Targeted therapy in lung cancer: IPASS and beyond, keeping abreast of the explosion of targeted therapies for lung cancer
Review Article

肺癌的靶向治疗：IPASS和未来，肺癌靶向治疗的里程碑

Peter Savas1, Brett Hughes2,3, Benjamin Solomon1

1The Peter MaCallum Cancer Centre, East Melbourne, Victoria, Australia;2Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia;3The Prince Charles Hospital, Chermside, Queensland, Australia

Corresponding to: A/Prof Benjamin Solomon. The Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. Email: Ben.Solomon@petermac.org.

摘要：在过去十几年中，非小细胞肺癌(NSCLC)关于NSCLC的治疗进展主要以分子靶向治疗为主导地位。这些分子靶点如表皮生长因子受体(EGFR)的突变或间变性淋巴瘤激酶(ALK)的重组。虽然多基因组检测被认可、罕见的分子亚型在治疗中取得突破，但是其他治疗靶点却很难被发现。肿瘤微环境为血管生成靶向治疗和宿主的免疫应答提供了可能。本文就当前NSCLC的靶向治疗进行综述并期望提供有前途的治疗方法。

关键词： 非小细胞肺癌(NSCLC)；分子靶向治疗；免疫治疗；表皮生长因子受体(EGFR)；间变性淋巴瘤激酶(ALK)

Submitted Jul 19, 2013. Accepted for publication Aug 19, 2013.

doi: 10.3978/j.issn.2072-1439.2013.08.52

引言

疾病的进展和治疗的毒副作用常影响晚期肺癌患者的生活质量，因此，提供一个高获益且有效的治疗至关重要。靶向治疗非小细胞肺癌(NSCLC)可以实现这个理想目标。靶向治疗是指药物作用于已知的肿瘤细胞或肿瘤微环境的分子靶点。通常在一些情况下，借助于各种组织学和分子生物学技术对肿瘤标本进行检测，在治疗前确定分子靶点。在某些情况下，大多数患者的分子靶点则是依赖于之前大样本的分析结果而推测得到的。已被检测的靶点表明在治疗中获益机会很高，这些被称为预测性标志物。与预后性标记物不同，预后性标记物仅仅表明对预后而不是治疗反应的影响。在晚期肺癌的治疗中，突变表皮生长因子受体(EGFR)基因与重排间变性淋巴瘤激酶(ALK)基因的检测作为预测性基因标志物已在临床常规开展。上述任何一个基因修饰(15%~50%取决于种群研究)发生突变的肺腺癌患者均可受益于靶向治疗，这些靶向药物如激酶抑制剂厄洛替尼和克唑替尼。其他潜在的预测基因组的生物标记物，如已知的致癌基因BRAF, ROS1, MET 和 PIK3CA已经被广泛认可，而且正在努力研制针对它们的新型药物化合物。

很明显，肺癌是一个不同分子相互影响的疾病群，它们对治疗的敏感性也不同。重新设象肺癌的两个病理分类肺鳞状细胞癌和腺癌，它们有明显不同的分子结构，区分它们的组织学仍然是一个引导后续分子分析的关键的第一步。确定肺癌的分子亚型在临床上需要不断努力去开发可靠的分子诊断学，如表皮生长因子受体基因突变和ALK基因重组的检测。肺癌治疗也有可能受益于肿瘤免疫疗法的新兴领域，初步证据表明针对肺癌宿主免疫反应的靶向治疗，在未来将是一个成功和通用的治疗方式。本文将总结目前非小细胞肺癌靶向治疗的现状，并探讨有前景的治疗靶点。

非小细胞肺癌的致癌基因突变和染色体畸变

NSCLC的EGFR突变

肺腺癌中发现的EGFR基因突变是第一个被发现可以预测NSCLC靶向治疗获益的生物标记物，同时人们希望(其他位点基因突变)得到类似于本范例的显著疗效。EGFR小分子抑制剂最初的试验及研究应用于未经筛选的肺癌患者，令人欣喜的发现是一部分患者疗效显著[1,2]。随后研究显示细胞内络氨酸激酶结构域(用于调节下游EGFR基因表达)存在基因突变的肿瘤患者口服酪氨酸激酶(TKIs)(如吉非替尼或厄洛替尼)具有显著的临床效果[3-5]。

在人们发现EGFR基因突变可以作为预测性生物标记物之前，研究发现对于腺癌、不吸烟、女性和亚裔等患者可以从EGFR-TKIs中获益更多。现在我们知道这些患者治疗效果较好是因为他们的EGFR基因突变率更高[5-8]，这种基因突变几乎只在肺腺癌患者中出现[7-9]。然而，并没有临床特征可用来代替EGFR基因的检测。

8项Ⅲ期临床随机试验证实EGFR-TKIs在有EGFR基因突变晚期肺癌患者中有显著疗效。第1项临床试验是重要IPASS研究，IPASS研究评估了吉非替尼与一线化疗方案(铂类+紫杉醇)在亚裔、少或不吸烟的晚期肺癌患者中的疗效[10]。本试验纳入超过1200名患者，其中437人的肿瘤标本检测出EGFR基因突变。本试验结果证实在所有患者中，吉非替尼与化疗药物相比较，无进展生存期(PFS)无明显减低。本试验同样证实EGFR基因突变在预测应用吉非替尼有较好PFS中有重要价值，在无基因突变的患者中应用吉非替尼效果不如化疗。这些结果在Ⅲ期临床试验First-SIGNAL得到证实，First-SIGNAL研究同样在非吸烟的晚期非小细胞肺癌患者中将吉非替尼与化疗进行疗效比较[11]。

除了IPASS和First-SIGNAL研究之外，还有6项Ⅲ期临床随机对照试验在有EGFR基因突变的亚裔及高加索人群中对EGFR-TKIs(包括吉非替尼、厄洛替尼、阿法替尼)与化疗的疗效进行了比较。这些试验汇总在表1中[12-17]，这些试验一致反映出EGFR-TKIs较细胞毒性药物治疗有较好的反应率、PFS、生存质量。但后续的试验数据表明[18-20]：没有试验证实一线应用EGFR有总生存期(OS)的获益，最可能的解释是一线应用化疗的患者在出现疾病进展后交叉到了应用EGFR-TKIs二线治疗。尽管没有直接比较，第二代EGFR-TKI阿法替尼较第一代(吉非替尼、厄洛替尼)显示出较大的毒性，严重腹泻与皮疹发生率更高[16]。

