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Clin Cancer Res. 2018 Jun 1;24(11):2594-2604. doi: 10.1158/1078-0432.CCR-17-1875. Epub 2018 Jan 3.

Targeting HER2 Aberrations in Non-Small Cell Lung Cancer with Osimertinib.

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Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Department of Pathology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York.
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York.
Contributed equally


Purpose:HER2 (or ERBB2) aberrations, including both amplification and mutations, have been classified as oncogenic drivers that contribute to 2% to 6% of lung adenocarcinomas. HER2 amplification is also an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKI). However, due to limited preclinical studies and clinical trials, currently there is still no available standard of care for lung cancer patients with HER2 aberrations. To fulfill the clinical need for targeting HER2 in patients with non-small cell lung cancer (NSCLC), we performed a comprehensive preclinical study to evaluate the efficacy of a third-generation TKI, osimertinib (AZD9291).Experimental Design: Three genetically modified mouse models (GEMM) mimicking individual HER2 alterations in NSCLC were generated, and osimertinib was tested for its efficacy against these HER2 aberrations in vivoResults: Osimertinib treatment showed robust efficacy in HER2wt overexpression and EGFR del19/HER2 models, but not in HER2 exon 20 insertion tumors. Interestingly, we further identified that combined treatment with osimertinib and the BET inhibitor JQ1 significantly increased the response rate in HER2-mutant NSCLC, whereas JQ1 single treatment did not show efficacy.Conclusions: Overall, our data indicated robust antitumor efficacy of osimertinib against multiple HER2 aberrations in lung cancer, either as a single agent or in combination with JQ1. Our study provides a strong rationale for future clinical trials using osimertinib either alone or in combination with epigenetic drugs to target aberrant HER2 in patients with NSCLC. Clin Cancer Res; 24(11); 2594-604. ©2018 AACRSee related commentary by Cappuzzo and Landi, p. 2470.

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