中国科技论文统计源期刊 中文核心期刊  
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊  
日本科学技术振兴机构数据库(JST)
第七届湖北十大名刊提名奖  
HERALD OF MEDICINE, 2018, 37(5): 531-535
doi: 10.3870/j.issn.1004-0781.2018.05.006
晚期非小细胞肺癌化学治疗的现状与未来
Current Situation and Future of Chemotherapy in Advanced Non-Small Cell Lung Cancer
章必成1, 朱波2,

摘要:

近年来,化学治疗(化疗)在晚期非小细胞肺癌(NSCLC)治疗中的基石地位已经受到了严重的挑战,疗效已经遭遇瓶颈。通过化疗与分子靶向药物、抗血管生成药物或免疫治疗药物的联合应用,挖掘现有化疗药物的潜力并研发新型化疗药物,寻找预测化疗疗效的生物标志物等手段,有望最大程度让晚期NSCLC患者在化疗中获益。

关键词: ; ; 非小细胞 ; 化学治疗 ; 分子靶向治疗 ; 抗血管生成药物 ; 免疫治疗

Abstract:

Nowadays, the cornerstone status of chemotherapy in advanced non-small cell lung cancer (NSCLC) is seriously challenged and its therapeutic effect has hit the bottlenecks. With the combination of chemotherapy and molecular targeted drugs, antiangiogenic agents or immunotherapy drugs, tapping the potential of chemotherapeutic drugs and developing new chemotherapeutic drugs, searching the biomarkers that can predict the efficacy of chemotherapy, most patients with advanced NSCLC may get the maximum benefit from chemotherapy.

Key words: Cancer ; lung ; non-small cell ; Chemotherapy ; Molecular targeted therapy ; Antiangiogenic agents ; Immunotherapy

在全球范围内,肺癌的发病率和死亡率已经高居恶性肿瘤之首。当前,肿瘤治疗已经进入精准医学时代,肺癌也不例外。占晚期肺癌绝大多数的非小细胞肺癌(non-small cell lung cancer,NSCLC)的治疗更是经历了从组织学时代到分子分型时代的转变。近年来,免疫治疗风头日盛,在晚期NSCLC的一线或二线治疗、局部晚期NSCLC的巩固治疗等领域均有不俗表现[1]。虽然化学治疗(化疗)的地位有所下降,但它仍然是晚期NSCLC不可或缺的基础治疗手段。通过化疗与分子靶向药物、抗血管生成药物或免疫治疗的联合应用,挖掘现有化疗药物的潜力并研发新型化疗药物,寻找预测化疗疗效的生物标志物等手段,以期最大程度让晚期NSCLC患者获益于化疗,是该领域的发展方向。

1 晚期NSCLC化疗疗效遭遇瓶颈,期待突破

2001年,含铂双药方案成为晚期NSCLC一线化疗的标准。随后,ECOG 1594研究提示4种含铂双药方案(紫杉醇+顺铂、吉西他滨+顺铂、多西他赛+顺铂和紫杉醇+卡铂)在总缓解率(overall response rate,ORR)、中位生存时间(median survival time,MST)和一年生存率上差异无统计学意义[2]。2008年,JMDB研究建议晚期肺鳞癌和非鳞NSCLC(主要是腺癌和大细胞癌)的一线化疗分别首选含有吉西他滨、培美曲塞的含铂双药方案[3]。这是首次根据组织病理学选择NSCLC化疗方案的报道。迄今为止,含铂双药方案治疗晚期NSCLC的ORR约35%,MST维持在8~10个月,一年生存率30%~40%,总生存(overall survival,OS)为1年之内。近年来,随着分子靶向药物、抗血管生成药物和免疫治疗药物大量应用于临床,化疗的基石地位已经受到严重的挑战。目前,晚期NSCLC化疗已经遭遇治疗疗效瓶颈,主要表现为:①鲜有新药问世,整体疗效较差;②不良反应较大;③缺乏预测疗效的生物标志物。

2 化疗与其他治疗方法联合治疗晚期NSCLC
2.1 化疗与分子靶向药物的联合

针对表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变、间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)基因融合或ROS1基因重排等的小分子酪氨酸激酶抑制药(tyrosine kinase inhibitor,TKI)是晚期NSCLC治疗的重大突破,真正体现了肿瘤的个体化精准治疗。针对这一部分患者,一线治疗当然应该首选分子靶向治疗。但无奈的是,几乎所有的患者会在1年之后出现耐药。为了提高治疗有效率,可以考虑化疗与分子靶向药物的联合应用。

以EGFR敏感突变为例,目前多个临床研究获得阳性结果。FASTACT II研究的亚组分析表明,在吉西他滨+顺铂(或卡铂)方案化疗间期给予厄洛替尼,能显著延长携带EGFR敏感突变的晚期NSCLC患者的无进展生存(progression-free survival,PFS)和OS[4]。NEJ005研究比较了吉非替尼联合同步化疗(培美曲塞+卡铂)或序贯化疗治疗晚期NSCLC的疗效,发现同步治疗组的PFS和OS均优于序贯治疗组[5]。HAN等[6]研究表明,培美曲塞+卡铂+吉非替尼组、吉非替尼组和培美曲塞+卡铂组治疗晚期NSCLC的中位PFS分别为17.9,11.9和5.7个月。研究表明,相对于吉非替尼单药组,加用培美曲塞之后显著延长了晚期NSCLC的中位PFS[7]