表1
表1 Phase III trials of EGFR TKIs in exclusively EGFR-mutant advanced NSCLC.
Full table

目前建议所有晚期腺癌患者均进行EGFR基因检测[21]，即应用基因测序法对内镜获得的福尔马林固定的肿瘤标本进行基因检测。曾经或正在吸烟的患者EGFR基因突变率约为10%[8,22]，不吸烟患者突变率可达40%~50%。由于EGFR-TKIs相比化疗有较高的反应率及生存质量，同样建议所有有EGFR基因突变的NSCLC可将EGFR-TKIs作为一线药物[23-25]。

EGFR-TKIs对于没有EGFR突变的NSCLC(即所谓的野生型EGFR)有一定作用，它可以抑制无突变蛋白的过度表达。Ⅲ期临床试验NCIC 临床试验组BR.21证实在疾病进展后二线或三线治疗中，厄洛替尼较安慰剂可以改善晚期NSCLC患者的OS[26]。本试验发表在证明EGFR突变与EGFR-TKIs关系之前，之后的亚组分型证实这种优势在野生型EGFR和非肺腺癌患者中得以保持。一个相似的Ⅲ期临床试验对预处理人群进行吉非替尼与安慰剂对照研究，结果并未显示出统计学意义，但吉非替尼能改善生存趋势[27]。

只有一项Ⅲ期临床试验将EGFR-TKIs与化疗作为二线治疗方案在野生型EGFR人群中进行比较 [28]。尽管这项试验提示多西他赛对治疗这组患者有优势，人们仍期待着最终结果的发表。未经选择人群的多项试验的统计分析显示EGFR-TKIs疗效与二线化疗相当[29]，这提示EGFR-TKIs可用于一线化疗后的维持治疗[30]，且对于一线化疗失败的人群EGFR-TKIs与二线化疗有相似功效[31]。没有数据建议对于EGFR野生型患者一线应用EGFR-TKIs，IPASS试验[10]及Ⅲ期临床试验TORCH(一线应用化疗后应用厄洛替尼与一线应用厄洛替尼后换用化疗方案相比较)显示这种策略是有害的[32]。

第二代EGFR-TKIs是不可逆的突变EGFR基因抑制剂，同样抑制其他表皮生长因子家族的其他受体。阿法替尼，一个ErbB受体家族的抑制剂，是取得较大研究进展的药物之一。在一项Ⅱb/Ⅲ期临床试验中，在进行过2种化疗方案(包括应用吉非替尼及厄洛替尼)的非选择的人群中，将阿法替尼和最佳支持治疗进行对比，PFS延长2个月，OS无明显延长[33]。在2项Ⅲ期临床随机试验中，将阿法替尼在有EGFR突变的NSCLC患者中作为一线治疗方案(表1)，阿法替尼相对于化疗PFS中显出优势[16,17]。美国FDA证明了这种迹象，一项Ⅱ期临床试验纳入了188名一线治疗失败的患者，证实另一种二代EGFR-TKIs dacomtinib 相对于厄洛替尼在PFS中显示出优势 [34]。目前关于dacomtinib的2项Ⅲ期临床试验[分别对于厄洛替尼(ARCHER)或安慰剂(BR26)进行比较]正在进行中。

另一种针对NSCLC的EGFR的靶向治疗方法是利用单克隆抗体对EGFR蛋白的高亲和力，如西妥昔单抗[35]。2项Ⅲ期临床随机试验是对晚期NSCLC进行化疗和化疗联合西妥昔单抗进行比较。FLEX试验对1 125名晚期NSCLC研究显示在化疗联合西妥昔单抗组OS延长约1个月[36]。另一项相似的研究在主要研究终点PFS中未显示出明显优势[37]。关于EGFR蛋白表达在在预测收益中的作用众说纷纭，尽管一项FLEX试验的回顾性分析显示：高EGFR表达预示着应用西妥昔单抗将获得更长的生存期[38,39]，但是缺少明确获益以及准确的生物标记物，限制了西妥昔单抗的开发。

EGFR-TKIs抵抗的后续治疗

现在关于EGFR-TKIs对EGFR突变的NSCLC的疗效几乎无疑。尽管有高的初始反应率，药物耐药、临床无效是患者治疗过程的必经阶段，这叫做获得性耐药。对比细胞毒化疗，EGFR-TKIs明确的作用机制意味着治疗无效是一种潜在的问题。EGFR-TKIs之前和之后连续的活组织检查可深入地阐释治疗失败的机制 [40-43]。对大量患者进行分析，这使得对常见耐药机制有了总体把握。大约60%的病例，治疗失败是由于出现了二次EGFR突变T790M，这种突变对目前使用的EGFR-TKIs耐药[40-43]。人们假设这种突变是由应用EGFR-TKIs治疗前存在的少量的对EGFR-TKIs抵抗的细胞发展而来[44]。另外的5%~15%病例，细胞内的旁路途径被激活，使得突变不依赖EGFR途径的信号传导，最常见的包括MET基因的扩增[40-42,45]及PIK3CA基因的突变[41]。细胞系中发现的BRAF基因突变同样使细胞耐药[46]，同样有HER2基因扩增[47]。激活AXL酶是获得耐药的另一种机制[48]。令人意外的是，大约5%的病例组织学分型转化为小细胞[41,42]，几个患者对于常规的小细胞肺癌化疗方案有效[41]。人们发现在一个肿瘤中可能几种耐药机制共存[41-43]，如T790M突变和MET扩增。

理解获得耐药的机制，其巨大价值在于提供了发展和改进治疗方法的方向。考虑到T790M是最主要的获得耐药的突变方式，发展能够抑制T790M突变的EGFR-TKIs是符合逻辑的方法。体外证据表明第二代EGFR-TKIs如阿法替尼，可能在抑制T790M突变中有更好的功效[49]，尽管人们预期人群中存在大量的T790M突变，但反应率仍较低[33]。一项将阿发单抗与西妥昔单抗联合应用的Ⅱ期临床试验提示了意外的结果，22例登记的患者中36%达到了部分控制[50]。但药物毒性是这种联合用药的问题。最终，第三代突变选择性EGFR-TKIs如CO-1868被研制出来，这种药物可以特异性地抑制T790M突变。CO-1868正在一期临床试验中，该试验的对象是晚期有EGFR突变的应用其他EGFR-TKIs后疾病进展的NSCLC患者，而且该试验已经在疾病治疗及可耐受的毒副作用方面有了初步的证据[51]。AP26113是另一个有抗T790M突变活性的三代EGFR-TKIs，目前仍在Ⅰ期/Ⅱ期临床试验中[52]。

