Introduction: We analyzed a large set of EGFR‐mutated (EGFR+) NSCLC to identify and characterize cases with co‐occurring kinase fusions as potential resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs). Methods: EGFR+ (del 19, L858R, G719X, S768I, L851Q) NSCLC clinical samples (formalin‐fixed paraffin‐embedded tumor and blood) were analyzed for the presence of receptor tyrosine kinase (RTK) and BRAF fusions. Treatment history and response were obtained from provided pathology reports and treating clinicians. Results: Clinical samples from 3505 unique EGFR+ NSCLCs were identified from June 2012 to October 2017. A total of 31 EGFR+ cases had concurrent kinase fusions detected: 10 (32%) BRAF, 7 (23%) ALK receptor tyrosine kinase (ALK), 6 (19%) ret proto‐oncogene (RET), 6 (19%) fibroblast growth factor receptor 3 (FGFR3), 1 (3.2%) EGFR, and 1 (3.2%) neurotrophic receptor tyrosine kinase 1 (NTRK1), including two novel fusions (SALL2‐BRAF and PLEKHA7‐ALK). Twenty‐seven of 31 patients had either a known history of EGFR+ NSCLC diagnosis or prior treatment with an EGFR TKI before the fusion+ sample was collected. Twelve of the 27 patients had paired pre‐treatment samples where the fusion was not present before treatment with an EGFR TKI. Multiple patients treated with combination therapy targeting EGFR and the acquired fusion had clinical benefit, including one patient with osimertinib resistance due to an acquired PLEKHA7‐ALK fusion achieving a durable partial response with combination of full‐dose osimertinib and alectinib. Conclusions: RTK and BRAF fusions are rare but potentially druggable resistance mechanisms to EGFR TKIs. Detection of RTK and BRAF fusions should be part of comprehensive profiling panels to determine resistance to EGFR TKIs and direct appropriate combination therapeutic strategies.

中文翻译：

---

受体酪氨酸激酶融合和 BRAF 激酶融合是对 EGFR 酪氨酸激酶抑制剂的罕见但可操作的耐药机制

简介：我们分析了大量 EGFR 突变 (EGFR+) NSCLC，以识别和表征同时发生激酶融合的病例作为对 EGFR 酪氨酸激酶抑制剂 (TKI) 的潜在耐药机制。方法：分析 EGFR+（del 19、L858R、G719X、S768I、L851Q）NSCLC 临床样本（福尔马林固定石蜡包埋的肿瘤和血液）中是否存在受体酪氨酸激酶 (RTK) 和 BRAF 融合。从提供的病理报告和治疗临床医生获得治疗史和反应。结果：从 2012 年 6 月至 2017 年 10 月鉴定了 3505 例独特 EGFR+ NSCLC 的临床样本。共检测到 31 例 EGFR+ 病例同时检测到激酶融合：10（32%）BRAF、7（23%）ALK 受体酪氨酸激酶（ALK）、 6 (19%) ret 原癌基因 (RET), 6 (19%) 成纤维细胞生长因子受体 3 (FGFR3), 1 (3.2%) EGFR, 和 1 个 (3.2%) 神经营养受体酪氨酸激酶 1 (NTRK1)，包括两个新的融合体（SALL2-BRAF 和 PLEKHA7-ALK）。31 名患者中有 27 名在收集融合 + 样本之前具有已知的 EGFR+ NSCLC 诊断史或既往接受过 EGFR TKI 治疗。27 名患者中有 12 名具有配对的治疗前样本，其中在用 EGFR TKI 治疗前不存在融合。多名接受靶向 EGFR 和获得性融合的联合疗法治疗的患者具有临床益处，包括一名因获得性 PLEKHA7-ALK 融合而对奥希替尼耐药的患者，通过全剂量奥希替尼和艾乐替尼的组合实现了持久的部分缓解。结论：RTK 和 BRAF 融合是罕见的，但可能是对 EGFR TKI 的耐药机制。