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.

中文翻译：

---

用奥西替尼靶向非小细胞肺癌中的HER2畸变。

目的：HER2（或ERBB2）畸变，包括扩增和突变，已被归类为致癌驱动因素，占肺腺癌的2％至6％。HER2扩增也是获得耐药性的酪氨酸激酶抑制剂（TKI）的重要机制。然而，由于有限的临床前研究和临床试验，目前仍然没有针对具有HER2畸变的肺癌患者的可用护理标准。为了满足针对非小细胞肺癌（NSCLC）患者靶向HER2的临床需求，我们进行了一项全面的临床前研究，以评估第三代TKI osimertinib（AZD9291）的功效。实验设计：三只转基因小鼠产生了模拟NSCLC中个别HER2改变的模型（GEMM），结果：Osimertinib治疗在HER2wt过表达和EGFR del19 / HER2模型中显示出强大的功效，但在HER2外显子20插入肿瘤中却没有。有趣的是，我们进一步发现，与奥西替尼和BET抑制剂JQ1联合治疗可显着提高HER2突变型NSCLC的应答率，而JQ1单次治疗未显示出疗效。结论：总体而言，我们的数据表明，奥西替尼对多种HER2有很强的抗肿瘤功效。单一药物或与JQ1组合治疗肺癌的畸变。我们的研究为单独使用奥西替尼或与表观遗传药物联合使用以靶向非小细胞肺癌患者HER2异常的未来临床试验提供了强有力的依据。临床癌症研究；24（11）; 2594-604。©2018 AACR请参阅Cappuzzo和Landi的相关评论，第11页。2470。