可见,针对携带EGFR敏感突变的患者,在化疗的基础上联用EGFR-TKI可以提高患者的生存率。然而,FASTACT II研究虽然是一个Ⅲ期临床研究,但在入选标准中并未限定EGFR敏感突变,所得结论来自亚组分析,科学性需要进一步验证。NEJ005研究、韩宝惠研究和JMIT研究都是Ⅱ期临床研究,所得结论尚需Ⅲ期临床研究进一步验证。在是否使用铂类药物这个问题上,NEJ005研究与JMIT研究的观点并不一致。此外,目前的研究并没有解决两者到底是同步还是序贯使用的问题。因此,这些研究的结论只是提供了下一步探索的方向,在现阶段尚不足以改变临床实践。

2.2 化疗与抗血管生成药物的联合

抗血管生成治疗在晚期NSCLC的治疗中发挥了重要的作用,不仅可以与TKI联用一线治疗携带敏感基因突变的患者,而且可以与化疗联用治疗无敏感基因突变的野生型患者,以及一线TKI治疗后耐药的晚期患者。目前用于治疗晚期NSCLC的抗血管生成药物包括VEGF抑制药贝伐珠单抗(bevacizumab,Avastin)、VEGFR2抑制药雷莫芦单抗(ramucirumab,RAM)、抗VEGF的小分子TKI尼达尼布(nintedanib)和直接靶向血管内皮细胞的内皮抑素(endostatin)等[8]

以贝伐珠单抗为例,化疗联合抗血管生成药物在晚期NSCLC的治疗中有不俗表现。ECOG 4599是全球第一个化疗联合贝伐珠单抗治疗晚期NSCLC的Ⅲ期临床研究[9]。结果表明,两者联用可使患者的ORR、PFS明显延长,而且OS超过1年。基于此研究,美国食品药品管理局(FDA)批准紫杉醇、卡铂联合贝伐珠单抗一线治疗晚期非鳞NSCLC。此后,Avail研究(Ⅲ期)[10]和Sail研究(Ⅳ期)[11]等均重复和印证了上述结果。2015年,贝伐珠单抗中国注册研究BEYOND(Ⅲ期)[12]证实了化疗联合贝伐珠单抗一线治疗能为中国非鳞NSCLC患者的PFS、OS和ORR显著获益,且患者耐受性良好;这种疗效提升不仅见于EGFR敏感突变患者,而且也见于EGFR野生型非鳞NSCLC患者。但是,由于贝伐珠单抗的副作用,它仅限于治疗晚期非鳞NSCLC,不推荐用于肺鳞癌。

除了贝伐珠单抗外,其他几个抗血管生成药物也有一定的治疗效果。化疗联合抗血管生成药物治疗已经成为晚期NSCLC的一种新的有效的治疗模式。但是由于缺乏分子标志、耐药机制不明、不良反应较大和疗效仍差等原因,目前化疗联合抗血管生成药物仍然处在一个比较尴尬的地位。

2.3 化疗与免疫治疗药物的联合

作为晚期NSCLC的治疗新贵,以免疫检查点抑制药为代表的免疫治疗将晚期NSCLC患者的5年OS提升至16%。2016年,Nivolumab、Pembrolizumab和Atezolizumab先后被FDA批准用于晚期NSCLC患者的二线治疗,其中Pembrolizumab还被批准用于PD-L1高表达患者一线治疗[13]。但是,免疫治疗的有效人群也不过约30%,大多数晚期NSCLC属于对免疫治疗不够敏感的“冷肿瘤”。针对这一部分患者,必须考虑联用免疫治疗与其他治疗手段。化疗是其中的选择之一,其作用基础是基于化疗的免疫调节效应,包括:降低免疫抑制性细胞的数量和活性(例如调节性T细胞、M2 巨噬细胞、髓系来源抑制性细胞等);诱导免疫原性死亡;增加肿瘤抗原递呈;激活和诱导树突状细胞成熟;增加效应T细胞功能;诱导肿瘤细胞PD-L1表达等[14]

综合目前的临床试验数据,化疗联合免疫治疗晚期NSCLC可以显著提高ORR(40%~70%),缩短平均起效时间,且毒副作用可控。KEYNOTE-021研究(Ⅱ期)比较了培美曲塞+卡铂+Pembrolizumab组与培美曲塞+卡铂组之间的疗效,发现化疗联用免疫治疗能显著提高晚期NSCLC患者的ORR和PFS[15]。基于此结果,2017年5月,FDA批准了培美曲塞+卡铂+Pembrolizumab一线治疗晚期非鳞NSCLC,而且不限患者的PD-L1表达水平。2017年ASCO报道了Atezolizumab联合含铂双药方案治疗晚期NSCLC的更新数据(Ib期),认为两者联合一线治疗晚期NSCLC的耐受性良好,ORR有明显获益[16]。此外,如果化疗和免疫治疗是序贯使用,则研究表明先化疗会降低后续的免疫治疗疗效,而先免疫治疗能增强后续的化疗疗效[17]

