【1648】【激荡20年】肺癌靶向治疗研究进展里程碑（下）
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. 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) [corrected]. J Clin Oncol 21:2237-46, 2003
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 290:2149-58, 2003
3.Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol 22:777-84, 2004
4.Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol 22:785-94, 2004
5.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 350:2129-39, 2004
6.Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497-500, 2004
7.Kobayashi S, Boggon TJ, Dayaram T, et al: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786-92, 2005
8.Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in Previously Treated Non–Small-Cell Lung Cancer. New England Journal of Medicine 353:123-132, 2005
9.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). The Lancet 366:1527-1537
10.Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-57, 2009
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 30:1122-8, 2012
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. The Lancet Oncology 11:121-128
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 362:2380-8, 2010
14.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 13:239-46, 2012
15.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 12:735-42, 2011
16. Wu YL, Zhou C, Liam CK, et al: First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 26:1883-9, 2015
17.Jackman D, Pao W, Riely GJ, et al: Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 28:357-60, 2010
18.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 31:3327-34, 2013
19.Wu YL, Zhou C, Hu CP, et al: Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 15:213-22, 2014
20.Yang JJ, Chen HJ, Yan HH, et al: Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer. Lung Cancer 79:33-9, 2013
21. Park K, Yu CJ, Kim SW, et al: First-Line Erlotinib Therapy Until and Beyond Response Evaluation Criteria in Solid Tumors Progression in Asian Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer: The ASPIRATION Study. JAMA Oncol 2:305-12, 2016
22.Soria JC, Wu YL, Nakagawa K, et al: Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol 16:990-8, 2015
23.Camidge DR, Pao W, Sequist LV: Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 11:473-81, 2014
24. Janne PA, Yang JC, Kim DW, et al: AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 372:1689-99, 2015
25.Goss G, Tsai CM, Shepherd FA, et al: Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 17:1643-1652, 2016
26. Mok TS, Wu Y-L, Ahn M-J, et al: Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer. New England Journal of Medicine, 2016
27.Wu YL, Lee JS, Thongprasert S, et al: Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol 14:777-86, 2013
28.Cheng Y, Murakami H, Yang PC, et al: Randomized Phase II Trial of Gefitinib With and Without Pemetrexed as First-Line Therapy in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations. J Clin Oncol 34:3258-66, 2016
29.Seto T, Kato T, Nishio M, et al: Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol 15:1236-44, 2014
30.Rosell R, Dafni U, Felip E, et al: Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial. Lancet Respir Med 5:435-444, 2017
31.Yuankai Shi LW, Baohui Han, Wei Li, Ping Yu, Yunpeng Liu, Cuimin Ding, Xia Song, Ma Zhi Yong, Xinling Ren, Ji Feng Feng, Helong Zhang, Gongyan Chen, Ning Wu, Xiaohong Han, Chen Yao, Yong Song, Shucai Zhang, Lieming Ding, Fenlai Tan.: First-line icotinib versus cisplatine/pemetrexed plus pemetrexed maintenance therapy in lung adenocarcinoma patients with sensitizing EGFR mutation (CONVINCE). J Clin Oncol 34:suppl; abstr 9041, 2016
32.Wu YL, Cheng Y, Zhou X, et al: Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 18:1454-1466, 2017
33.Soria JC, Ohe Y, Vansteenkiste J, et al: Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 378:113-125, 2018
34.Goss GD, O'Callaghan C, Lorimer I, et al: Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol 31:3320-6, 2013
35.Kelly K, Altorki NK, Eberhardt WE, et al: Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 33:4007-14, 2015
36.Zhong WZ, Wang Q, Mao WM, et al: Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol 19:139-148, 2018
37.Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-6, 2007
38.Kwak EL, Bang YJ, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-703, 2010
39.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 13:1011-9, 2012
40.Kim D, Ahn M, Yang P, et al: updated results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer(NSCLC). Annals of Oncology 23:402-402, 2012
41.Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-94, 2013
42. Solomon BJ, Mok T, Kim DW, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-77, 2014
43. Shaw AT, Kim DW, Mehra R, et al: Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370:1189-97, 2014
44. Gainor JF, Tan DS, De Pas T, et al: Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib. Clin Cancer Res 21:2745-52, 2015
45.Gadgeel SM, Gandhi L, Riely GJ, et al: Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 15:1119-28, 2014
46. Shaw AT, Gandhi L, Gadgeel S, et al: Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol 17:234-42, 2016
47.Shun Lu TM, You Lu, Jianying Zhou, Yuankai Shi, Virote Sriuranpong, James C. M. Ho, Choo Khoon Ong, Chun-Ming Tsai, Chin-Hee Chung, Keith D. Wilner, Yiyun Tang, Elizabeth Masters, Paulina Selaru, Yi-Long Wu: Phase 3 study of first-line crizotinib vs pemetrexed−cisplatin/carboplatin (PCC) in East Asian patients (pts) with ALK+ advanced non-squamous non-small cell lung cancer (NSCLC). J Clin Oncol 34:suppl; abstr 9058, 2016
48.Hiroshi Nokihara TH, Masashi Kondo, Young Hak Kim, Koichi Azuma, Takashi Seto, Yuichi Takiguchi, Makoto Nishio, Hiroshige Yoshioka, Fumio Imamura, Katsuyuki Hotta, Satoshi Watanabe, Koichi Goto, Kazuhiko Nakagawa, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Hiroshi Kuriki, Ryoichi Asabe, Tomohiro Tanaka, Tomohide Tamura: Alectinib (ALC) versus crizotinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study. J Clin Oncol 34:suppl; abstr 9008, 2016
49. Soria JC, Tan DS, Chiari R, et al: First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 389:917-929, 2017
50.Peters S, Camidge DR, Shaw AT, et al: Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 377:829-838, 2017
51. Shaw AT, Felip E, Bauer TM, et al: Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol 18:1590-1599, 2017
52.Bergethon K, Shaw AT, Ou SH, et al: ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30:863-70, 2012
53. Shaw AT, Ou SH, Bang YJ, et al: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371:1963-71, 2014
54.Mazieres J, Zalcman G, Crino L, et al: Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol 33:992-9, 2015
55. Lim SM, Kim HR, Lee JS, et al: Open-Label, Multicenter, Phase II Study of Ceritinib in Patients With Non-Small-Cell Lung Cancer Harboring ROS1 Rearrangement. J Clin Oncol 35:2613-2618, 2017
56.Planchard D, Smit EF, Groen HJM, et al: Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol 18:1307-1316, 2017
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