作用于其他分子通道(包括HER2，BRAF，PIK3CA和MET)的可解决获得耐药的靶向治疗正在进展。将这些方法与EGFR-TKIs联合应用可能为抑制或延迟获得耐药提供了新的道路。将EGFR-TKIs与MET抑制剂联合应用于EGFR-TKIs抵抗的病患中，已经在体外进行实施[53,54]。如何计划及处置联合用药带来的可能上升的毒性反应依旧存在着挑战。

ALK阳性的非小细胞肺癌

2007年在肺腺癌患者中ALK最初作为融合致癌基因被发现[55,56]，最初认为它是大细胞淋巴瘤中由于染色体2p和5q之间的移位形成的融合致癌基因[57]。在非小细胞肺癌中，大多数ALK基因重组的发生是由于染色体2p中的基因倒置，使得ALK基因与EML4基因出现融合。这种异常的融合蛋白EML4-ALK在体外可促进细胞生长，足以使细胞转化为恶性细胞[55]。ALK阳性细胞几乎全部依赖融合蛋白促进细胞的生长与存活，这种致癌基因依赖同样适用于EGFR突变的NSCLC[58]。由于这个原因，在依赖EML4-ALK的肿瘤细胞中抑制致癌基因的功能可导致生长停滞和细胞死亡。这在应用ALK小分子激酶抑制剂的动物模型中被观测到[59,60]。

尽管最初克唑替尼是作为致癌基因c-MET的小分子抑制剂而研发，目前人们发现克唑替尼同样可抑制ALK激酶[61]，在人们发现ALK在肺癌中有一定作用以后，克唑替尼已经被用于Ⅰ期临床试验中。一种可靠的诊断方法[利用小分子探针的免疫原位杂交技术(FISH)]同样被用于检测肺组织标本中的ALK融合突变。这使得ALK阳性的晚期肺癌患者迅速被登记进入了克唑替尼的Ⅰ期临床试验中，这项试验显示克唑替尼反应率达60%[62,63]。这些患者中大多数都接受了前期化疗，一项拥有更多成熟数据的后续报道显示：Ⅰ期临床试验比较了接受克唑替尼治疗的ALK阳性患者与ALK阴性患者的总生存期(OS)，尽管没有随机对照，但是与历史数据对比，应用克唑替尼可以延长生存期[64]。人们同样注意到不应用克唑替尼时ALK融合突变不能预示生存期。

Ⅰ期临床试验从1 500名患者中筛选ALK突变，突变率仅为5%[62]。类似于EGFR突变，一些临床病理特征预示了更高的ALK阳性率，这些特征包括年轻、非吸烟、实体腺癌、腺泡或印戒细胞癌类型。在非选择的非小细胞肺癌患者中，ALK阳性频率约为4%[62,65-68]。ALK融合在存在其他基因突变(如EGFR或KRAS)的肺癌患者中更稀少[67]。

一项多中心随机、对照、Ⅲ期试验曾将克唑替尼与二线化疗进行了比较，该研究纳入342名ALK阳性的一线化疗后疾病进展的晚期非小细胞肺癌患者[69]。几乎所有的患者在进行标准治疗时均接受了培美曲塞或多西他赛治疗。该研究以中位无进展生存期(PFS)为主要研究终点，表明应用克唑替尼中位PFS达7.7个月而二线化疗中位PFS为3.0个月，结果见图1 (HR 0.49；95% CI：0.37-0.64；P<0.0001)[69]。在生活质量分析中克唑替尼较化疗更大程度地改善了基线症状、延迟了恶化时间。该试验没有观察到总生存期的获益，可能是由于64%的化疗组患者随后接受了克唑替尼的治疗。一项在ALK阳性肺癌患者中将克唑替尼作为一线治疗方案的Ⅲ期临床试验近期结束。克唑替尼在欧洲和美国得到监管和认证，国际指南推荐对所有肺腺癌患者检测ALK融合突变[23,70]。

图1
图1 ALK阳性NSCLC的无进展生存期：二线药物克唑替尼与化疗之间的比较。来自“Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.N Engl J Med 2013;368:2385-94。版权所有©2013马萨诸塞州医学会”。重印已获许可

克唑替尼和ALK阳性融合突变是靶向治疗的独特实例，从发现肺癌的EML4-ALK融合突变到FDA批准应用克唑替尼、临床广泛应用，经过了4年时间。

克唑替尼的获得耐药

随着时间推移，对ALK抑制剂克唑替尼耐药的发生是不可避免的。最大规模的临床试验提示克唑替尼的中位PFS是7.7个月[69]。类似于EGFR-TKIs，对克唑替尼治疗进展后的病灶活组织进行深入检查深入证实了耐药的产生机制[71-74]。ALK基因突变的患者约1/3出现耐药，尽管ALK基因突变看起来比前文提及的以T790M占主导地位的肺癌中的EGFR突变范围更广。替代信号传导通路包括EGFR和c-KIT(伊马替尼的靶基因)的激活在耐药突变中同样起着重要的作用[71]。体外实验证实以现有的药品抑制替代途径，如吉非替尼抑制EGFR，伊马替尼抑制c-KIT，可以逆转克唑替尼的耐药[71]。目前约有1/3的ALK阳性肿瘤出现克唑替尼耐药，其机制依旧不明确[75]。更重要的是，多种不同的耐药机制可能在同一患者身上同时出现[71]。

下一代拥有与克唑替尼不同特性的ALK抑制剂可能有更强的效能和潜在的抗突变性。CH5424802处于ALK阳性的NSCLC的Ⅰ期和Ⅱ期临床试验中，值得注意的是总反应率达93%[76]。另一种药物LDK378在克唑替尼耐药、ALK阳性NSCLC患者的Ⅰ期临床试验中显示出了功效[77]，反应率约为70%，其对ALK突变耐药的患者同样有效。

非小细胞肺癌的KRAS突变

约30%的NSCLC患者发生KRAS突变[73]，这是未选择人群中最常见的驱动基因突变。KRAS突变主要发生在NSCLC中的腺癌中[78]，且和吸烟史呈正相关[79]。KRAS突变可能预示了野生型EGFR应用EGFR-TKI后预后欠佳，但相关数据仍存在争议[80-82]。尽管目前研究取得了进展，但仍无证据表明可以以KRAS作为靶基因进行治疗[83]。替代策略涉及到以KRAS的下游传导通路作为目标[84]，如MEK抑制剂司美替尼[85]。一项KRAS突变的晚期非小细胞肺癌的Ⅱ期临床随机试验，司美替尼联合多西他赛相对于多西他赛作为二线治疗时在反应率及PFS更佳[86]。其他的以NSCLC中KRAS突变为靶目标的早期临床试验包括PIK3CA/mTOR/AKT抑制剂联合MEK抑制剂有效地阻止了KRAS下游序列的信号传导[87]。