化疗联合免疫治疗虽然展示了一定的疗效和乐观的前景,但是,尚有很多问题需要回答:①缺乏有效性预测标志物:PD-L1<1%?PD-L1>50%?肿瘤突变负荷?免疫微环境分型?②联合策略:序贯还是同步?③化疗药物选择;④免疫治疗药物的选择及治疗时间;⑤疗效评估体系:假性进展?真性进展?⑥不良反应预防、评估及控制;⑦耐药/进展后治疗策略是什么?目前在晚期NSCLC领域,还有多项化疗联合免疫治疗的临床研究正在进行中。

3 挖掘现有晚期NSCLC化疗药物的潜力

近年来,针对晚期NSCLC化疗药物的研究乏善可陈。一是对现有药物进行改造或替换效果甚微。如将紫杉醇换成白蛋白结合型紫杉醇,将顺铂(或卡铂)换成奈达铂或洛铂等。Ⅲ期临床试验结果显示,对于晚期肺鳞癌患者,白蛋白结合型紫杉醇+卡铂方案的ORR明显高于紫杉醇+卡铂方案,而对于非鳞NSCLC患者两方案的总有效率相似[18]。WJOG5208L研究表明,相对于顺铂+多西他赛方案,奈达铂+多西他赛一线治疗虽可提高晚期肺鳞癌OS,但仅提高了2.2个月[19]

二是维持治疗能带来疗效获益。其一是同药维持。CECOG和IFCT-GFPC 0502等研究提示在吉西他滨+顺铂方案一线治疗晚期NSCLC后采用吉西他滨维持治疗,可使患者OS明显获益[20]。PARAMOUNT研究提示在一线使用培美曲塞+铂类药物治疗晚期非鳞NSCLC后继续采用单药培美曲塞维持治疗,可将生存延长至13.9个月[21]。另有研究认为采用培美曲塞+贝伐珠单抗双药维持治疗可以改善晚期非鳞NSCLC患者的预后[22]。其二是换药维持。即在一线治疗后对获得稳定以上疗效的患者改用不同的单药进行维持治疗。但有的专家认为这是将二线治疗提前实施,并不认可。

三是特殊人群的化疗。高龄或体力状况评分为2分的患者不应轻易放弃化疗。对于这部分患者,多项临床研究证实,与最佳支持治疗比较,单药化疗可以延长生存期并提高生活质量。可选的单药包括吉西他滨、长春瑞滨、紫杉醇、多西他赛及培美曲塞等。当然,笔者认为也可以选择含铂双药方案,但必须对剂量进行下调。

四是二线化疗。目前的循证医学证据表明在一线化疗失败后,二线化疗选择两药方案并未显示生存获益[23]。因此,国内外指南一致推荐选择单药化疗即可,可选药物包括多西他赛或培美曲塞(如一线未给同一药物)。但根据患者的身体状况,国内大部分医院通常会更多地选择联合化疗。此外,如果一线治疗选择的是分子靶向治疗或免疫治疗,二线治疗也可以选择化疗。

4 研发新型治疗晚期NSCLC的化疗药物

抗体-药物共轭物(antibody-drug conjugate,ADC)是将具有免疫特性的单克隆抗体结合一个生化毒物,使其在进入人体后直接与肿瘤发生免疫反应,并引导毒物杀死肿瘤细胞的一类新型药物[24]。因其良好的靶向性及抗癌活性,ADC已成为抗肿瘤抗体药物研发的新热点和重要趋势,受到越来越多的关注。目前,已有多个ADC进入临床研究阶段,部分产品已经上市销售。如T-DM1已于2013年11月获欧盟批准用于治疗HER2阳性转移性乳腺癌;作为一种有效的微管抑制药,抗-CD30抗体耦联药物Brentuximabvedotin (Adcetris)对霍奇金淋巴瘤和间变性大细胞淋巴瘤极为有效。目前,针对晚期NSCLC的ADC包括BAY 1129980、Sacituzumabgovitecan (IMMU-132)、Rovalpituzumabtesirine(SC16LD6.5)等,但尚无相关疗效的报道[25,26]。ADC未来的发展需考虑靶点高选择性、细胞毒药物的杀伤潜能、发展新型的连接物和克服继发性耐药等问题。

5 寻找预测晚期NSCLC化疗疗效的分子标志物

药物基因组学的发展为寻找可以预测化疗疗效的标志物成为可能。单核苷酸多态性由于在铂类药物药效学、代谢和作用机制等方面发挥重要作用,可以用于预测化疗疗效及毒性。在采用含铂双药治疗晚期NSCLC时,DNA修复通路(包括NER通路、BER通路和DSB通路等)、PI3K/PTEN/AKT通路、 TGF-β通路、p53通路(如TP53、MDM2)、药物转运蛋白(如ATP结合盒、MDR/ TAP、ABCB1/MDR1等)、谷胱甘肽代谢途径(如GSTP1)、叶酸代谢酶(如MTHFR、MTR、SLC19A1等)和细胞因子信号通路(如IL-1B、IL-6、IL-12A、IL-13、IL-16等)等的基因多态性均与患者的疗效、生存和不良反应有关。其中,证据最为充分的结论来自DNA修复通路:NER通路中ERCC2和ERCC5基因多态性与患者OS、PFS相关,而ERCC1的作用尚待进一步研究;BER通路中XRCC1基因多态性似乎只与亚洲晚期NSCLC患者的疗效相关;DSB通路中XRCC3基因多态性与患者ORR相关。因此,ERCC2、ERCC5、XRCC1、XRCC3基因多态性有望用于预测含铂双药方案治疗晚期NSCLC的预后和疗效[27]

