关于肺癌的八大基因及其靶向药物治疗
<img src="https://mmbiz.qpic.cn/mmbiz_png/G1CsdzFVCfYI1VopKvX5ibVicHFL9mR4Lwclwm8wjicjiaDlDDVmuBaa1WrXVlPaIwoTbCB15GXkE3BzDOB6via1pIA/640?wx_fmt=png&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"><p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"> 尽管<span style="color: black;">咱们</span>有众多的靶向<span style="color: black;">药品</span>和免疫<span style="color: black;">药品</span>，但晚期肺癌仍<span style="color: black;">没</span>法根治，<span style="color: black;">由于</span></span><span style="color: black;"><span style="color: black;">最少</span>在<span style="color: black;">日前</span>，<span style="color: black;">咱们</span><span style="color: black;">无</span>办法完全避免耐药。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;">针对肺癌的八大耐药基因，我整理了相应的治疗<span style="color: black;">选取</span>。</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;">（一）</span></strong><strong style="color: blue;"><span style="color: black;">EGFR突变 </span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">EGFR突变是<span style="color: black;">日前</span>肺癌靶向<span style="color: black;">药品</span>对应的<span style="color: black;">重点</span>驱动基因，<span style="color: black;">平常</span>的突变位点<span style="color: black;">出现</span>在18、19、20和21号外显子上。最<span style="color: black;">平常</span>的有两种，<span style="color: black;">第1</span>种是19号外显子的缺失（19DEL，45%），<span style="color: black;">另一</span>一种是21号外显子L858R（40-45%）的突变。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;">针对这两种突变的肺癌<span style="color: black;">病人</span>， 最新版NCCN指南以及我国CSCO2018版的指南都<span style="color: black;">举荐</span>一代EGFR<span style="color: black;">控制</span>剂（易瑞沙、特罗凯、凯美纳）和二代EGFR<span style="color: black;">控制</span>剂阿法替尼<span style="color: black;">做为</span>一线治疗。</span></strong></span><span style="color: black;">但不论是一代、二代还是最新上市的三代靶向药，都存在耐药问题。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://mmbiz.qpic.cn/mmbiz_jpg/G1CsdzFVCfYI1VopKvX5ibVicHFL9mR4LwJz0wNMP6E2EbJubia678N4FwPPvicXoZgvcn8AicNjtVPiajibMvsBEzxicg/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;"><span style="color: black;">第1</span>代EGFR<span style="color: black;">控制</span>剂耐药后处理</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">都数</span>病人在<span style="color: black;">运用</span><span style="color: black;">第1</span>代靶向<span style="color: black;">药品</span>1-2年时间内，会<span style="color: black;">显现</span>耐药，肿瘤<span style="color: black;">发展</span>。在所有耐药的<span style="color: black;">病人</span>中，大概50-60%都是<span style="color: black;">由于</span></span><span style="color: black;"><span style="color: black;">显现</span>了T790M突变</span><span style="color: black;">，其他突变的<span style="color: black;">原由</span><span style="color: black;">包含</span>c-MET扩增、表型转化等，关于耐药的机制和处理<span style="color: black;">方法</span>如下。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">60%的<span style="color: black;">病人</span>是<span style="color: black;">因为</span><span style="color: black;">显现</span>继发耐药突变----T790M 突变，一旦T790M突变，<span style="color: black;">能够</span><span style="color: black;">运用</span>三代靶向<span style="color: black;">药品</span>奧希替尼（泰瑞沙）；</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">20%的<span style="color: black;">病人</span>耐药是<span style="color: black;">由于</span>旁路激活，<span style="color: black;">例如</span>c-MET 扩增，<span style="color: black;">亦</span><span style="color: black;">便是</span>说肿瘤细胞的增殖绕开了EGFR，走了<span style="color: black;">另一</span>一条路。