非小细胞肺癌的其他致癌基因

随着下一代测序技术的出现，不断发现NSCLC的除了EGFR、ALK、KRAS之外的驱动基因，频率大约小于5%[88]。靶向治疗已经在几个突变基因中存在，并且在其他类型肿瘤中得到应用。目前人们正关注如何鉴别肺癌患者(基因)的这些改变，并且正在进行这些突变基因的靶向治疗的早期研究[89]。因为驱动致癌基因的不同，鳞癌和腺癌在组织学类型上也显示出明显差异[9,90]，所以他们应该被分别讨论。基因突变的类型及频率参见图2。

图2
图2 腺癌和鳞癌的基因组改变的相对比率。数据改编来源于多篇参考文献(见正文)且仅仅只是估计

腺癌

ROS1易位

通常情况下，从来不吸烟的非小细胞肺癌或轻度吸烟的腺癌患者中有1%~2%能够发现融合基因受体酪氨酸激酶(ROS1)[91,92]。这种融合对克唑替尼抑制很敏感，所以受到学者的关注[91,93]，进而定义了一个肺癌的分子亚型，与ALK阳性肿瘤具有临床相似性。

MET扩增

MET是肝细胞生长因子受体(HGFR)基因。MET信号的激活足以使细胞转化为恶性表型，且对细胞周期和存活有影响。非小细胞肺癌通常高表达MET，而MET扩增是抗EGFR TKIs的确定路径[40-42,45]。单克隆抗体onartuzumab(MetMAb)阻止HGF与MET受体结合。一项Ⅱ期随机临床试验研究在初始治疗失败的晚期非小细胞肺癌患者中将onartuzumab与厄洛替尼联合应用，联合治疗组中MET高表达的受试者较对照组单用厄洛替尼的受试者总生存期延长，从4.6个月延长至12.6个月(HR 0.37；95%CI：0.2~0.71；P=0.002)。在一项联用厄洛替尼的Ⅲ期临床试验中检测到Tivantinib(一种小分子MET抑制剂)，但该研究在初期因无效而被停止(Press Release, ArQule Inc. and Daiichi Sankyo Co.)。

BRAF 突变

BRAF基因突变在黑色素瘤中突变率最高，可通过口服BRAF抑制剂如维罗非尼或者dabrafenib来治疗黑色素瘤。在BRAF突变的非小细胞肺癌中进行dabrafenib治疗的 Ⅱ期试验中，前期17例患者中有7例在检测中显示部分应答[94]。BRAF基因突变的非小细胞肺癌为1%~5%[88,95,96]，正在或曾吸烟者与非吸烟者相比频率几乎一致。仅50%BRAF突变的肺癌患者发现典型的V600E突变，这可能会限制目前可用的BRAF抑制剂的使用[95]。

HER2扩增和突变

HER2扩增或突变在其他类型的肺癌中是众所周知的，突变频率为3%左右[97]。利用HER2的单克隆抗体曲妥珠单抗治疗HER2扩增的NSCLC以失败告终[98]。20号外显子中的HER2突变是更有希望的小分子亚组，目前存在几种小分子的HER2络氨酸激酶抑制剂如阿法替尼或dacomitinib[99]。目前有一些关于应用这些药物治疗HER2突变的NSCLC患者的报道，并且试验正在进行中[100]。

RET基因融合

受体酪氨酸激酶RET融合基因在肺腺癌中被发现，并且体外试验已确认至少某些可识别的融合基因具有潜在的致癌性[101]。 RET基因重排的患病率估计在1%~2%，高于从未或轻度吸烟者[92,101]。RET激酶抑制剂凡德他尼[102]是治疗髓甲状腺癌的有效药物，它可能会成为治疗RET融合基因阳性肺腺癌的一个选择。

PIK3CA突变

PIK3CA被认为是致癌基因磷酸肌醇3激酶(PI3K)主要通路的核心基因，与多种类型肿瘤有关[103]。PIK3CA在肺腺癌中突变率约为1%~2%，且可能与其他致癌基因突变共存[104-106]。目前人们在其他类型肿瘤中以此基因为靶点做了大量研究工作，在PIK3CA基因突变阳性的肺腺癌患者中进行的以此为靶点治疗(无论是单独应用或联合其他靶向治疗药物或化疗)的早期试验正在进行中。

鳞癌

最近研究证实肺鳞状细胞癌有三个潜在的治疗靶点。研究显示有21%~22%肺鳞状细胞癌扩增出成纤维细胞生长因子受体1(FGFR1)靶点[107,108]。这些研究还表明，当用小分子FGFR1抑制剂治疗时，FGFR1促进了细胞的凋亡，应用抑制剂治疗FGFR1可使小鼠肿瘤萎缩，这表明FGFR1是促使某些鳞状细胞癌发生的重要凶手之一。许多小分子FGFR1抑制剂正在被研发，并且已进入初期临床试验阶段，并取得初步成果[109]。

研究发现2%肺鳞状细胞癌有受体酪氨酸激酶DDR2基因突变[9,110]。TKI广泛用于治疗慢性粒细胞白血病，如达沙替尼，其对DDR2也有效。在Ⅰ期临床试验中发现达沙替尼对某些鳞状非小细胞肺癌患者也有部分效果[111,112]。在一个有效果的患者中，对肿瘤活检标本测序，发现DDR2基因突变[110]。达沙替尼治疗肺鳞状细胞癌的Ⅱ期临床试验正在进行。

基因的改变在PI3K通路中起着重要的作用。目前，在30%~50%的鳞状细胞癌中存在PIK3CA扩增、突变和PTEN肿瘤抑制基因的缺失[9,106]。PI3K通路对维持细胞的存活和促进生长非常重要[103]，但这一途径的改变和对抑制剂的应答之间的关系比较复杂。PIK3CA抑制剂在鳞癌中的Ⅰ期临床试验正在进行。

