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随着基因组学研究的进展，与肺癌相关的基因突变，从1984年发现KRAS突变后，不断涌现，基于驱动基因的靶向药物问世引领了肺癌治疗史上的重要变革。然而，已发现的10余种肺癌相关基因突变中，至今可以为临床所用的仅仅只有表皮生长因子受体（EGFR）突变、间变性淋巴瘤激酶（ALK）融合、ROS1融合和BRAF突变等。昨天为大家梳理了肺癌EGFR突变治疗领域的研究进展，今天继续为大家盘点ALK重排、ROS重排、BRAF突变领域的里程碑。 （二）ALK重排 1. 2007年，日本学者Soda等首次在1例吸烟的男性肺腺癌患者标本中发现了EML4-ALK融合基因。研究者在该患者标本中扩增出由EML4与ALK融合的DNA片段。EML4基因断裂后与ALK基因的20号外显子融合，形成EML4-ALK融合基因inv(2)(p21p23)。临床前研究证实具有EML4-ALK融合基因的肿瘤均依赖ALK基因及其下游的RAS-MAPK及PI3K-AKT及JAK-STST通路活化来驱动和维持其生长，ALK抑制剂能显著抑制其生长37。 2. 克唑替尼(crizotinib)是一种小分子ATP竞争性抑制剂，对ALK, c-MET 和ROS1驱动的肿瘤具有选择性抑制作用。克唑替尼的Ⅰ期临床试验PROFILE 1001分两部分。第一部分为剂量爬坡试验，确定了克唑替尼的最大耐受剂量为250mg bid，并且观察到ALK重排患者临床获益明显。试验的第二部分仅纳入ALK FISH阳性的患者。2010年，研究结果发布，该部分可评价疗效的患者共82例，其中ORR为57%，DCR为90%38。2011年8月26日，美国FDA批准了克唑替尼用于ALK FISH阳性的局部晚期或转移性非小细胞肺癌患者。 3. 2012年，研究者更新了PROFILE 1001及其拓展试验的数据，入组149例ALK阳性患者，其中143人可评价疗效，ORR为60.8%（87/143），其中3例完全缓解（CR），84例部分缓解（PR）。中位PFS为9.7m(95%CI 7.7-12.8)。克唑替尼主要的毒副作用是视觉损伤，胃肠道副反应和间质性肺炎39。 4. 2012年，克唑替尼的II期临床研究PROFILE1005结果发布。该研究纳入ALK FISH 阳性，既往化疗失败的非小细胞肺癌患者，主要研究终点为ORR。85%的患者既往接受过多线化疗（≥2种化疗方案）。入组患者可以评价疗效的有261人，其中ORR为60%(95%CI：54-66)，中位疗效持续时间为46周，中位PFS为8.1m (95%CI：6.8-9.7) 40。 5. 2013年，克唑替尼的III期临床试验PROFILE1007结果发表。PROFILE1007比较克唑替尼和培美曲塞或多西他赛二线治疗晚期ALK重排NSCLC患者。PROFILE 1007共入组347人，接受克唑替尼和接受化疗患者的ORR分别为65%和20%(P<0.001)。克唑替尼组患者的PFS明显优于化疗组，7.7m vs. 3.0m(HR=0.49, P<0.001)。PROFILE1007的试验结果奠定了克唑替尼用于ALK重排NSCLC患者的二线治疗地位41。 6. 2014年，克唑替尼用于ALK重排NSCLC一线治疗的研究PROFILE1014结果发表。PROFILE1014研究是一线克唑替尼与化疗头对头的比较III期临床研究，入组343例ALK重排NSCLC患者随机接受克唑替尼和培美曲塞顺铂（或卡铂）化疗。克唑替尼组和化疗组的ORR分别为74%和45%(P<0.001)，PFS分别为10.9m和7.0m(HR=0.45, 95%CI: 0.35-0.60, P<0.001)。克唑替尼与化疗的一线对比奠定了克唑替尼用于ALK重排NSCLC患者的一线治疗地位42。 