此外,RRM1、TS分别是预测吉西他滨和培美曲塞治疗NSCLC疗效的较好生物标志物。其他潜在标志物包括预测吉西他滨疗效的hENT1、预测纺锤体抑制药疗效的Ⅲ类β-微管蛋白、预测足叶乙苷疗效的TOP2A和 CEP17等[28]

但是,这些标志物尚不被主流肿瘤内科专家认可,尚不能用于指导临床实践。原因之一是晚期NSCLC通常会在一线选择联合治疗而非单药治疗。未来的研究方向包括:①采用前瞻性、随机研究验证对这些标志物的有效性;②选择多个标志物联合检测;③采用第2代测序技术筛选多基因图谱。

6 结束语

近二十多年来,化疗治疗晚期NSCLC的疗效没有得到明显提升,不良反应依然十分明显,其地位已经遭遇了分子靶向治疗、抗血管生成治疗和免疫治疗等新型治疗手段的严重挑战。但是,化疗仍然是晚期NSCLC治疗的基石,在短时间内仍将发挥重要的作用。通过联合其他治疗手段、挖掘现有化疗药物潜力、研发新型化疗药物、寻找预测化疗疗效的分子标志物有望给晚期NSCLC化疗增效减毒提供可行的策略。但是,这些途径尚充满太多未知,化疗的未来仍道阻且长。

The authors have declared that no competing interests exist.