肿瘤微环境的靶向治疗

肺癌的血管形成

由于任何大小的肿瘤均需要形成新的血供以维持生长[113,114]，目前血管生成已经广泛成为多种肿瘤的有效靶点。研究最成熟的抑制血管生成途径包括血管内皮生长因子(VEGF)家族，其配体和相关受体在细胞内有络氨酸激酶结构域，可以影响下游的信号转导 [115]。

尽管有多种药物正在Ⅲ期临床试验中，应用小分子抑制剂以VEGF络氨酸激酶受体作为靶点的治疗通常是不成功的[116-122]。在2项Ⅲ期临床试验中，作为晚期NSCLC的二线治疗方案，VEGF和FGF受体抑制剂nintedanib联合化疗较单独应用化疗PFS延长不足1个月[123,124]。

贝伐单抗是临床实践中应用最广泛的抗血管生成药物，它是VEGF的一个重组人单克隆抗体，尤其是VEGF-A型，阻止VEGF受体的激活[125]。东部肿瘤协作组E4599试验纳入878例晚期NSCLC患者，将贝伐单抗联合卡铂、紫杉醇化疗与单独化疗进行比较[126]，贝伐单抗同样可作为6个疗程化疗结束后的维持治疗，直至疾病进展。应用贝伐单抗的中位OS更优越(12.3个月vs. 10.3个月；HR 0.79；95% CI：0.67~0.92；P=0.003)。在一项Ⅲ期临床试验AVAiL中，应用贝伐单抗发现尽管OS无显著差异，PFS和反应率都表现出了优势[127]。贝伐单抗的副作用包括动脉血栓栓塞、高血压、增加化疗相关的血液学毒性、出血[126]。由于大咯血风险增加，贝伐单抗不应该用于鳞癌患者。由于担心出现毒性反应、花费、缺乏预测获益的生物标记物，除美国之外贝伐单抗并没有被作为标准一线药物。

免疫治疗

肿瘤免疫学研究最新进展显示，免疫系统在控制恶性生长、塑造恶性肿瘤的最终临床特征方面起重要作用[128]。将免疫治疗作为治疗方案已经在晚期黑色素瘤[129]和前列腺癌[130]中获得成功。尽管传统上认为肺癌并不是产生免疫性的肿瘤类型，但是有证据表明肺癌的一个宿主免疫应答标记在适应环境和肿瘤进展方面有重要的预示作用[131-134]。因此增强免疫应答有可能是一个合理的治疗靶点。肺癌的免疫治疗主要包括两个方面：来源于肿瘤细胞系或肿瘤相关抗原的疫苗，免疫刺激点抗体。

疫苗

几个疫苗在Ⅱ期临床试验中显示出了效果，目前正处于Ⅲ期随机临床试验中。这儿将讨论几个大型试验。

治疗性疫苗是将包括肺腺癌、大细胞癌、鳞癌的多种细胞系及部分免疫辅助剂进行整细胞辐射照射后的产品[135]。一项小型Ⅱ期临床试验显示，早期和晚期肺癌患者在15%患者中放射反应，可预测疾病、更长总生存期与更高剂量之间的正相关[135]。一项Ⅲ期临床试验正在紧锣密鼓地进行，它招募Ⅲ期~IV期一线治疗后疾病稳定或有效的患者，对治疗性疫苗进行进一步评估。

其他疫苗由完全或主要在肺癌细胞中表达的抗原组成，黑色素瘤相关抗体A3(MAGE-A3)在35%NSCLC患者中表达[136]，被制作为单抗原疫苗。一项随机、安慰剂对照的Ⅱ期临床试验纳入表达MAGE-A3的Ⅰ～Ⅱ期NSCLC术后并进行后续治疗患者，并对该抗体进行了检测[137]。比较术后患者的PFS和OS，疫苗组与安慰剂组之间的差异无统计学意义，但是注射疫苗组在术后44个月复发例数更少(疫苗组35% vs. 安慰剂组43%)。一项有关MAGE-A3疫苗的Ⅲ期临床试验招募了2 270名患者，其试验结果令人期待。

MUC-1是一种不同于恶性细胞糖基化的上皮细胞蛋白[138]，该蛋白在NSCLC中过度表达[139,140]。BLP25疫苗包含了一个脂质传送系统的MUC-1肽和包裹的免疫辅助剂[141]。在一项Ⅲ期随机临床试验中，在Ⅲ期放化疗后NSCLC中将BLP25与安慰剂进行对比，试验组中位OS(30.8个月)较安慰剂组(20.6个月)延长(HR 0.78；95% CI：0.64-0.95；P=0.016)[142]。在一项晚期NSCLC的Ⅱ期临床试验中BLP25较最佳支持治疗可延长生存期，但无显著的统计学差异[141]。TG4010是另一种MUC-1疫苗，是编码MUC-1蛋白和白介素-2的减毒活病毒[143]。一项Ⅱ期随机临床试验，在148例晚期NSCLC中将铂类联合吉西他滨的化疗联合TG4010与单独应用化疗相对比，6个月后联合用药组PFS为43%，化疗组为35%，但这种差异无统计学意义[144]。BLP25与TG4010仍有待进一步研究。

免疫点阻滞

免疫检测点是指控制T细胞对外界抗原免疫应答的分子机制。部分免疫检测点系统包括刺激或抑制的共同受体，这些受体调节T细胞受体(TCR)与表达在靶细胞上的人类白细胞抗原(HLA)之间的相互作用。这两个受体成为肿瘤治疗的重要靶点。CTLA-4受体在T细胞表面表达，被抗原激活，可以抑制T细胞免疫应答，增强自身耐受性，防止自身免疫的激活。程序性细胞死亡蛋白1(PD1)同样在T细胞表面表达，遇到配体(PD-L1，又名B7)后下调T细胞免疫应答。通过在肿瘤免疫中扰乱免疫抑制信号，防止肿瘤免疫中的T细胞抑制，这给晚期肺癌患者提供了一个有希望的治疗策略，也可应用于肿瘤的辅助治疗。