<span style="color: black;">倘若</span>基因检测<span style="color: black;">表示</span>MET扩增或突变，<span style="color: black;">能够</span>联合克唑替尼治疗；</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">表型改变<span style="color: black;">亦</span>是一代靶向<span style="color: black;">药品</span>产生耐药的一种<span style="color: black;">状况</span>，<span style="color: black;">例如</span>腺癌会向小细胞肺癌转化，上皮细胞癌会向间叶细胞恶性肿瘤转化。针对这种<span style="color: black;">状况</span>，就<span style="color: black;">必须</span>联合小细胞肺癌的化疗<span style="color: black;">方法</span>进行相应治疗；</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">EGFR驱动基因的下游信号通路激活，<span style="color: black;">亦</span>会<span style="color: black;">引起</span>原发耐药或<span style="color: black;">得到</span>性耐药。要<span style="color: black;">按照</span><span style="color: black;">详细</span><span style="color: black;">状况</span>判断，<span style="color: black;">倘若</span><span style="color: black;">无</span>任何靶向<span style="color: black;">药品</span>可<span style="color: black;">选择</span>，看<span style="color: black;">是不是</span><span style="color: black;">思虑</span>化疗。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;">第三代EGFR<span style="color: black;">控制</span>剂耐药处理</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">奧希替尼<span style="color: black;">做为</span>一代靶向药耐药后的选择，仍然会产生耐药。如下图所示，它的耐药<span style="color: black;">一样</span>是<span style="color: black;">伴同</span><span style="color: black;">各样</span>基因层面的<span style="color: black;">原由</span>，<span style="color: black;">例如</span>继发C797S的共生突变，其他旁路激活等。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">针对三代<span style="color: black;">药品</span>耐药后的处理<span style="color: black;">办法</span>，<span style="color: black;">亦</span>是<span style="color: black;">必须</span>先找到<span style="color: black;">原由</span>，再看<span style="color: black;">怎样</span>处理。</span><strong style="color: blue;"><span style="color: black;">（注：<span style="color: black;">倘若</span>EGFR基因C797S和T790M<span style="color: black;">位置于</span>不同等位的基因上，<span style="color: black;">便是</span>反式突变；<span style="color: black;">位置于</span>相同等位基因上，则是顺式突变。）</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://mmbiz.qpic.cn/mmbiz_png/Uia9ysy1SpiaH4A2enuTM4xJ3G2CuiaSZJYhVaJYYSSZ1ibam95WZ3BdTiaV7ZXB0ibhUAQhusKh5WavFGPaAibYDHvlA/640?wx_fmt=png&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;">EGFR罕见突变和<span style="color: black;">插进</span>突变</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">在EGFR突变的<span style="color: black;">病人</span>中，除了<span style="color: black;">平常</span>的19/21位点突变外，还有3种罕见突变：<strong style="color: blue;">G719X（18外显子）、S768I（20外显子）和L861Q（21外显子）。</strong></span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">针对这3种位点突变，吴一龙教授<span style="color: black;">举荐</span><span style="color: black;">运用</span>阿法替尼，<span style="color: black;">然则</span>，阿法替尼对存在T790M突变、20号外显子<span style="color: black;">插进</span>突变的<span style="color: black;">病人</span><span style="color: black;">掌控</span>效果较差。另外，今年ASCO<span style="color: black;">报告</span>了奧希替尼针对这类不<span style="color: black;">平常</span>突变的疗效<span style="color: black;">亦</span>不错，<span style="color: black;">因此呢</span><span style="color: black;">亦</span>可做<span style="color: black;">选取</span><span style="color: black;">药品</span>。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">EGFR 20外显子<span style="color: black;">插进</span>突变是EGFR突变的第三大类型，<span style="color: black;">出现</span>率4%<span style="color: black;">上下</span>。EGFR 20 外显因子<span style="color: black;">插进</span>突变的<span style="color: black;">病人</span>对普通的靶向<span style="color: black;">药品</span>疗效不是很好。