参考文献

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DOI:10.1016/S1470-2045(16)30123-1      PMID:27511159      URL    
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[2] SCHILLER J H,HARRINGTON D,BELANI C P,et al.Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer[J].N Engl J Med,2002,346(2):92-98.
Abstract BACKGROUND: We conducted a randomized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non-small-cell lung cancer. METHODS: A total of 1207 patients with advanced non-small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. RESULTS: The response rate for all 1155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent), and a 2-year survival rate of 11 percent (95 percent confidence interval, 8 to 12 percent). The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens. Treatment with cisplatin and gemcitabine was associated with a significantly longer time to the progression of disease than was treatment with cisplatin and paclitaxel but was more likely to cause grade 3, 4, or 5 renal toxicity (in 9 percent of patients, vs. 3 percent of those treated with cisplatin plus paclitaxel). Patients with a performance status of 2 had a significantly lower rate of survival than did those with a performance status of 0 or 1. CONCLUSIONS: None of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non-small-cell lung cancer.
DOI:10.1056/NEJMoa011954      PMID:11784875      URL    
[本文引用:1]
[3] SCAGLIOTTI G V,PARIKH P,VON PAWEL J,et al.Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer[J].J Clin Oncol,2008,26(21):3543-3551.
DOI:10.1200/JCO.2007.15.0375      URL    
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[4] WU Y L,LEE J S,Thongprasert S,et al.Intercalated com-bination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2):a randomised,double-blind trial[J].Lancet Oncol,2013,14(8):777-786.
BACKGROUND: The results of FASTACT, a randomised, placebo-controlled, phase 2 study, showed that intercalated chemotherapy and erlotinib significantly prolonged progression-free survival (PFS) in patients with advanced non-small-cell lung cancer. We undertook FASTACT-2, a phase 3 study in a similar patient population. METHODS: In this phase 3 trial, patients with untreated stage IIIB/IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio by use of an interactive internet response system with minimisation algorithm (stratified by disease stage, tumour histology, smoking status, and chemotherapy regimen) to receive six cycles of gemcitabine (1250 mg/m(2) on days 1 and 8, intravenously) plus platinum (carboplatin 564×64area under the curve or cisplatin 75 mg/m(2) on day 1, intravenously) with intercalated erlotinib (150 mg/day on days 15-28, orally; chemotherapy plus erlotinib) or placebo orally (chemotherapy plus placebo) every 4 weeks. With the exception of an independent group responsible for monitoring data and safety monitoring board, everyone outside the interactive internet response system company was masked to treatment allocation. Patients continued to receive erlotinib or placebo until progression or unacceptable toxicity or death, and all patients in the placebo group were offered second-line erlotinib at the time of progression. The primary endpoint was PFS in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00883779. FINDINGS: From April 29, 2009, to Sept 9, 2010, 451 patients were randomly assigned to chemotherapy plus erlotinib (n=226) or chemotherapy plus placebo (n=225). PFS was significantly prolonged with chemotherapy plus erlotinib versus chemotherapy plus placebo (median PFS 7·6 months [95% CI 7·2-8·3], vs 6·0 months [5·6-7·1], hazard ratio [HR] 0·57 [0·47-0·69]; p<0·0001). Median overall survival for patients in the chemotherapy plus erlotinib and chemotherapy plus placebo groups was 18·3 months (16·3-20·8) and 15·2 months (12·7-17·5), respectively (HR 0·79 [0·64-0·99]; p=0·0420). Treatment benefit was noted only in patients with an activating EGFR gene mutation (median PFS 16·8 months [12·9-20·4] vs 6·9 months [5·3-7·6], HR 0·25 [0·16-0·39]; p<0·0001; median overall survival 31·4 months [22·2-undefined], vs 20·6 months [14·2-26·9], HR 0·48 [0·27-0·84]; p=0·0092). Serious adverse events were reported by 76 (34%) of 222 patients in the chemotherapy plus placebo group and 69 (31%) of 226 in the chemotherapy plus erlotinib group. The most common grade 3 or greater adverse events were neutropenia (65 [29%] patients and 55 [25%], respectively), thrombocytopenia (32 [14%] and 31 [14%], respectively), and anaemia (26 [12%] and 21 [9%], respectively). INTERPRETATION: Intercalated chemotherapy and erlotinib is a viable first-line option for patients with non-small-cell lung cancer with EGFR mutation-positive disease or selected patients with unknown EGFR mutation status.
DOI:10.1016/S1470-2045(13)70254-7      PMID:23782814      URL    
[本文引用:1]
[5] SUGAWARA S,OIZUMI S,MINATO K,et al.Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations:NEJ005/TCOG0902[J].Ann Oncol,2015,26(5):888-894.
Background: The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III evaluation. Patients and methods: Chemotherapy-naive patients with advanced non-squamous, EGFR-mutant NSCLC were randomly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib (250 mg) and carboplatin/pemetrexed [area under the curve (AUC) = 6 and 500 mg/m(2); 3-weekly]. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety. Results: All 80 patients enrolled were eligible and assessable for efficacy (41 and 39 patients in the concurrent and sequential alternating regimen groups, respectively). Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen [hazard ratio (HR) 0.71 (0.42-1.20), P = 0.20]. Although OS data are immature (16 and 24 death events), median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups, respectively [HR 0.51 (0.26-0.99); P = 0.042]. Response rates were similar in both groups (87.8% and 84.6%). Hematological and non-hematological adverse events were common and reversible; interstitial lung disease was neither frequent nor fatal (two cases in each group; 5% of all patients). Conclusion: This is the first randomized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better OS. The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study.
DOI:10.1093/annonc/mdv063      PMID:25669832      URL    
[本文引用:1]
[6] HAN B H,JIN B,CHU T Q,et al.Combination of chemo-therapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations:a randomized controlled trial[J].Int J Cancer,2017,141(6):1249-1256.
1281PCOMBINATION OF CHEMOTHERAPY AND GEFITINIB AS FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED LUNG ADENOCARCINOMA AND SENSITIVE EGFR MUTATIONS: A RANDOMISED CONTROLLED TRIAL
DOI:10.1016/S1556-0864(16)30244-1      PMID:27198271      URL    
[本文引用:1]
[7] CHENG Y,MURAKAMI H,YANG P C,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].J Clin Oncol,2016,34(27):3258-3266.