各种免疫检测点抗体的毒性反应均相似，且都和自身免疫反应有关，如结肠炎、皮疹、肺炎、内分泌疾病等。因为这些和化疗的毒性反应均不重叠，将这种方法与化疗联合是一种可行的方法。Ipilimumab是一种人抗CTLA-4受体的IgG1抗体，且对晚期黑色素瘤的疗效获得认可[129]。一项随机安慰剂对照试验纳入204名晚期NSCLC患者，对比Ipilimumab联合化疗(顺铂+紫杉醇)与安慰剂联合化疗的疗效[145]。Ipilimumab按照两种方式给药：同时给药(第一疗程化疗开始时给药)和定时给药(前两个疗程结束后给药)。鉴于黑色素瘤的治疗经验，Ipilimumab应用初期可能使以PFS作为的评价指标的影像学表现更严重，该试验应用了免疫相关的放射性损伤标准[146]。该试验在主要研究终点免疫相关的PFS中得到阳性结果，试验组PFS 5.7个月，对照组4.6个月(HR 0.72，P=0.05)。Ipilimumab在鳞癌患者中效果更显著。一项相似的Ⅱ期临床随机试验在130名SCLC广泛期患者中进行，在免疫相关的PFS中联合用药较单独化疗显示出了优势(6.4个月 vs. 5.3个月；HR 0.64；95% CI：0.4~1.02；P=0.03)[147]。关于鳞癌和SCLC的试验正在进一步实施中。

更多的细胞类型在细胞表面表达PD-L1配体，突出显示了PD-L1配体在抑制抗肿瘤T细胞活性方面的价值[148]。PD-1与PD-L1的共同单克隆抗体在多个包含了大样本NSCLC的Ⅰ期临床试验中得到证实[148,149]。抗PD-1的单克隆抗体nivolumab(又名BMS-936558/MDX-1106)在129名NSCLC中显示出了18%的反应率，这些患者均接受过复杂的前期治疗，一半以上的患者接受过三线或更多的治疗[148]。另外，一项纳入49名NSCLC患者的Ⅰ期试验结果表明抗PD-L1单抗BMS-936559反应率达10% [149]。在鳞癌和腺癌患者中均明显受益。这两项试验显示出了早期的证据，表明在肿瘤微环境中表达PD-L1配体(可通过免疫组化技术检测)可能预示了对PD-1/PD-L1单克隆抗体治疗有效。除了nivolumab，lambrolizumab是另一种抗PD-1抗体，它在黑色素瘤中显示出了确切疗效，其在肺癌中的作用正在评估中。即将开展的有关nivolumab、lambrolizumab的试验见表2。

表2
表2 Upcoming trials of anti-PD-1 therapy in advanced NSCLC.
Full table

结论

在过去的10年中，我们看到了肺癌概念和治疗的变革，而这有赖于基因组学、细胞生物学和药物开发技术的进步。同样推动这场变革的还有新靶点的检测及对治疗失败和耐药机制的阐释，这将为持续改进的变革提供一个方向标。克唑替尼从一个研究的化合物到批准用于治疗仅用了4年，它的飞速发展在不久的将来还会为患者的治疗提供新的选择。同样，免疫治疗提供了一组全新的预测疗效和毒副反应的免疫因子。然而，随着靶向治疗的到来，多重挑战也接踵而至：靶向治疗往往与传统的临床试验监管部门的要求不一致，他们认定将Ⅲ期临床试验能提高生存率作为金标准；此外，靶向治疗花费更高，现用靶向药物长期的经济效益并不确切；最后，大部分晚期肺癌患者在当前并没有可用的靶向治疗药物，要么是由于他们的肿瘤缺乏已知的靶点，要么是难以获得新型制剂。如果过去10年的成就得以保持，这些问题将首先被攻克。

Acknowledgements

Disclosure: Brett Hughes has served on Advisory Boards for Roche, Pfizer and Boehringer Inglheim. Benjamin Solomon has served on Advisory Boards for Roche, Pfizer, Novartis, Astra Zeneca, Eli Lilly, Clovis Oncology and Boehringer Ingelheim.