7. 2014年，克唑替尼一线治疗ALK阳性NSCLC患者的中位PFS位11个月左右，获得性耐药机制主要为ALK激酶域的二次突变（22-33%）；EGFR通路活化（30-35%）和其他未知的机制等23。 8. 2014年，二代ALK抑制剂Ceritinib用于ALK阳性患者的I期临床研究结果发布。入组患者中，80例为克唑替尼耐药患者，接受Ceritinib治疗的ORR为56%，中位PFS位7.0个月。无论患者有无ALK激酶区的二次突变，都能从Ceritinib治疗中获益43。2014年，Ceritinib获得美国FDA批准用于克唑替尼耐药后的ALK阳性NSCLC 。2015年，一项回顾性研究表明，晚期ALK重排非小细胞肺癌患者序贯应用一代和二代ALK抑制剂（Ceritinib），患者的中位OS可达49.4m (95%CI：35.3-63.1)44。 9. 2014年，另一二代ALK抑制剂Alectinib用于克唑替尼耐药的ALK阳性患者的I期临床研究AF-002JG结果发布。在44例可评价疗效的患者中，ORR为55%；在21例基线有脑转移的患者，11例（52%）取得客观缓解45。2016年，Alectinib用于克唑替尼耐药的ALK阳性患者的II期临床研究公布，确认的ORR为48%46。2015年，Alectinib获得美国FDA批准用于克唑替尼耐药后的ALK阳性NSCLC。 10. 2016年，PROFILE 1029试验结果在ASCO发布。这一随机、开放、双臂III期临床研究，旨在评价在东亚人群，克唑替尼一线治疗既往未经过系统性治疗的ALK阳性NSCLC患者的疗效和安全性。PROFILE1029研究设计与PROFILE1014研究相似，但是患者人群不一样。最终入组207例患者，其中中国患者183例。研究达到了主要研究终点，即在东亚人群，与标准含铂双药化疗相比，克唑替尼组患者的无进展生存期（PFS）显著延长（中位PFS 为11.1个月 vs 6.8个月；HR = 0.39；95%CI, 0.28-0.56；P <0.0001），肿瘤缓解率明显提高（88% vs 46%；P <0.0001）47。 11. 2016年ASCO大会，Alectinib对比克唑替尼用于ALK阳性晚期NSCLC的III期临床研究J-ALEX发表。研究入组207例患者。其中Alectinib组103例，Crizotinib组104例，允许患者既往接受过<=1线化疗。独立评估委员会评价的Alectinib组和Crizotinib组的ORR分别为91.6%和78.9%；中位PFS分别为未达到（95%CI：20.3-未达到）和10.2m（95%CI：8.2-12.0）（HR＝0.34；99.6826% CI：0.17-0.70）。在预先设定的中期评估中，因为已经看到了Alectinib绝对的优势，独立评审建议提前终止trial并且释放数据。据估计，ALC的PFS可能超过24.3m，研究者认为Alectinib有潜力冲进ALK阳性患者的标准一线治疗48。 12. 2016年WCLC会议，Ceritinib对比含铂双药化疗一线治疗ALK阳性NSCLC的III期研究发布。研究入组376例ALK阳性晚期NSCLC，1:1随机接受Ceritinib（n=189）或培美曲塞铂类化疗（n=187）治疗，两组的中位PFS分别位16.6月和8.1个月（HR=0.55；P<0.0001）。研究结果显示ALK阳性的晚期NSCLC，一线Ceritinib显著优于化疗49。 13. 2017年ASCO大会，Alectinib对比克唑替尼用于ALK阳性晚期NSCLC的全球III期临床研究ALEX发表。与J-ALEX研究相比，ALEX研究在设计上稍有不同，入组的患者均为初治的晚期NSCLC，允许脑转移患者入组，且作为分层因素，并计划分析至CNS进展时间，所有患者均接受Alcetinib 600mg，BID治疗。