肺癌大咖談丨將新研究成果融入實踐，應對EGFR Ex20ins突變NSCLC治療中的挑戰
EGFR 20 號外顯子插入（exon20 insertion mutation,Ex20ins）突變發生率居 EGFR 基因突變第 3 位，僅次於 19 號外顯子缺失突變和 21 號外顯子 L858R 點突變。本文介紹 ASCO Daily News 釋出的一篇廣東省人民醫院吳一龍教授和林嘉欣教授關於EGFR Ex20ins突變非小細胞肺癌（NSCLC）治療的文章。
要點：
EGFR突變是NSCLC中關鍵的致癌驅動變異之一。高達90%的EGFR突變是外顯子19缺失和外顯子21L858R置換。約10%的EGFR突變NSCLC可檢測到Ex20ins，這是第三大最常見的啟用EGFR突變亞型[1]。與經典EGFR變體類似，Ex20ins在女性、從不吸煙或輕度吸煙者以及腺癌組織學型別患者中最常見。
EGFR Ex20ins由C-螺旋（AA761-766）和緊鄰C-螺旋的環（AA767-775）出現的1-4個胺基酸（AA）插入組成。在已鑒定的60多種獨特的EGFR Ex20ins亞型中，大多數位於C螺旋後的環內[2]。這種復雜的突變譜導致了EGFR Ex20ins突變腫瘤的生物學差異和對EGFR抑制劑的不同敏感性。例如，EGFRA763_Y764insFQEA對第一代EGFR-TKI敏感，而環內突變亞型則對EGFR-TKI不敏感[3]。為了盡可能檢測出所有可靶向治療的EGFR Ex20ins，指導臨床實踐中的治療決策，中國指南和國際指南建議進行下一代測序（NGS）檢測[4]。
不同於敏感EGFR突變患者在EGFR-TKI研發問世後實作了臨床治療效果顯著改善，EGFR Ex20ins患者的預後較差[5,6]。近年來，專門針對EGFR Ex20ins的新型靶向藥物取得了重大進展，例如mobocertinib、amivantamab和舒沃替尼。然而，這些新藥的療效數據無法媲美高效靶向療法（例如奧希替尼）。在這裏，我們對EGFR Ex20ins晚期NSCLC患者的分子檢測和治療管理的最新發現和即將面臨的挑戰進行概述（圖）[7]。
圖. 治療EGFR Ex20ins晚期NSCLC的一般方法和當前治療策略
*NCCN指南2024 V5版推薦。
EGFR Ex20ins突變NSCLC的治療策略
一線治療
由於現有EGFR-TKI的臨床獲益有限， 鉑類雙藥化療 仍然是一線治療中推薦用於攜帶EGFR Ex20ins的患者的最有效治療方法[6]。
值得註意的是，靶向EGFR和MET的新型雙特異性抗體amivantamab在III期PAPILLON試驗中顯示出令人鼓舞的結果。對於未經治療的EGFR Ex20ins患者，與單純化療相比，amivantamab聯合化療可改善無進展生存期（HR=0.40；95%CI: 0.30-0.53）和客觀緩解率（73%；95%CI: 1.32-1.68]）[8]。鑒於其優越的療效，FDA批準 amivantamab聯合化療 的一線治療適應癥[9]。
在現實世界中，化療的療效始終優於現有的EGFR-TKI，但在化療中添加免疫檢查點抑制劑（ICI）幾乎沒有臨床獲益[10,11]。到目前為止，ICI聯合化療的獲益以及ICI在EGFR Ex20ins突變NSCLC治療中的最佳位置都沒有明確結論。但值得註意的是， 無論PD-L1表達水平如何，單藥ICI都不應作為EGFR Ex20ins患者的一線療法 [12]。
二線及後續治療
根據I期CHRYSALIS試驗的結果，amivantamab被批準用於初始化療期間或之後疾病進展的EGFR Ex20ins晚期NSCLC患者[13,14]。後續治療選擇包括標準全身治療或納入臨床試驗。
EGFR Ex20ins突變NSCLC的新型靶向藥物
表. EGFR Ex20ins突變NSCLC靶向治療的主要前瞻性臨床試驗
Eblast/網站的摘要：在NSCLC領域，專門針對EGFR Ex20ins的新型靶向藥物取得了重大進展，然而，這些新型藥物的療效數據無法與高效靶向療法相媲美，因此產生了在臨床實踐中使用哪種藥物的問題。
結論和觀點
隨著選擇性靶向EGFR Ex20ins新型TKI的研發以及amivantamab獲批EGFR Ex20ins突變NSCLC治療的適應癥，EGFR Ex20ins突變NSCLC治療的前景令人興奮。然而，未來仍存在新的挑戰。新藥物的探索應尋求在提高療效和降低毒性的基礎上進行改進。一線治療存在巨大未被滿足的需求，亟需有效的治療策略。未來的臨床試驗也可能考慮比較Ex20ins特異性TKI vs amivantamab聯合化療。最後，確定最佳治療順序對於改善患者的長期預後至關重要。總之，仍需要進一步研究針對該患者群體的治療方法。
參考文獻
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