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知否?奥希替尼耐药机制逐一告破!四大策略助力肺癌精准治疗!

来源:全球肿瘤医生网2019-02-25 09:08

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人表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)给EGFR基因敏感突变患者带来巨大的临床获益。经历近15年的临床实践探索与持续的新药研发,目前已问世的三代EGFR-TKIs类药物,主要包括:第一代吉非替尼、厄洛替尼以及埃克替尼(中国自主研发的1.1类新药),第二代药物主要有阿法替尼和达克替尼,第三代药物奥希替尼也于2018年获批上市。


大部分患者在使用一代或二代EGFR-TKI治疗后会产生耐药,耐药患者中约50%发生了EGFR T790M突变。奥希替尼是第三代EGFR-TKI,能够高效、选择性的作用于EGFR敏感突变和T790M耐药突变,同时具有中枢神经系统活性。相关研究表明,服用奥希替尼(AZD9291)的平均耐药期大约为11个月,那么,奥西替尼耐药后该如何应对呢?


首先,介绍一下第三代EGFR-TKIs——奥希替尼!


奥斯替尼|塔格瑞斯简介

英文名称:

 Osimertinib

商品名:

塔格瑞斯 | Tagrisso/Tagrix(俗称AZD9291)

价格:

51000元/盒,低保患者免费获赠,非低保连续服药满4个月后赠药8个月

靶点:

T790M

适应症:

主要用于治疗晚期非小细胞肺癌

副作用:

副作用较轻微,主要是红疹、指甲变色和腹泻等


随着三代EGFR TKI奥希替尼在临床的广泛应用,探寻奥希替尼的耐药机制,从而精准克服耐药,已成为当下研究的热点。敲定EGFR T790M突变晚期NSCLC接受奥希替尼治疗的耐药机制后,再对症下药!


2018 年在德国慕尼黑举行了极具影响力的欧洲肿瘤内科学会(ESMO)年会,靶向治疗作为晚期非小细胞肺癌(NSCLC)重要的治疗模式,在ESMO大会上亦有众多研究报道,关于三代EGFR TKI奥希替尼耐药机制的报道更是引发了医学界的高度关注与认可。


奥希替尼耐药的原因是什么?

研究报道显示:奥希替尼耐药主要与旁路激活、下游信号的上调、其他位点的突变、小细胞肺癌转化等有关。


具体地说,无论奥希替尼一线或二线用药,耐药后突变多为MET扩增及C797X共突变,相关的后续治疗方案的研究也主要集中于这两个基因突变的用药。但是,T790M突变丢失(约42%-68%)是奥西替尼耐药的主要原因,提示体内肿瘤细胞群分布比例发生变化。


有些患者同时存在不同耐药机制,最常见的包括EGFR C797S突变伴随MET基因扩增。其它的耐药机制包括但不局限于除C797S突变的其他EGFR获得性罕见突变以及EGFR,HER2,KRAS,PIK3CA基因扩增等。


奥西替尼耐药后处理方案有哪些?

【一】根据最新2019第二版NCCN指南,对于奥希替尼耐药后的治疗方案做出了如下推荐!

  • 对于以下三类肺癌患者,

1.无症状进展;

2.有症状的脑转移(配合脑转移处理,如全脑放疗、培美曲赛、替莫唑胺、鞘内注射等);

3.有症状的全身性(颅外)孤立病灶。

NCCN指南推荐可以考虑根治性局部治疗(如立体定向放疗或手术),同时继续使用奥希替尼!


  • 对于全身性多发病灶的肺癌患者,指南建议使用系统性治疗(全身化疗)。


  • 奥希替尼耐药后无可用靶向处理方案该怎么办?

阿法替尼联合西妥昔单抗可以考虑作为TKI耐药后的治疗。此外,值得注意的是,不论PDL1表达如何,PD1免疫治疗作为EGFR/ALK突变肺癌靶向耐药后的二线治疗,并不是很有效。


虽然NCCN指南并未推荐靶向治疗作为奥希替尼耐药后的方案,但已有多个研究结果证实可用靶药来克服奥西替尼耐药,下面,一起来看!