针对EGFR 20外显子<span style="color: black;">插进</span>突变，<span style="color: black;">日前</span>尚<span style="color: black;">没</span><span style="color: black;">准许</span>的<span style="color: black;">药品</span>。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://mmbiz.qpic.cn/mmbiz_jpg/G1CsdzFVCfbGia5dyQ9cKtibfqmrpghPSiaIYCIt73pibFuSjJiaWYicbFlGQMySwfzmQxntictWxML4n90nqxVRiapG2g/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;">（二）</span></strong><strong style="color: blue;"><span style="color: black;">ALK基因融合突变</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">ALK是间变性淋巴瘤激酶的缩写，ALK融合基因突变在非小细胞肺癌<span style="color: black;">病人</span>中突变率<span style="color: black;">仅有</span>3%-8%，但却被<span style="color: black;">叫作</span>为“钻石突变”，<span style="color: black;">原由</span>是针对ALK靶点的靶向药比较多，<span style="color: black;">况且</span>有些靶向药<span style="color: black;">能够</span>逆转上个靶向药的耐药，因而<span style="color: black;">病人</span><span style="color: black;">能够</span><span style="color: black;">得到</span>更长的<span style="color: black;">存活</span>期。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://mmbiz.qpic.cn/mmbiz_png/Uia9ysy1SpiaH4A2enuTM4xJ3G2CuiaSZJY3sX68AU7c65F5kIFj7O3rfvp6PFu4PRnqMhemU2C6nOPR3NMydvic1Q/640?wx_fmt=png&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">如上图所示，汇总了<span style="color: black;">日前</span><span style="color: black;">平常</span>的五种ALK<span style="color: black;">控制</span>剂。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;"><span style="color: black;">首要</span><span style="color: black;">便是</span><span style="color: black;">第1</span>代ALK<span style="color: black;">控制</span>剂克唑替尼，其次是第二代ALK<span style="color: black;">控制</span>剂色瑞替尼、艾乐替尼和布加替尼，以及第三代ALK<span style="color: black;">控制</span>剂劳拉替尼。</span></strong><span style="color: black;"><span style="color: black;">针对</span>ALK阳性的非小细胞肺癌<span style="color: black;">病人</span>的首选治疗<span style="color: black;">方法</span>为克唑替尼，但这个<span style="color: black;">药品</span>入脑性不强，<span style="color: black;">倘若</span><span style="color: black;">显现</span>了脑转移，治疗效果并<span style="color: black;">欠好</span>。</span><span style="color: black;"><span style="color: black;">倘若</span><span style="color: black;">显现</span>耐药，后续治疗<span style="color: black;">能够</span><span style="color: black;">思虑</span>二代ALK<span style="color: black;">控制</span>剂艾乐替尼、色瑞替尼或布加替尼。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">布加替尼是一种新型的ALK和EGFR双重<span style="color: black;">控制</span>剂，可强效<span style="color: black;">控制</span>这两种突变。<span style="color: black;">日前</span>在美国<span style="color: black;">已然</span><span style="color: black;">获准</span>用于治疗克唑替尼用药<span style="color: black;">时期</span>病情<span style="color: black;">发展</span>或<span style="color: black;">没</span>法耐受克唑替尼的ALK阳性转移性非小细胞肺癌<span style="color: black;">病人</span>。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">劳拉替尼是ALK阳性第三代靶向<span style="color: black;">药品</span></span><span style="color: black;">，<span style="color: black;">能够</span><span style="color: black;">控制</span>克唑替尼耐药的9种突变，对二代靶向<span style="color: black;">药品</span>耐药后仍有较高的有效性。<span style="color: black;">同期</span>劳拉替尼<span style="color: black;">亦</span><span style="color: black;">拥有</span>较强的血脑屏障透过能力，入脑效果较强，<span style="color: black;">尤其</span>适合对其他ALK耐药的晚期非小细胞肺癌<span style="color: black;">病人</span>。