References

  1. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) J Clin Oncol 2003;21:2237-46. [PubMed]
  2. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149-58. [PubMed]
  3. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-39. [PubMed]
  4. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500. [PubMed]
  5. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306-11. [PubMed]
  6. Miller VA, Kris MG, Shah N, et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 2004;22:1103-9. [PubMed]
  7. Marchetti A, Martella C, Felicioni L, et al. EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 2005;23:857-65. [PubMed]
  8. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958-67. [PubMed]
  9. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-25. [PubMed]
  10. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57. [PubMed]
  11. Han JY, Park K, Kim SW, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 2012;30:1122-8. [PubMed]
  12. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8. [PubMed]
  13. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8. [PubMed]
  14. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42. [PubMed]
  15. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46. [PubMed]
  16. Sequist LV, Yang JC, Yamamoto N, et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol 2013. [Epub ahead of print]. [PubMed]
  17. Wu YL, Zhou C, Hu CP, et al. LUX-Lung 6: A randomized, open-label, phase III study of afatinib versus gemcitabine/cisplatin as first-line treatment for Asian patients with EGFR mutation-positive advanced adenocarcinoma of the lung. J Clin Oncol 2013;31:abstr 8016.
  18. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011;29:2866-74. [PubMed]
  19. Inoue A, Kobayashi K, Maemondo M, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013;24:54-9. [PubMed]
  20. Mitsudomi T, Morita S, Yatabe Y, et al. Updated overall survival results of WJTOG 3405, a randomized phase III trial comparing gefitinib with cisplatin plus docetaxel as the first-line treatment for patients with non-small cell lung cancer harboring mutations of the epidermal growth factor rece. J Clin Oncol 2012;30:abstr 7521.
  21. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) Mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol 2011;29:2121-7. [PubMed]
  22. Dogan S, Shen R, Ang DC, et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res 2012;18:6169-77. [PubMed]
  23. Peters S, Adjei AA, Gridelli C, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23:vii56-64. [PubMed]
  24. Ettinger DS, Akerley W, Bepler G, et al. Non-small cell lung cancer. J Natl Compr Canc Netw 2010;8:740-801. [PubMed]
  25. Mok T, Yang JJ, Lam KC. Treating patients with EGFR-sensitizing mutations: first line or second line--is there a difference? J Clin Oncol 2013;31:1081-8. [PubMed]
  26. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32. [PubMed]
  27. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527-37. [PubMed]
  28. Garassino M, Martelli O, Bettini A, et al. TAILOR: A phase III trial comparing erlotinib with docetaxel as the second-line treatment of NSCLC patients with wild-type EGFR. J Clin Oncol 2012;30:abtract LBA7501.
  29. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008;372:1809-18. [PubMed]
  30. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010;11:521-9. [PubMed]
  31. Ciuleanu T, Stelmakh L, Cicenas S, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol 2012;13:300-8. [PubMed]
  32. Gridelli C, Ciardiello F, Gallo C, et al. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. J Clin Oncol 2012;30:3002-11. [PubMed]
  33. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012;13:528-38. [PubMed]
  34. Ramalingam SS, Blackhall F, Krzakowski M, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 2012;30:3337-44. [PubMed]
  35. Kurai J, Chikumi H, Hashimoto K, et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res 2007;13:1552-61. [PubMed]
  36. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009;373:1525-31. [PubMed]
  37. Lynch TJ, Patel T, Dreisbach L, et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 2010;28:911-7. [PubMed]
  38. Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012;13:33-42. [PubMed]
  39. Khambata-Ford S, Harbison CT, Hart LL, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2010;28:918-27. [PubMed]
  40. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 2007;104:20932-7. [PubMed]
  41. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26. [PubMed]
  42. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res 2011;17:1169-80. [PubMed]
  43. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240-7. [PubMed]
  44. Chmielecki J, Foo J, Oxnard GR, et al. Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med 2011;3:90ra59. [PubMed]
  45. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039-43. [PubMed]
  46. Ohashi K, Sequist LV, Arcila ME, et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A 2012;109:E2127-33. [PubMed]
  47. Takezawa K, Pirazzoli V, Arcila ME, et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov 2012;2:922-33. [PubMed]
  48. Zhang Z, Lee JC, Lin L, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet 2012;44:852-60. [PubMed]
  49. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008;27:4702-11. [PubMed]
  50. Janjigian YY, Groen HJM, Horn L, et al. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. J Clin Oncol 2011;29:abstr 7525.
  51. Sequist L V, Soria JC, Gadgeel SM, et al. First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M. J Clin Oncol 2013;31:abstr 2524.
  52. Rivera VM, Wang F, Anjum R, et al. AP26113 is a dual ALK/EGFR inhibitor: Characterization against EGFR T790M in cell and mouse models of NSCLC. Cancer Res 2012;72:abstr 1794.
  53. Wang W, Li Q, Takeuchi S, et al. Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer. Clin Cancer Res 2012;18:1663-71. [PubMed]
  54. Nakagawa T, Takeuchi S, Yamada T, et al. Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer. Mol Cancer Ther 2012;11:2149-57. [PubMed]
  55. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-6. [PubMed]
  56. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007;131:1190-203. [PubMed]
  57. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994;263:1281-4. [PubMed]
  58. McDermott U, Iafrate AJ, Gray NS, et al. Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 2008;68:3389-95. [PubMed]
  59. Soda M, Takada S, Takeuchi K, et al. A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A 2008;105:19893-7. [PubMed]
  60. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008;14:4275-83. [PubMed]
  61. Cui JJ, Tran-Dubé M, Shen H, et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 2011;54:6342-63. [PubMed]
  62. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693-703. [PubMed]
  63. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:1011-9. [PubMed]
  64. Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 2011;12:1004-12. [PubMed]
  65. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27:4247-53. [PubMed]
  66. Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 2009;15:5216-23. [PubMed]
  67. Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 2009;115:1723-33. [PubMed]
  68. Zhang YG, Jin ML, Li L, et al. Evaluation of ALK rearrangement in Chinese non-small cell lung cancer using FISH, immunohistochemistry, and real-time quantitative RT-PCR on paraffin-embedded tissues. PLoS One 2013;8:e64821. [PubMed]
  69. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med 2013;368:2385-94. [PubMed]
  70. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular Testing Guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn 2013;15:415-53. [PubMed]
  71. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012;4:120ra17.
  72. Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012;18:1472-82. [PubMed]
  73. Gainor JF, Varghese AM, Ou SH, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013;19:4273-81. [PubMed]
  74. Kim S, Kim TM, Kim DW, et al. Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer. J Thorac Oncol 2013;8:415-22. [PubMed]
  75. Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013;31:1105-11. [PubMed]
  76. Seto T, Kiura K, Nishio M, et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol 2013;14:590-8. [PubMed]
  77. Shaw AT, Mehra R, Kim DW, et al. Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC. J Clin Oncol 2013;31:abstr 8010.
  78. Graziano SL, Gamble GP, Newman NB, et al. Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer. J Clin Oncol 1999;17:668-75. [PubMed]
  79. Slebos RJ, Kibbelaar RE, Dalesio O, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med 1990;323:561-5. [PubMed]
  80. Linardou H, Dahabreh IJ, Kanaloupiti D, et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 2008;9:962-72. [PubMed]
  81. Mao C, Qiu LX, Liao RY, et al. KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 2010;69:272-8. [PubMed]