Abstract PURPOSE: To determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations. PATIENTS AND METHODS: Chemotherapy-nave for advanced NSCLC patients from China, Japan, Korea, and Taiwan (35 sites) with advanced, EGFR-mutant, NS NSCLC were randomly assigned (2:1; computer-generated, interactive voice response) to open-label pemetrexed (500 mg/m(2) on day 1 of every 21-day cycle) plus gefitinib (250 mg/d [n = 129]) or gefitinib alone (n = 66). The primary end point was progression-free-survival (PFS); secondary end points were time to progressive disease, overall survival, tumor response rates, duration of response, and safety. All end points were assessed in the intent-to-treat and safety population (P+G, n = 126; gefitinib alone, n = 65). RESULTS: PFS was significantly longer with P+G (median, 15.8 months; 95% CI, 12.6 to 18.3 months) than with gefitinib (median, 10.9 months; 95% CI, 9.7 to 13.8 months; adjusted hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; one-sided P = .014; two-sided P = .029). Results of EGFR exon 19 deletion and EGFR exon 21 L858R point mutation subgroup analyses were consistent with the intent-to-treat result. P+G, compared with gefitinib alone, resulted in significantly longer time to progressive disease (median, 16.2 v 10.9 months, respectively; HR, 0.66; 95% CI, 0.47 to 0.93) and numerically longer duration of response (median, 15.4 v 11.3 months, respectively; HR, 0.74; 95% CI, 0.50 to 1.08). Tumor response rates did not differ. Overall survival data are immature. Drug-related grade 3 or 4 adverse events were more common with P+G, but toxicities were manageable. CONCLUSION: P+G improved PFS compared with gefitinib alone in East Asian patients with advanced NS NSCLC and activating EGFR mutations. This combination may offer EGFR mutation-positive patients new treatment options and improved clinical outcomes compared with the current standard of care. 2016 by American Society of Clinical Oncology.
DOI:10.1200/JCO.2016.66.9218      PMID:27507876      URL    
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[8] WANG J,CHEN J,GUO Y,et al.Strategies targeting angio-genesis in advanced non-small cell lung cancer[J].Oncotarget,2017,8(32):53854-53872.
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[9] SANDLER A,GRAY R,PERRY M C,et al.Paclitaxelcar-boplatin alone or with bevacizumab for non-small-cell lung cancer[J].N Engl J Med,2006,355(24):2542-2550.
Abstract BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been shown to benefit patients with a variety of cancers. METHODS: Between July 2001 and April 2004, the Eastern Cooperative Oncology Group (ECOG) conducted a randomized study in which 878 patients with recurrent or advanced non-small-cell lung cancer (stage IIIB or IV) were assigned to chemotherapy with paclitaxel and carboplatin alone (444) or paclitaxel and carboplatin plus bevacizumab (434). Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status, >1) were excluded. The primary end point was overall survival. RESULTS: The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; P=0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; P<0.001), with corresponding response rates of 35% and 15% (P<0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P<0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage. CONCLUSIONS: The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060 .) 2006 Massachusetts Medical Society
DOI:10.1056/NEJMoa061884      PMID:17167137      URL    
[本文引用:1]
[10] RECK M,VON PAWEL J,ZATLOUKAL P,et al.Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer:AVAil[J].J Clin Oncol,2009,27(8):1227-1234.
PURPOSE: Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, improves survival when combined with carboplatin/paclitaxel for advanced nonsquamous non-small-cell lung cancer (NSCLC). This randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine (CG) plus bevacizumab in this setting. PATIENTS AND METHODS: Patients were randomly assigned to receive cisplatin 80 mg/m2 and gemcitabine 1,250 mg/m(2) for up to six cycles plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The trial was not powered to compare the two doses directly. The primary end point was amended from overall survival (OS) to progression-free survival (PFS). Between February 2005 and August 2006, 1,043 patients were randomly assigned (placebo, n = 347; low dose, n = 345; high dose, n = 351). RESULTS: PFS was significantly prolonged; the hazard ratios for PFS were 0.75 (median PFS, 6.7 v 6.1 months for placebo; P = .003) in the low-dose group and 0.82 (median PFS, 6.5 v 6.1 months for placebo; P = .03) in the high-dose group compared with placebo. Objective response rates were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus CG, respectively. Duration of follow-up was not sufficient for OS analysis. Incidence of grade 3 or greater adverse events was similar across arms. Grade > or = 3 pulmonary hemorrhage rates were < or = 1.5% for all arms despite 9% of patients receiving therapeutic anticoagulation. CONCLUSION: Combining bevacizumab (7.5 or 15 mg/kg) with CG significantly improved PFS and objective response rate. Bevacizumab plus platinum-based chemotherapy offers clinical benefit for bevacizumab-eligible patients with advanced NSCLC.
DOI:10.1200/JCO.2007.14.5466      PMID:19188680      URL    
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[11] CRINO L,DANSIN E,GARRIDO P,et al.Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL,MO19390):a phase 4 study[J].Lancet Oncol,2010,11(8):733-740.
F Hoffmann-La Roche Ltd.
DOI:10.1016/S1470-2045(10)70151-0      PMID:20650686      URL    
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[12] ZHOU C,WU Y L,CHEN G,et al.BEYOND:a randomiz-ed,double-blind,placebo-controlled,multicenter,phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer[J].J Clin Oncol,2015,33(19):2197-2204.
The phase III BEYOND trial was undertaken to confirm in a Chinese patient population the efficacy seen with first-line bevacizumab plus platinum doublet chemotherapy in globally conducted studies. Patients age 18 years with locally advanced, metastatic, or recurrent advanced nonsquamous non-small-cell lung cancer (NSCLC) were randomly assigned to receive carboplatin (area under the curve, 6) intravenously and paclitaxel (175 mg/m(2)) intravenously (CP) on day 1 of each 3-week cycle, for six cycles, plus placebo (Pl+CP) or bevacizumab (B+CP) 15 mg/kg intravenously, on day 1 of each cycle, until progression, unacceptable toxicity, or death. The primary end point was progression-free survival (PFS); secondary end points were objective response rate, overall survival, exploratory biomarkers, safety. A total of 276 patients were randomly assigned, 138 to each arm. PFS was prolonged with B+CP versus Pl+CP (median, 9.2 v 6.5 months, respectively; hazard ratio [HR], 0.40; 95% CI, 0.29 to 0.54; P < .001). Objective response rate was improved with B+CP compared with Pl+CP (54% v 26%, respectively). Overall survival was also prolonged with B+CP compared with Pl+CP (median, 24.3 v 17.7 months, respectively; HR, 0.68; 95% CI, 0.50 to 0.93; P = .0154). Median PFS was 12.4 months with B+CP and 7.9 months with Pl+CP (HR, 0.27; 95% CI, 0.12 to 0.63) in EGFR mutation-positive tumors and 8.3 and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21 to 0.53), in wild-type tumors. Safety was similar to previous studies of B+CP in NSCLC; no new safety signals were observed. The addition to bevacizumab to carboplatin/paclitaxel was well tolerated and resulted in a clinically meaningful treatment benefit in Chinese patients with advanced nonsquamous NSCLC.