这种<span style="color: black;">药品</span><span style="color: black;">已然</span>被美国FDA授予突破性疗法的认定，</span><span style="color: black;">用于治疗先前接受过一种或多种ALK<span style="color: black;">控制</span>剂的ALK阳性转移性非小细胞肺癌<span style="color: black;">病人</span>。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://mmbiz.qpic.cn/mmbiz_jpg/G1CsdzFVCfZr8YCzdicsYG0400KpfdaZutabjeA6hUA1nc8upnvoiadlgTvicxRcNvd5WdLVIwweKPUhxy9ctpJIQ/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;"><span style="color: black;">以上</span><strong style="color: blue;"><span style="color: black;">EGFR突变和<strong style="color: blue;"><span style="color: black;">ALK基因融合突变是<span style="color: black;">日前</span><span style="color: black;">举荐</span>肺腺癌<span style="color: black;">病人</span>常规进行的基因检测。</span></strong></span></strong></span></strong></span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;">（三）</span></strong><strong style="color: blue;"><span style="color: black;">ROS1融合基因突变</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">大约2%的非小细胞肺癌<span style="color: black;">病人</span>会<span style="color: black;">显现</span>ROS1融合，与ALK基因突变类似，<span style="color: black;">显现</span>ROS1突变的<span style="color: black;">病人</span>，<span style="color: black;">更加多</span>的是<span style="color: black;">青年</span>的、非吸烟的肺癌<span style="color: black;">病人</span>，其中肺腺癌<span style="color: black;">占多数</span>。非小细胞肺癌中<span style="color: black;">发掘</span>ROS1<span style="color: black;">能够</span>与14种基因<span style="color: black;">出现</span>融合，最<span style="color: black;">平常</span>的融合形式是CD74-ROS1融合。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">FDA<span style="color: black;">准许</span>治疗ROS1阳性的<span style="color: black;">药品</span>除了克唑替尼，还有色瑞替尼、卡博替尼、劳拉替尼、Entrectinib、TPX005以及DS-6051b，如下图所示。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://mmbiz.qpic.cn/mmbiz_png/Uia9ysy1SpiaH4A2enuTM4xJ3G2CuiaSZJYhPDsHsyFE7H0KzR6piccWRxtQtN5GmDotybR6x8sejdKibsicEialhNDPA/640?wx_fmt=png&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">克唑替尼治疗ROS1融合，<span style="color: black;">做为</span>靶向药，不可避免会<span style="color: black;">显现</span>耐药，其中<span style="color: black;">平常</span>的耐药机制有以下4点：ROS1本身激酶结构域突变、拷贝数扩增、可能激活了其他的信号通路（如c-KIT或KRAS基因突变）以及未知的耐药<span style="color: black;">原由</span>。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">下图是ROS1激酶区域的突变<span style="color: black;">导致</span>克唑替尼的耐药以及<span style="color: black;">关联</span>的处理<span style="color: black;">方法</span>。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://mmbiz.qpic.cn/mmbiz_png/Uia9ysy1SpiaH4A2enuTM4xJ3G2CuiaSZJYac2rkEffckIAdE2wgIApteBaCkianiar9wJdnBkLkDorIDdeYyYB8cgg/640?wx_fmt=png&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">运用</span>克唑替尼<span style="color: black;">做为</span>ROS1基因突变肺癌的一线治疗，耐药后，面临两种<span style="color: black;">状况</span>：</span><strong style="color: blue;"><span style="color: black;">一种是ROS1基因<span style="color: black;">出现</span>突变<span style="color: black;">引起</span>耐药，<span style="color: black;">另一</span>一种是非ROS1基因突变<span style="color: black;">引起</span>的耐药。</span></strong><span style="color: black;">这两种<span style="color: black;">状况</span>又分<span style="color: black;">有些</span><span style="color: black;">详细</span>的治疗<span style="color: black;">前提</span>。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">针对</span>ROS1基因<span style="color: black;">出现</span>突变<span style="color: black;">引起</span>耐药，又被分<span style="color: black;">成为了</span>两种<span style="color: black;">状况</span>；</span><strong style="color: blue;"><span style="color: black;">一种是<span style="color: black;">显现</span>了G2032R突变，<span style="color: black;">此时</span>候<span style="color: black;">能够</span>用卡博替尼、洛普替尼<span style="color: black;">或</span>化疗；另一种是非G2032R突变，<span style="color: black;">此时</span>候<span style="color: black;">能够</span><span style="color: black;">运用</span>劳拉替尼<span style="color: black;">或</span>洛普替尼。