厄洛替尼对EGFR突变的IA-IIIA期NSCLC术后维持治疗可能获益（SELECT研究）

2014-06-15 钟文昭吴一龙中国医学论坛报

表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗EGFR敏感突变的晚期非小细胞肺癌(NSCLC)疗效卓越，多个随机对照研究确定了一线使用EGFR-TKI可改善EGFR突变肺癌的肿瘤缓解率和无进展生存期(PFS)，本届ASCO上，报告了LUX3和LUX6研究的汇总结果，一线TKI可改善EGFR突变肺癌，尤其是19缺失肺癌的总体生存(OS)。EGFR突变肺癌TKI的适应症已从二线到一线，能否从

表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗EGFR敏感突变的晚期非小细胞肺癌(NSCLC)疗效卓越，多个随机对照研究确定了一线使用EGFR-TKI可改善EGFR突变肺癌的肿瘤缓解率和无进展生存期(PFS)，本届ASCO上，报告了LUX3和LUX6研究的汇总结果，一线TKI可改善EGFR突变肺癌，尤其是19缺失肺癌的总体生存(OS)。EGFR突变肺癌TKI的适应症已从二线到一线，能否从进展期一线进一步扩展到早中期肺癌辅助治疗，从延长晚期肺癌PFS到提高手术患者的治愈率是一个备受关注的研究方向。TKI临床应用近十年，虽然目前ESMO指南明确反对辅助TKI，NICE指南则提示可作为研究的方向，然而多达51%受访医师仍建议辅助靶向治疗。系列临床研究为此孜孜不倦的探索，直至今天对于TKI辅助治疗时程、疗效、获益人群等规律仍然颇具争议。

辅助治疗的原理是通过清除极少量的循环肿瘤细胞，从而提高一部分病人的治愈率;对于另外一些残留癌细胞比较多、对治疗相对不敏感的病人，退而求此次，希望能延长无瘤生存期(DFS)。在第二个原理中，可以理解成进展期一线治疗在出现影像学或肉眼可见病灶的提前应用。

关于肿瘤辅助靶向治疗，已有一些成功的例子，比如imatinib用于GIST，herceptin用于乳腺癌。但也有不少失败的例子，结肠癌辅助靶向治疗的C-08研究，在avastin术后应用的1年期间内，生存曲线有所分离，但停药后很快就汇合，在avastin用药期间降低了复发风险，但停药后复发风险反而产生反弹效应，提示对残留癌细胞的抑制只是一过性的，该研究中avastin联合化疗并未延长3年DFS，也没有提高治愈率。在肺癌TKI辅助治疗的BR 19研究中，总体人群的OS和DFS两组都没有显著性差异，gefitinib组的生存曲线整个行程甚至都在安慰剂组的下方。该研究2005年提前终止，纳入了接近一半在辅助化疗中也无获益的Ib期患者，TKI中位治疗时间仅4.8个月，TKI的治疗效应被大量野生型非选择性人群承受的毒副反应掩盖。更令人难以理解的是，15例 EGFR突变患者的OS生存曲线，gefitinib组仍然在安慰剂组队下方，易瑞沙增加了死亡风险。其中一种解释是，在BR 19研究中，由于辅助gefitinib组的中位治疗时间只有4.8个月，而安慰剂组进展后接受TKI治疗的时间更长，从而使安慰剂组从TKI获益更多。MSKCC一项回顾性研究提示：在167例(IB 70%, II 15%, III 15%)均存在EGFR敏感突变的选择性人群中，TKI辅助治疗(gefitinib或erlotinib)和含铂化疗对比有延长EGFR突变人群2年DFS的趋势(89% vs 72%，P=0.06)，该研究TKI中位治疗时间为20个月，DFS生存曲线重复结肠癌C-08研究中间分开、两头相接的特征。从这一系列患者的后续随访资料中发现，在TKI辅助治疗后进展的患者中，二次TKI治疗的有效率仍高达73%，中位PFS为10月，接近一线TKI治疗的数据。

本次ASCO报道了MSKCC发起的一项EGFR突变病人TKI辅助治疗2年的单组前瞻性研究。这项SELECT研究在2012年ASCO报告了初步结果，本次为扩大样本量的后续追踪。EGFR活化突变、IA-IIIA期NSCLC术后接受常规辅助化疗或放化疗后，口服erlotinib 150 mg/d持续 2年，目前入组由两年前的36例扩展至100例。然而，erlotinib毒性使部分患者治疗期间减量和停药，11%的患者由于难以耐受在一个月内停药，69%的患者完成超过22个月的辅助治疗;24%的患者剂量调整至100mg，16%的患者剂量调整至50mg。患者中位2年DFS比率达89%。62%的患者复发后接受Erlotinib再次治疗，治疗中位时间为10月，接近一线TKI治疗的数据。TKI辅助治疗期间进展的患者中T790M的出现频率显著高于TKI辅助治疗停药后进展的患者，一种推测的机制为失去TKI刺激后，更具生长优势的敏感克隆重新覆盖了相对惰性的T790M克隆，使肿瘤再次获得了对TKI的敏感性，从而有可能延长患者的总体生存期。辅助后TKI二次应用仍然有效为TKI辅助治疗提供了进一步支持的证据，可以把EGFR突变病人TKI的治疗手段发挥的更充分。研究者总结：“erlotinib辅助治疗至少对微转移病灶具有细胞生长抑制作用”。值得注意的是，该研究中纳入了45%I期的患者，而II期患者2年DFS(78%)甚至劣于在III期患者(91%)，提示相对早期的患者获益不明显的趋势;此外，该研究是II期单组研究，在没有随机对照研究长期随访结果之前，仍难以确定TKI术后治疗使患者获益。

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2017-06-27 1e145228m78(暂无匿称)

学习了，谢谢作者分享!

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2015-03-18 juliusluan78

#III#

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2015-05-03 zhangxingru

#SeLECT#

81 0
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2014-06-17 ms306040998833292

#厄洛替尼#

62 0
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2014-06-17 liuyiping

#GFR#

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