer Drug Combination Convergence Team), the V Foundation, and the National Science Foundation. Authors from Memorial Sloan Kettering were funded by NIH grant P30 CA008748.

ID: 58961138