</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">倘若</span>不是ROS1基因<span style="color: black;">出现</span>突变，那就要看症状表现，<span style="color: black;">倘若</span><span style="color: black;">显现</span>了脑转移，就要优先<span style="color: black;">运用</span>入脑能力强的<span style="color: black;">药品</span>，<span style="color: black;">例如</span>色瑞替尼或劳拉替尼；<span style="color: black;">倘若</span><span style="color: black;">显现</span>了系统的<span style="color: black;">发展</span>，最好的<span style="color: black;">选取</span><span style="color: black;">便是</span><span style="color: black;">运用</span>第二代ROS1靶向药和化疗联用的方式治疗。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://mmbiz.qpic.cn/mmbiz_jpg/G1CsdzFVCfbGia5dyQ9cKtibfqmrpghPSiaIYCIt73pibFuSjJiaWYicbFlGQMySwfzmQxntictWxML4n90nqxVRiapG2g/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;">（四）</span></strong><strong style="color: blue;"><span style="color: black;">MET基因突变 </span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">MET<span style="color: black;">指的是</span>肺癌中间质上皮转化因子，它的基因<span style="color: black;">反常</span>有三种形式：MET 14外显子跳跃性突变、MET扩增以及MET蛋白的过表达。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">如下图所示，<span style="color: black;">日前</span>针对MET基因<span style="color: black;">反常</span>的<span style="color: black;">药品</span>较多，<span style="color: black;">日前</span>克唑替尼及卡博替尼在临床中应用比较<span style="color: black;">广泛</span>，除此之外Capmatinib(INC280)、Tepotinib、Onartuzumab (MetMAb)、Rilotumumab、Savolitinib等<span style="color: black;">药品</span><span style="color: black;">亦</span>逐步进入II及III期临床<span style="color: black;">实验</span>.</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://mmbiz.qpic.cn/mmbiz_png/Uia9ysy1SpiaH4A2enuTM4xJ3G2CuiaSZJYiac4j7icBp3Bm5E92Z3m8MGrt3e9es9OXcP4ocpDMdYXjeYvATiaPDRkw/640?wx_fmt=png&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">随着靶向<span style="color: black;">药品</span>的发展，MET基因的<span style="color: black;">反常</span><span style="color: black;">亦</span><span style="color: black;">常常</span><span style="color: black;">作为</span>其他靶向治疗耐药的<span style="color: black;">原由</span>。在临床治疗层面，经常会出<span style="color: black;">此刻</span>EGFR基因阳性的<span style="color: black;">病人</span>中，<span style="color: black;">重点</span><span style="color: black;">便是</span><span style="color: black;">引起</span>靶向治疗耐药，<span style="color: black;">处理</span>这种<span style="color: black;">状况</span>的理想对策<span style="color: black;">便是</span>进行EGFR靶向药和MET靶向药的联合治疗。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;">（五）</span></strong><strong style="color: blue;"><span style="color: black;">HER2基因突变 </span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">HER2突变是肺癌的<span style="color: black;">平常</span>驱动突变基因之一，在2%的肺癌中<span style="color: black;">能够</span>检测出。<span style="color: black;">日前</span>可用的<span style="color: black;">药品</span>有： T-DM1、阿法替尼、曲妥珠单抗、吡咯替尼（Pyrotinib）和波奇替尼。在肺癌的现行NCCN指南中，<span style="color: black;">针对</span>HER2突变的肺癌推荐以T-DM1为主。