结果显示，Alcetinib对比克唑替尼，显著延长PFS，独立评估委员会评估的mPFS，两组分别为25.7个月和10.4个月（HR 0.50；95%CI 0.36-0.70；P<0.0001）50。基于ALEX研究结果，Alectinib被推荐作为ALK阳性晚期NSCLC一线治疗的优选。 14. 2017年，三代ALK抑制剂Lorlatinib用于ALK或ROS1阳性的晚期NSCLC的第一项I期临床试验结果公布。结果显示，对既往接受过ALK抑制剂治疗后产生耐药突变的患者（如G1202R），Lorlatinib同样有效。在ALK阳性患者中，Lorlatinib的ORR为46%，颅内为ORR42%，mPFS为9.6个月；在ROS1阳性的患者中，Lorlatinib的ORR为50%。这一研究提示，Lorlatinib用于既往一代或二代ALK抑制剂耐药的患者显示出较好的疗效51。目前，Lorlatinib对比克唑替尼用于ALK阳性晚期NSCLC一线治疗的III期临床试验CROWN正在进行。 （三）ROS1重排 1. ROS1基因可表达一个与ALK相关的罕见酪氨酸激酶 ，属于胰岛素受体家族。与其他的酪氨酸激酶受体类似，ROS1 融合基因也可激活细胞生长和存活的信号传导通路。大约1–2% 的NSCLC中具有ROS1 基因重排52。 2. 2014年，Alice Shaw报道了克唑替尼用于ROS1阳性患者的I期 PROFILE 1001研究。 研究入组了50例ROS重排的晚期NSCLC，接受克唑替尼治疗后，疗效显著，ORR为72%，中位PFS为19.6个月53。2016年3月11日美国FDA扩展了克唑替尼的适应证，批准克唑替尼用于ROS1阳性转移性NSCLC的治疗。 3. 2015年，欧洲的一项回顾性研究分析了31例ROS1阳性的NSCLC患者，接受克唑替尼治疗的ORR为80%，PFS为9.1个月54。 4. 2015年，WCLC会议上报道了法国的一项II期研究队列分析结果，入组37例ROS1阳性的NSCLC患者，接受克唑替尼治疗的ORR为69%，PFS为9.1个月50。 5. 2016年ASCO大会和CSCO大会报道ROS1用于东亚人群的临床研究。这是一项在东亚人群中评估克唑替尼治疗ROS1重排阳性晚期NSCLC患者的单臂的II期研究。研究共入组了127例ROS1阳性的晚期NSCLC（采用RT-PCR法检测ROS1融合），克唑替尼的ORR为88%，中位PFS约为13.4个月51。 6. 2017年，Ceritinib用于ROS1融合的晚期NSCLC的II期临床研究公布。研究入组32例ROS1阳性的患者，其中28例可以评价疗效。在总体人群中，Ceritinib的ORR为62%，mPFS为9.3个月；在既往未接受过克唑替尼治疗的患者中，Ceritinib的ORR为66%，mPFS为19.3个月。这一研究提示，Ceritinib用于既往经过多线治疗的ROS1融合的晚期NSCLC，显示出较好的临床疗效，期待进一步研究55。 （四）BRAF突变 BRAF V600E突变在肺腺癌中的发生率为1-2%。2017年，Dabrafenib 联合Trametinib用于BRAF V600E突变型NSCLC的II期临床研究结果公布。研究入组36例BRAF V600E突变的晚期NSCLC，接受一线Dabrafenib 联合Trametinib治疗，结果显示，研究者确认的ORR为64%，mPFS为10.9个月，mOS为24.6个月56。2017年6月，Dabrafenib 联合Trametinib已经批准用于BRAF V600E突变型晚期NSCLC。 1. 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