Introduction: EGFR exon 20 insertions (EGFRex20ins) comprise an uncommon subset of EGFR‐activating alterations relatively insensitive to first‐ and second‐generation EGFR tyrosine kinase inhibitors (TKIs). However, recent early clinical data suggests these patients may benefit from newer‐generation EGFR‐TKIs. Comprehensive genomic profiling (CGP) identifies a broad spectrum of EGFRex20ins and associated co‐occurring genomic alterations (GAs) present in NSCLC. Methods: Hybrid capture‐based CGP was performed prospectively on 14,483 clinically annotated consecutive NSCLC specimens to a mean coverage depth of greater than 650X for 236 or 315 cancer‐related genes. Results: Of 14,483 NSCLC cases, CGP identified 263 (1.8%) cases with EGFRex20ins, representing 12% (263 of 2251) of cases with EGFR mutations. Sixty‐four unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%). EGFR amplification occurred in 22% (57 of 263). The most common co‐occurring GAs effected tumor protein p53 (TP53) (56%), cyclin dependent kinase inhibitor 2A (CDKN2A) (22%), cyclin dependent kinase inhibitor 2B (CDKN2B) (16%), NK2 homeobox 1 (NKX2‐1) (14%) and RB transcriptional corepressor 1 (RB1) (11%); co‐occurring GAs in other known lung cancer drivers were rare (5%). Average tumor mutational burden was low (mean 4.3, range 0 to 40.3 mutations/Mb). Clinical outcomes to first‐ and second‐generation EGFR TKIs were obtained for five patients and none responded. Conclusions: In the largest series of EGFRex20ins NSCLC, diverse EGFRex20ins were detected in 12% of EGFR‐mutant NSCLC, a higher frequency than previously reported in smaller single‐institution studies. Clinical outcomes showed lack of response to EGFR TKIs. Tumor mutational burden was low, consistent with non–smoking associated NSCLC. Comprehensive sequencing revealed increased proportion and wide variety of EGFRex20ins, representing a population of patients significant enough for focused efforts on effective interventions.

中文翻译：

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通过非小细胞肺癌的综合基因组分析识别出不同的 EGFR 外显子 20 插入和共同发生的分子改变

简介：EGFR 外显子 20 插入 (EGFRex20ins) 包括一个罕见的 EGFR 激活改变子集，对第一代和第二代 EGFR 酪氨酸激酶抑制剂 (TKI) 相对不敏感。然而，最近的早期临床数据表明，这些患者可能受益于新一代 EGFR-TKI。综合基因组分析 (CGP) 确定了 NSCLC 中存在的广谱 EGFRex20ins 和相关的共发生基因组改变 (GA)。方法：基于混合捕获的 CGP 前瞻性地对 14,483 个临床注释的连续 NSCLC 标本进行，平均覆盖深度大于 650 倍，涉及 236 或 315 个癌症相关基因。结果：在 14,483 例 NSCLC 病例中，CGP 鉴定出 263 例 (1.8%) EGFRex20ins 病例，占 EGFR 突变病例的 12%（2251 例中的 263 例）。鉴定了 64 个独特的 EGFRex20ins，最常见的是 D770_N771>ASVDN (21%) 和 N771_P772>SVDNP (20%)。EGFR 扩增发生率为 22%（263 个中的 57 个）。最常见的 GA 影响肿瘤蛋白 p53 (TP53) (56%)、细胞周期蛋白依赖性激酶抑制剂 2A (CDKN2A) (22%)、细胞周期蛋白依赖性激酶抑制剂 2B (CDKN2B) (16%)、NK2 同源框 1 (NKX2) ‐1) (14%) 和 RB 转录辅抑制因子 1 (RB1) (11%)；其他已知肺癌驱动因素中同时发生的 GA 很少见 (5%)。平均肿瘤突变负荷低（平均 4.3，范围 0 至 40.3 突变/Mb）。获得了 5 名患者对第一代和第二代 EGFR TKI 的临床结果，没有人有反应。结论：在最大的 EGFRex20ins NSCLC 系列中，在 12% 的 EGFR 突变 NSCLC 中检测到不同的 EGFRex20ins，频率高于先前在较小的单机构研究中报告的频率。临床结果显示对 EGFR TKI 缺乏反应。肿瘤突变负荷低，与非吸烟相关非小细胞肺癌一致。综合测序显示 EGFRex20ins 的比例增加且种类繁多，这代表了足够重要的患者群体，可以集中精力进行有效的干预。