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://mmbiz.qpic.cn/mmbiz_png/Uia9ysy1SpiaH4A2enuTM4xJ3G2CuiaSZJYZKXJamJupbJ67gR1E5CTMuRaELEKV6ch80GQjxJzD1XyPzjBccibfHg/640?wx_fmt=png&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;">（六）</span></strong><strong style="color: blue;"><span style="color: black;">BRAF基因突变</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">非小细胞肺癌中BRAF突变率为1%-3%，其中50%为BRAF V600E突变，大部分为腺癌，多<span style="color: black;">出现</span>于吸烟肺癌<span style="color: black;">病人</span>。<span style="color: black;">日前</span>针对BRAF突变的肺癌<span style="color: black;">病人</span>，美国FDA<span style="color: black;">获准</span>了达拉菲尼联合曲美替尼的治疗<span style="color: black;">方法</span>，有效率是64%，<span style="color: black;">没</span><span style="color: black;">发展</span><span style="color: black;">存活</span>期的中位数为9.7个月。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">另外</span>，达拉菲尼、威罗菲尼单药用于BRAF突变肺癌<span style="color: black;">病人</span>的治疗，威罗菲尼单药治疗有效率ORR 是42%，中位的<span style="color: black;">没</span><span style="color: black;">发展</span><span style="color: black;">存活</span>期是7.3个月。达拉菲尼单药治疗有效率是33%。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;">（七）</span></strong><strong style="color: blue;"><span style="color: black;">RET基因突变</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">约1%-2%的非小细胞肺癌<span style="color: black;">病人</span>会<span style="color: black;">出现</span>RET基因融合突变，在非吸烟<span style="color: black;">病人</span>和腺癌<span style="color: black;">病人</span>中更<span style="color: black;">平常</span>。在EGFR突变的非小细胞肺癌<span style="color: black;">病人</span>中，<span style="color: black;">亦</span>发现了RET融合，是EGFR<span style="color: black;">控制</span>剂的耐药<span style="color: black;">原由</span>之一。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">日前</span>，NCCN的肺癌治疗指南<span style="color: black;">意见</span>凡德他尼和卡博替尼用于RET阳性的非小细胞肺癌<span style="color: black;">病人</span>。<span style="color: black;">近期</span><span style="color: black;">报告</span>的RET<span style="color: black;">控制</span>剂BLU-667和LOXO-292以及RXDX-105在治疗RET融合的NSCLC<span style="color: black;">病人</span>中效果<span style="color: black;">亦</span>非常好，但<span style="color: black;">日前</span>正处在临床<span style="color: black;">实验</span><span style="color: black;">周期</span>。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://mmbiz.qpic.cn/mmbiz_png/Uia9ysy1SpiaH4A2enuTM4xJ3G2CuiaSZJYomKRPzyVq4emGLLQjibknb7UIrjKh6B9QhDcmia65klUpcHxtMBpsvpg/640?wx_fmt=png&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;">（八）</span></strong><strong style="color: blue;"><span style="color: black;">KRAS基因突变</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">KRAS突变在肺癌里非常<span style="color: black;">平常</span>，肺腺癌<span style="color: black;">病人</span>中KRAS突变的比例约为25%，肺鳞癌<span style="color: black;">病人</span>中KRAS基因突变的比例为5%。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">非常多</span><span style="color: black;">科研</span><span style="color: black;">表示</span>，KRAS基因突变是影响靶向<span style="color: black;">药品</span>疗效的<span style="color: black;">有害</span><span style="color: black;">原因</span>。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">但<span style="color: black;">日前</span>并<span style="color: black;">无</span>治疗KRAS基因突变的靶向<span style="color: black;">药品</span>，各大<span style="color: black;">机构</span>的<span style="color: black;">科研</span>重点<span style="color: black;">亦</span>都集中在KRAS突变的下游通路上，如MEK，CDK4/6以及免疫治疗。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://mmbiz.qpic.cn/mmbiz_jpg/G1CsdzFVCfZr8YCzdicsYG0400KpfdaZuQPiaibYbZSibqicZweOBmiclZZlGriaOuyWPp74O5fT0NvgI8BMk9kPc3oFQ/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"></p>
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