DOI:10.1200/JCO.2014.59.4424      PMID:26014294      URL    
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[13] MALHOTRA J,JABBOUR S K,AISNER J.Current state of immunotherapy for non-small cell lung cancer[J].Transl Lung Cancer Res,2017,6(2):196-211.
Abstract [This corrects the article on p. 196 in vol. 6, PMID: 28529902.].
DOI:10.21037/tlcr.2017.08.08      PMID:29114477      URL    
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[14] APETOH L,LADOIRE S,COUKOS G,et al.Combining immunotherapy and anticancer agents:the right path to achieve cancer cure?[J].Ann Oncol,2015,26(9):1813-1823.
Abstract Recent clinical trials revealed the impressive efficacy of immunological checkpoint blockade in different types of metastatic cancers. Such data underscore that immunotherapy is one of the most promising strategies for cancer treatment. In addition, preclinical studies provide evidence that some cytotoxic drugs have the ability to stimulate the immune system, resulting in anti-tumor immune responses that contribute to clinical efficacy of these agents. These observations raise the hypothesis that the next step for cancer treatment is the combination of cytotoxic agents and immunotherapies. The present review aims to summarize the immune-mediated effects of chemotherapeutic agents and their clinical relevance, the biological and clinical features of immune checkpoint blockers and finally, the preclinical and clinical rationale for novel therapeutic strategies combining anticancer agents and immune checkpoint blockers. The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
DOI:10.1093/annonc/mdv209      PMID:25922066      URL    
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[15] LANGER C J,GADGEEL S M,BORGHAEI H,et al.Carboplatin and pemetrexed with or without pembrolizumab for advanced,non-squamous non-small-cell lung cancer:a randomised,phase 2 cohort of the open-label KEYNOTE-021 study[J].Lancet Oncol,2016,17(11):1497-1508.
Merck & Co.
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[18] SOCINSKI M A,BONDARENKO I,KARASEVA N A,et al.Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer:final results of a phase III trial[J].J Clin Oncol,2012,30(17):2055-2062.
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[19] SHUKUYA T,YAMANAKA T,SETO T,et al.Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L):a randomised,open-label,phase 3 trial[J].Lancet Oncol,2015,16(16):1630-1638.
West Japan Oncology Group and Sanofi.
DOI:10.1016/S1470-2045(15)00305-8      PMID:26522337      URL    
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[20] PéROL M,CHOUAID C,PéROL D,et al.Randomized,phase III study of gemcitabine or erlotinib maintenance therapy versus observation,with predefined second-line treatment,after cisplatin-gemcitabine induction chemo-therapy in advanced non-small-cell lung cancer[J].J Clin Oncol,2012,30(28):3516-3524.
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[21] PAZ-ARES L G,DE MARINIS F,DEDIU M,et al.PARAMOUNT:final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer[J].J Clin Oncol,2013,31(23):2895-2902.
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[22] PATEL J D,SOCINSKI M A,GARON E B,et al.Point-Break:a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer[J].J Clin Oncol,2013,31(34):4349-4357.
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[23] DI MAIO M,CHIODINI P,GEORGOULIAS V,et al.Meta-analysis of single-agent chemotherapy compared with combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer[J].J Clin Oncol,2009,27(11):1836-1843.
Abstract PURPOSE: Doublet chemotherapy is more effective than single-agent as first-line treatment of advanced non-small-cell lung cancer (NSCLC). As second-line treatment, several randomized trials have been performed comparing single-agent with doublet chemotherapy, but each trial had an insufficient power to detect potentially relevant differences in survival. METHODS: We performed meta-analysis of individual patient data from randomized trials, both published and unpublished, comparing single-agent with doublet chemotherapy as second-line treatment of advanced NSCLC. Primary end point was overall survival (OS). All statistical analyses were stratified by trial. RESULTS: Eight eligible trials were identified. Data of two trials were not available, and data of six trials (847 patients) were collected. Median age was 61 years. Performance status was 0 or 1 in 90%; 80% of patients had received previous platin-based chemotherapy. OS was not significantly different between arms (P = .32). Median OS was 37.3 and 34.7 weeks in the doublet and single-agent arms, respectively. Hazard ratio (HR) was 0.92 (95% CI, 0.79 to 1.08). Response rate was 15.1% with doublet and 7.3% with single-agent (P = .0004). Median progression-free survival was 14 weeks for doublet and 11.7 weeks for single agent (P = .0009; HR, 0.79; 95% CI, 0.68 to 0.91). There was no significant heterogeneity among trials for the three efficacy outcomes. Patients treated with doublet chemotherapy had significantly more grade 3 to 4 hematologic (41% v 25%; P < .0001) and grade 3 to 4 nonhematologic toxicity (28% v 22%; P = .034). CONCLUSION: Doublet chemotherapy as second-line treatment of advanced NSCLC significantly increases response rate and progression-free survival, but is more toxic and does not improve overall survival compared to single-agent.
DOI:10.1200/JCO.2008.17.5844      PMID:19273711      URL    
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[24] DEGOEIJ B E,LAMBERT J M.New developments for antibody-drug conjugate-based therapeutic approaches[J].Curr Opin Immunol,2016,40(1):14-23.
Abstract The clinical success of Adcetris(0003) (brentuximab vedotin) and Kadcyla(0003) (ado-trastuzumab emtansine) has sparked clinical development of novel ADCs. These powerful anti-cancer agents are designed to allow specific targeting of highly potent cytotoxic agents to tumor cells while sparing healthy tissues. Despite the use of tumor-specific antibodies, the emerging clinical data with ADCs indicates that adverse effects frequently occur before ADCs have reached their optimal therapeutic dose, resulting in a relatively narrow therapeutic window. This review summarizes the therapeutic window of ADCs currently in clinical development, along with some strategies that may help to widen the window. Copyright 0008 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI:10.1016/j.coi.2016.02.008      PMID:26963132      URL    