  82. Sun JM, Hwang DW, Ahn JS, et al. Prognostic and predictive value of KRAS mutations in advanced non-small cell lung cancer. PLoS One 2013;8:e64816. [PubMed]
  83. Zimmermann G, Papke B, Ismail S, et al. Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. Nature 2013;497:638-42. [PubMed]
  84. Wang Y, Kaiser CE, Frett B, et al. Targeting Mutant KRAS for Anticancer Therapeutics: A Review of Novel Small Molecule Modulators. J Med Chem 2013. [Epub ahead of print]. [PubMed]
  85. Yeh TC, Marsh V, Bernat BA, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res 2007;13:1576-83. [PubMed]
  86. Jänne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013;14:38-47. [PubMed]
  87. Khan KH, Yan L, Mezynski J, et al. A phase I dose escalation study of oral MK-2206 (allosteric Akt inhibitor) with oral selumetinib (AZD6244; ARRY-142866) (MEK 1/2 inhibitor) in patients with advanced or metastatic solid tumors. J Clin Oncol 2012;30:abstr e13599.
  88. Barlesi F, Blons H, Beau-Faller M, et al. Biomarkers France: Results of routine EGFR, HER2, KRAS, BRAF, PI3KCA mutations detection and EML4-ALK gene fusion assessment on the first 10,000 non-small cell lung cancer patients. J Clin Oncol 2013;31:abstr 8000.
  89. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov 2011;1:44-53. [PubMed]
  90. Imielinski M, Berger AH, Hammerman PS, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012;150:1107-20. [PubMed]
  91. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863-70. [PubMed]
  92. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012;18:378-81. [PubMed]
  93. Awad MM, Katayama R, McTigue M, et al. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 2013;368:2395-401. [PubMed]
  94. Planchard D, Mazieres J, Riely GJ, et al. Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation-positive non-small cell lung cancer (NSCLC) patients. J Clin Oncol 2013;31:abstr 8009.
  95. Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 2011;29:2046-51. [PubMed]
  96. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 2011;29:3574-9. [PubMed]
  97. Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 2005;65:1642-6. [PubMed]
  98. Clamon G, Herndon J, Kern J, et al. Lack of trastuzumab activity in nonsmall cell lung carcinoma with overexpression of erb-B2: 39810: a phase II trial of Cancer and Leukemia Group B. Cancer 2005;103:1670-5. [PubMed]
  99. Kwak E. The role of irreversible HER family inhibition in the treatment of patients with non-small cell lung cancer. Oncologist 2011;16:1498-507. [PubMed]
  100. De Grève J, Teugels E, Geers C, et al. Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer 2012;76:123-7. [PubMed]
  101. Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 2012;18:382-4. [PubMed]
  102. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012;30:134-41. [PubMed]
  103. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009;9:550-62. [PubMed]
  104. Garnett MJ, Edelman EJ, Heidorn SJ, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 2012;483:570-5. [PubMed]
  105. Chaft JE, Arcila ME, Paik PK, et al. Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Mol Cancer Ther 2012;11:485-91. [PubMed]
  106. Yamamoto H, Shigematsu H, Nomura M, et al. PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 2008;68:6913-21. [PubMed]
  107. Weiss J, Sos ML, Seidel D, et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2010;2:62ra93. [PubMed]
  108. Dutt A, Ramos AH, Hammerman PS, et al. Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS One 2011;6:e20351. [PubMed]
  109. Wolf J, LoRusso PM, Camidge RD, et al. A phase I dose escalation study of NVP-BGJ398, a selective pan FGFR inhibitor in genetically preselected advanced solid tumors. Cancer Res 2012;72:abstr nr LB-122.
  110. Hammerman PS, Sos ML, Ramos AH, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov 2011;1:78-89. [PubMed]
  111. Haura EB, Tanvetyanon T, Chiappori A, et al. Phase I/II study of the Src inhibitor dasatinib in combination with erlotinib in advanced non-small-cell lung cancer. J Clin Oncol 2010;28:1387-94. [PubMed]
  112. Johnson FM, Bekele BN, Feng L, et al. Phase II study of dasatinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 2010;28:4609-15. [PubMed]
  113. Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 1972;175:409-16. [PubMed]
  114. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-74. [PubMed]
  115. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669-76. [PubMed]
  116. Paz-Ares LG, Biesma B, Heigener D, et al. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol 2012;30:3084-92. [PubMed]
  117. Scagliotti G, Novello S, von Pawel J, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 2010;28:1835-42. [PubMed]
  118. Scagliotti GV, Krzakowski M, Szczesna A, et al. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial. J Clin Oncol 2012;30:2070-8. [PubMed]
  119. Lee JS, Hirsh V, Park K, et al. Vandetanib Versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol 2012;30:1114-21. [PubMed]
  120. De Boer RH, Arrieta Ó, Yang CH, et al. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol 2011;29:1067-74. [PubMed]
  121. Natale RB, Thongprasert S, Greco FA, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2011;29:1059-66. [PubMed]
  122. Scagliotti GV, Vynnychenko I, Park K, et al. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol 2012;30:2829-36. [PubMed]
  123. Reck M, Kaiser R, Mellemgaard A, et al. Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-blind phase III trial. J Clin Oncol 2013;31:abstr LBA8011.
  124. Hanna NH, Kaiser R, Sullivan RN, et al. Lume-lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy. J Clin Oncol 2013;31:abstr 8034.
  125. Ferrara N, Hillan KJ, Gerber HP, et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004;3:391-400. [PubMed]
  126. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50. [PubMed]
  127. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 2010;21:1804-9. [PubMed]
  128. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011;331:1565-70. [PubMed]
  129. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23. [PubMed]
  130. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411-22. [PubMed]
  131. Al-Shibli KI, Donnem T, Al-Saad S, et al. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 2008;14:5220-7. [PubMed]
  132. Kawai O, Ishii G, Kubota K, et al. Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer 2008;113:1387-95. [PubMed]
  133. Petersen RP, Campa MJ, Sperlazza J, et al. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 2006;107:2866-72. [PubMed]
  134. Tao H, Mimura Y, Aoe K, et al. Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer 2012;75:95-101. [PubMed]
  135. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol 2006;24:4721-30. [PubMed]
  136. Sienel W, Varwerk C, Linder A, et al. Melanoma associated antigen (MAGE)-A3 expression in Stages I and II non-small cell lung cancer: results of a multi-center study. Eur J Cardiothorac Surg 2004;25:131-4. [PubMed]
  137. Vansteenkiste J, Zielinski M, Linder A, et al. Adjuvant MAGE-A3 Immunotherapy in Resected Non-Small-Cell Lung Cancer: Phase II Randomized Study Results. J Clin Oncol 2013;31:2396-403. [PubMed]
  138. Gendler SJ, Lancaster CA, Taylor-Papadimitriou J, et al. Molecular cloning and expression of human tumor-associated polymorphic epithelial mucin. J Biol Chem 1990;265:15286-93. [PubMed]
  139. Rochlitz C, Figlin R, Squiban P, et al. Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1 as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer. J Gene Med 2003;5:690-9. [PubMed]
  140. Ho SB, Niehans GA, Lyftogt C, et al. Heterogeneity of mucin gene expression in normal and neoplastic tissues. Cancer Res 1993;53:641-51. [PubMed]
  141. Butts C, Murray N, Maksymiuk A, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol 2005;23:6674-81. [PubMed]
  142. Butts CA, Socinski MA, Mitchell P, et al. START: A phase III study of L-BLP25 cancer immunotherapy for unresectable stage III non-small cell lung cancer. J Clin Oncol 2013;31:abstr 7500.
  143. Ramlau R, Quoix E, Rolski J, et al. A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV Non-small cell lung cancer. J Thorac Oncol 2008;3:735-44. [PubMed]
  144. Quoix E, Ramlau R, Westeel V, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol 2011;12:1125-33. [PubMed]
  145. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 2012;30:2046-54. [PubMed]
  146. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-20. [PubMed]
  147. Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol 2013;24:75-83. [PubMed]
  148. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54. [PubMed]
  149. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-65. [PubMed]

(译者：潘磊；校对：骆华春)

（本译文仅供学术交流，实际内容请以英文原文为准。）

Cite this article as: Savas P, Hughes B, Solomon B. Targeted therapy in lung cancer: IPASS and beyond, keeping abreast of the explosion of targeted therapies for lung cancer. J Thorac Dis 2013;5(S5):S579-S592. doi: 10.3978/j.issn.2072-1439.2013.08.52

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