Data from Targeting <i>HER2</i> Aberrations in Non–Small Cell Lung Cancer with Osimertinib

Abstract

<div>Abstract<p><b>Purpose:</b> <i>HER2</i> (or <i>ERBB2</i>) aberrations, including both amplification and mutations, have been classified as oncogenic drivers that contribute to 2% to 6% of lung adenocarcinomas. <i>HER2</i> 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 <i>HER2</i> aberrations. To fulfill the clinical need for targeting <i>HER2</i> 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).</p><p><b>Experimental Design:</b> Three genetically modified mouse models (GEMM) mimicking individual <i>HER2</i> alterations in NSCLC were generated, and osimertinib was tested for its efficacy against these <i>HER2</i> aberrations <i>in vivo</i>.</p><p><b>Results:</b> Osimertinib treatment showed robust efficacy in HER2<sup>wt</sup> overexpression and <i>EGFR del19/HER2</i> models, but not in <i>HER2</i> exon 20 insertion tumors. Interestingly, we further identified that combined treatment with osimertinib and the BET inhibitor JQ1 significantly increased the response rate in <i>HER2</i>-mutant NSCLC, whereas JQ1 single treatment did not show efficacy.</p><p><b>Conclusions:</b> Overall, our data indicated robust antitumor efficacy of osimertinib against multiple <i>HER2</i> 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 <i>HER2</i> in patients with NSCLC. <i>Clin Cancer Res; 24(11); 2594–604. ©2018 AACR</i>.</p><p><i>See related commentary by Cappuzzo and Landi, p. 2470</i></p></div>