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[25] WILLUDA J,LINDEN L,LERCHEN H G,et al.Preclinical antitumor efficacy of BAY 1129980-a novel auristatin-based anti-C4.4A(LYPD3) antibody-drug conjugate for the treatment of non-small cell lung cancer[J].Mol Cancer Ther,2017,16(5):893-904.
C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non-small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.4A expression is scarce in normal tissues, presenting an opportunity to selectively treat cancers with a C4.4A-directed antibody-drug conjugate (ADC). We have generated BAY 1129980 (C4.4A-ADC), an ADC consisting of a fully human C4.4A-targeting monoclonal antibody conjugated to a novel, highly potent derivative of the microtubule-disrupting cytotoxic drug auristatin via a non-cleavable alkyl hydrazide linker. In vitro, C4.4A-ADC demonstrated potent anti-proliferative efficacy in cell lines endogenously expressing C4.4A and inhibited proliferation of C4.4A-transfected A549 lung cancer cells showing selectivity compared to a non-targeted control ADC. In vivo, C4.4A-ADC was efficacious in human NSCLC cell line (NCI-H292 and NCI-H322) and patient-derived xenograft (PDX) models (Lu7064, Lu7126, Lu7433, and Lu7466). C4.4A expression level correlated with in vivo efficacy, the most responsive being the models with C4.4A expression in over 50% of the cells. In NCI-H292 NSCLC model C4.4A-ADC demonstrated equal or superior efficacy compared to cisplatin, paclitaxel, and vinorelbine. Furthermore, an additive antitumor efficacy in combination with cisplatin was observed. Finally, a repeated dosing with C4.4A-ADC was well tolerated without changing the sensitivity to the treatment. Taken together, C4.4A-ADC is a promising therapeutic candidate for the treatment of NSCLC and other cancers expressing C4.4A. A Phase I study (NCT02134197) with the C4.4A-ADC BAY 1129980 is currently ongoing.
DOI:10.1158/1535-7163.MCT-16-0474      PMID:28292941      URL    
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[26] DHOLARIA B,HAMMOND W,SHREDERS A,et al.Emerging therapeutic agents for lung cancer[J].J Hematol Oncol,2016,9(1):138.
Abstract Lung cancer continues to be the most common cause of cancer-related mortality worldwide. Recent advances in molecular diagnostics and immunotherapeutics have propelled the rapid development of novel treatment agents across all cancer subtypes, including lung cancer. Additionally, more pharmaceutical therapies for lung cancer have been approved by the US Food and Drug Administration in the last 5/years than in previous two decades. These drugs have ushered in a new era of lung cancer managements that have promising efficacy and safety and also provide treatment opportunities to patients who otherwise would have no conventional chemotherapy available. In this review, we summarize recent advances in lung cancer therapeutics with a specific focus on first in-human or early-phase I/II clinical trials. These drugs either offer better alternatives to drugs in their class or are a completely new class of drugs with novel mechanisms of action. We have divided our discussion into targeted agents, immunotherapies, and antibody drug conjugates for small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). We briefly review the emerging agents and ongoing clinical studies. We have attempted to provide the most current review on emerging therapeutic agents on horizon for lung cancer.
DOI:10.1186/s13045-016-0365-z      PMID:27938382      URL    
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[27] PEREZ-RAMIREZ C,CANADAS-GARRE M,MOLINA M Á,et al.Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer[J].Mutat Res,2017,771(1):32-58.
Finally, SNPs in genes coding proteins of the p53, PI3K, TGF-, membrane transporters, gluthatione metabolism enzymes and cytokine pathways have been less extensively investigated. Some polymorphisms have been reported to be associated with toxicity or clinical outcome, but data generally come from a limited number of studies and need to be confirmed.
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[本文引用:1]
[28] OLAUSSEN K A,POSTEL-VINAY S.Predictors of chemo-therapy efficacy in non-small-cell lung cancer:a challenging landscape[J].Ann Oncol,2016,27(11):2004-2016.
Abstract BACKGROUND: Conventional cytotoxic chemotherapy (CCC) is the backbone of non-small cell lung cancer (NSCLC) treatment since decades, and still represents a key element of the therapeutic armamentarium. Contrary to molecularly targeted therapies and immune therapies, for which predictive biomarkers of activity have been actively looked for and developed in parallel to the drug development process ("companion biomarkers"), no patient selection biomarker is currently available for CCC, precluding customizing treatment. METHODS: We reviewed preclinical and clinical studies that assessed potential predictive biomarkers of CCC used in NSCLC (platinum, antimetabolites, topoisomerase inhibitors and spindle poisons). Biomarker evaluation method, analytical validity and robustness are described and challenged for each biomarker. RESULTS: The best-validated predictive biomarkers for efficacy are currently ERCC1, RRM1, and TS for platinum agents, gemcitabine and pemetrexed, respectively. Other potential biomarkers include hENT1 for gemcitabine, class III -tubulin for spindle poisons, TOP2A expression and CEP17 duplication (mostly studied for predicting anthracyclines efficacy) whose applicability concerning etoposide would deserve further evaluation. However, none of these biomarkers has till now been validated prospectively in an appropriately designed and powered randomized trial, and none of them is currently ready for implementation in routine clinical practice. CONCLUSION: The search for predictive biomarkers to CCC has been proven challenging. If a plethora of biomarkers have been evaluated either in the pre-clinical or clinical setting, none of them is ready for clinical implementation yet. Considering that most mechanisms of resistance or sensitivity to CCC are multifactorial, a combinatorial approach might be relevant and further efforts are required. The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
DOI:10.1093/annonc/mdw321      PMID:27502726      URL    
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关键词(key words)
非小细胞
化学治疗
分子靶向治疗
抗血管生成药物
免疫治疗

Cancer
lung
non-small cell
Chemotherapy
Molecular targeted therap...
Antiangiogenic agents
Immunotherapy

作者
章必成
朱波

ZHANG Bicheng
ZHU Bo