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EGFR突变阳性非小细胞肺癌耐药后精准治疗

2017-03-20 佚名 中华肿瘤杂志

随着分子分型的研究进展,非小细胞肺癌(NSCLC)的治疗已迈入精准治疗时代。表皮生长因子受体(EGFR)敏感突变阳性患者可从EGFR-酪氨酸激酶抑制剂(EGFR-TKI)一线治疗中获益,无疾病进展生存期(PFS)从标准含铂双药化疗的4~6个月延长到9~13个月,疾病客观反应率(objective response rate, ORR)从50%提高到80%,但遗憾的是均不可避免地出现了耐药。常见的耐

随着分子分型的研究进展,非小细胞肺癌NSCLC)的治疗已迈入精准治疗时代。表皮生长因子受体(EGFR)敏感突变阳性患者可从EGFR-酪氨酸激酶抑制剂(EGFR-TKI)一线治疗中获益,无疾病进展生存期(PFS)从标准含铂双药化疗的4~6个月延长到9~13个月,疾病客观反应率(objective response rate, ORR)从50%提高到80%,但遗憾的是均不可避免地出现了耐药。常见的耐药机制有T790M突变和MET扩增,另外还有小细胞转化、上皮-间叶转化、PIK3CA突变、EGFR过表达、IGF1R过表达等。

针对T790M突变的精准治疗

EGFR20外显子T790M突变是首个被发现的EGFR-TKI耐药机制,也是目前发现的最常见的EGFR-TKI耐药机制,存在于50%~60% EGFR-TKI治疗后的患者。

针对T790M的克服耐药研究已经取得巨大进展,第三代EGFR-TKI为针对此靶点的特异性靶向药物,包括奥希替尼(AZD9291)、rociletinib(CO-1686)、olmutinib(HM61723)、EGF816、ASP8273等。

奥希替尼为一种口服、强效、不可逆的EGFR-TKI抑制剂。两项Ⅱ期临床试验的合并分析显示,奥希替尼治疗第一代EGFR-TKI耐药后伴有T790M突变患者的ORR为66%,中位PFS为11个月。

奥希替尼现已被美国食品与药品管理局(FDA)批准用于EGFR-TKI耐药后伴有T790M突变患者的治疗。

rociletinib也是一种口服的不可逆的第三代EGFR-TKI,作用靶点同样是EGFR敏感突变和T790M突变,因ORR远低于预期,且有高血糖和心电图QT间期延长两种比较严重的毒副反应,此药物停止了研发。

2016年美国临床肿瘤学会(ASCO)年会上还报告了另外3个第三代EGFR-TKI(olmutinib、EGF816、ASP8273)的临床试验数据,其有效性及安全性均需临床试验进一步检验。目前越来越多的第三代EGFR-TKI正在涌现,为耐药后T790M阳性患者的克服耐药策略提供了更多选择,也显着改善了第一代EGFR-TKI耐药后患者的生存。

针对MET扩增的精准治疗

随着分子生物学的不断发展及研究的不断深入,MET扩增作为另一耐药机制逐渐进入大家的视野。

MET扩增占第一代EGFR-TKI耐药机制的5%~22%,跟T790M突变一样,MET基因扩增也可见于未经第一代EGFR-TKI治疗的患者,是第一代EGFR-TKI原发性耐药机制之一。

最近的研究表明,MET信号通路激活不仅仅表现为MET基因扩增,蛋白过表达、14外显子剪切突变等也是其激活方式。该结果提示,在临床上,对EGFR-TKI治疗失败的患者,除了常规检测MET基因扩增外,也应该检测MET基因的表达和序列。

针对MET信号通路激活的特异性抑制剂也一直是临床研究的热点。INC280为一新型MET靶向抑制剂。2016年ASCO年会上报道了一项有关INC280的Ⅰb/Ⅱ期临床试验(NCT10610336)结果,吉非替尼联合INC280治疗EGFR-TKI治疗失败后出现MET扩增或过表达的患者,ORR为31%,疾病控制率(DCR)为81%,且疗效与MET基因拷贝数呈正相关。

这提示INC280可能成为EGFR-TKI耐药后伴有MET扩增或过表达患者的治疗选择,EGFR-TKI联用MET抑制剂可能是克服此耐药机制的有效方法。

针对组织学类型改变的精准治疗

肿瘤细胞组织学类型改变已被证明为EGFR-TKI获得性耐药的原因之一,主要包括EMT和小细胞转化两种,分子机制暂时不明确。EGFR-TKI耐药后发现小细胞转化的患者,通常仍保留原有的EGFR敏感突变,这类患者可能从针对小细胞肺癌的标准化疗中获益。

对于接受EGFR-TKI治疗后的EGFR敏感突变阳性的晚期NSCLC患者,克服耐药策略是一个值得深入研究的临床问题。充分整合临床耐药模式和耐药分子机制是当前制订精准克服耐药策略的最佳思路。

相信在精准医学理念指导下,克服耐药的研究将取得更多突破性成果,使更多患者获益。

原始出处:

皮灿, 张一辰, 徐崇锐,等. 表皮生长因子受体敏感突变阳性非小细胞肺癌耐药后的精准治疗. 中华肿瘤杂志,2017.

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    2021-11-09 湘雅科教

    已拜读,受益匪浅。

    0

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    2017-03-22 liuyiping

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