【二】奥希替尼耐药后有新突变的靶药治疗策略有哪些?

1.MET扩增(比例约为20%)为奥希替尼最常见的耐药原因。对此目前处理方式比较明确,采用奥希替尼联合MET抑制剂方式即可成功克服。目前的MET靶药也较多,有克唑替尼、卡博替尼(XL184)、沃利替尼、INC280、替泊替尼(Tepotinib)、Capmatinib等,所以奥希替尼耐药的患者应积极进行MET基因的检测。


2.继发耐药突变C797X突变(主要是为C797S类型),发生率15%左右。但治疗上需注意 是否单发还是与T790M共发,共发是顺式还是反式。对于单发C797S,一代TKI即可解决。但更常见的是共发,要明确区分顺式和反式。当T790M突变和C797S突变位于同一条染色体上,我们称之为顺式构型(cis);位于相对面的染色体上,称之为反式构型(trans)。两种方式的治疗策略完全不同。


有研究案例显示:

针对顺式突变,治疗方式为奥希替尼联合贝伐单抗+布加替尼,三药联合可能起关键作用;针对反式突变,治疗方式为1代EGFR靶药联合3代EGFR靶药【易瑞沙(吉非替尼)联合奥希替尼治疗可能起到较好的疗效】。(通过基因检测可检出顺反式,如有基因检测等相关咨询,可直接点击下方在线咨询。)针对C797S单突变(无T790M),有用1代EGFR靶药(吉非替尼)成功控制的案例。


3.HER2的继发扩增。有研究表明,采用HER2单抗曲妥珠单抗+多西他赛治疗成功的案例。


4.RET融合,奥希替尼联合BLU-667治疗案例,表明该方案耐受性良好,患者肿瘤明显缩小,病情得到控制。


 5.BRAF突变,研究表明,采用奥希替尼+康奈非尼(encorafenib)治疗方案可明显减少癌细胞增殖。


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【三】无可用靶向药怎么办?

还有化疗及免疫治疗策略!奥希替尼耐药患者理论上都应积极转归化疗。Mok TS的研究显示化疗对于经治的T790M阳性患者有效率可达31%,中位PFS(无进展生存期)有4.4个月。除了常规化疗,研究显示间插治疗及再挑战EGFR靶药的方法也有一定的临床疗效!


化疗方案包括间插治疗(即化疗与靶药轮换治疗)和化疗后再挑战奥希替尼两种。另有研究表明,无可用靶向治疗的情况下,免疫治疗方案对PDL1高表达及抽烟者来说是获益人群。


写在最后

全球肿瘤医生网提醒大家:在服用奥西替尼耐药后,依然要保持积极心态配合治疗,积极配合基因检测,尽快制定下一步治疗方案。另外,对于未知原因或无靶药可用的患者,应转归化疗,化疗后亦可再尝试靶药。部分患者可选择免疫用药。


我们相信,在科研人员在奥希替尼耐药新机制的不断探索中,对应的治疗策略应运而生,为肺癌患者的生存获益作出了巨大保障!最后,为大家介绍两位国际上知名度很高的顶级肺癌专家!如有国际专家会诊需求,或基因检测方面的咨询需求,可直接拨打全球肿瘤医生网医学部电话400-666-7998。



美国顶尖癌症专家简介


肺癌


Christopher Azzoli

麻省总医院胸部肿瘤中心专家

ASCO临床实践指南委员会主席


Lennes, Inga,T

麻省总医院胸部肿瘤中心专家

擅长领域:肺癌、胸部肿瘤、食道癌、胸腺瘤

全球肿瘤医生网仅为患者提供全球抗癌新药上市及用药最新信息,如需了解详情可致电医学部400-666-7998。
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