肺癌大咖谈丨将新研究成果融入实践，应对EGFR Ex20ins突变NSCLC治疗中的挑战
EGFR 20 号外显子插入（exon20 insertion mutation,Ex20ins）突变发生率居 EGFR 基因突变第 3 位，仅次于 19 号外显子缺失突变和 21 号外显子 L858R 点突变。本文介绍 ASCO Daily News 发布的一篇广东省人民医院吴一龙教授和林嘉欣教授关于EGFR Ex20ins突变非小细胞肺癌（NSCLC）治疗的文章。
要点：
EGFR突变是NSCLC中关键的致癌驱动变异之一。高达90%的EGFR突变是外显子19缺失和外显子21L858R置换。约10%的EGFR突变NSCLC可检测到Ex20ins，这是第三大最常见的激活EGFR突变亚型[1]。与经典EGFR变体类似，Ex20ins在女性、从不吸烟或轻度吸烟者以及腺癌组织学类型患者中最常见。
EGFR Ex20ins由C-螺旋（AA761-766）和紧邻C-螺旋的环（AA767-775）出现的1-4个氨基酸（AA）插入组成。在已鉴定的60多种独特的EGFR Ex20ins亚型中，大多数位于C螺旋后的环内[2]。这种复杂的突变谱导致了EGFR Ex20ins突变肿瘤的生物学差异和对EGFR抑制剂的不同敏感性。例如，EGFRA763_Y764insFQEA对第一代EGFR-TKI敏感，而环内突变亚型则对EGFR-TKI不敏感[3]。为了尽可能检测出所有可靶向治疗的EGFR Ex20ins，指导临床实践中的治疗决策，中国指南和国际指南建议进行下一代测序（NGS）检测[4]。
不同于敏感EGFR突变患者在EGFR-TKI研发问世后实现了临床治疗效果显著改善，EGFR Ex20ins患者的预后较差[5,6]。近年来，专门针对EGFR Ex20ins的新型靶向药物取得了重大进展，例如mobocertinib、amivantamab和舒沃替尼。然而，这些新药的疗效数据无法媲美高效靶向疗法（例如奥希替尼）。在这里，我们对EGFR Ex20ins晚期NSCLC患者的分子检测和治疗管理的最新发现和即将面临的挑战进行概述（图）[7]。
图. 治疗EGFR Ex20ins晚期NSCLC的一般方法和当前治疗策略
*NCCN指南2024 V5版推荐。
EGFR Ex20ins突变NSCLC的治疗策略
一线治疗
由于现有EGFR-TKI的临床获益有限， 铂类双药化疗 仍然是一线治疗中推荐用于携带EGFR Ex20ins的患者的最有效治疗方法[6]。
值得注意的是，靶向EGFR和MET的新型双特异性抗体amivantamab在III期PAPILLON试验中显示出令人鼓舞的结果。对于未经治疗的EGFR Ex20ins患者，与单纯化疗相比，amivantamab联合化疗可改善无进展生存期（HR=0.40；95%CI: 0.30-0.53）和客观缓解率（73%；95%CI: 1.32-1.68]）[8]。鉴于其优越的疗效，FDA批准 amivantamab联合化疗 的一线治疗适应症[9]。
在现实世界中，化疗的疗效始终优于现有的EGFR-TKI，但在化疗中添加免疫检查点抑制剂（ICI）几乎没有临床获益[10,11]。到目前为止，ICI联合化疗的获益以及ICI在EGFR Ex20ins突变NSCLC治疗中的最佳位置都没有明确结论。但值得注意的是， 无论PD-L1表达水平如何，单药ICI都不应作为EGFR Ex20ins患者的一线疗法 [12]。
二线及后续治疗
根据I期CHRYSALIS试验的结果，amivantamab被批准用于初始化疗期间或之后疾病进展的EGFR Ex20ins晚期NSCLC患者[13,14]。后续治疗选择包括标准全身治疗或纳入临床试验。
EGFR Ex20ins突变NSCLC的新型靶向药物
表. EGFR Ex20ins突变NSCLC靶向治疗的主要前瞻性临床试验
Eblast/网站的摘要：在NSCLC领域，专门针对EGFR Ex20ins的新型靶向药物取得了重大进展，然而，这些新型药物的疗效数据无法与高效靶向疗法相媲美，因此产生了在临床实践中使用哪种药物的问题。
结论和观点
随着选择性靶向EGFR Ex20ins新型TKI的研发以及amivantamab获批EGFR Ex20ins突变NSCLC治疗的适应症，EGFR Ex20ins突变NSCLC治疗的前景令人兴奋。然而，未来仍存在新的挑战。新药物的探索应寻求在提高疗效和降低毒性的基础上进行改进。一线治疗存在巨大未被满足的需求，亟需有效的治疗策略。未来的临床试验也可能考虑比较Ex20ins特异性TKI vs amivantamab联合化疗。最后，确定最佳治疗顺序对于改善患者的长期预后至关重要。总之，仍需要进一步研究针对该患者群体的治疗方法。
参考文献
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