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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): 536-541
doi: 10.3870/j.issn.1004-0781.2018.05.007
非小细胞肺癌表皮生长因子受体-酪氨酸激酶抑制药治疗的现状与挑战
Current Situation and Challenges of EGFR-TKI in Non-Small Cell Lung Cancer
彭敏, 宋启斌

摘要:

过去十年,针对表皮生长因子受体(EGFR)的酪氨酸激酶抑制药(TKI)引领了非小细胞肺癌(NSCLC)治疗的精准医学之路,在晚期NSCLC的治疗中取得了重大突破。NSCLC的治疗理念已由以病理分型为基础的传统放射治疗、化学治疗转变为以分子分型为依据的精准治疗。优化第3代EGFR-TKI的管理,扩大EGFR-TKI的适应证,联合其他治疗提升疗效,探索耐药机制及应对策略都是EGFR-TKI面临的重要挑战。

关键词: 表皮生长因子受体 ; 酪氨酸激酶抑制药 ; ; ; 非小细胞

Abstract:

Last decade, EGFR-TKI have led the way of precision medicine for NSCLC and have made significant breakthroughs in the treatment of advanced NSCLC. The treatment concept of NSCLC have changed from traditional chemoradiotherapy based on pathological type to precise treatment based on molecular type. Optimizing the management of the third generation of EGFR-TKI, expanding the indications of EGFR-TKI, improving efficacy with the combination of other treatments, exploring the mechanisms and strategies of drug resistance are significant challenges for EGFR-TKI.

Key words: Epidermal growth factor receptor ; Tyrosine kinase inhibitor ; Cancer ; lung ; non-small cell

肺癌为全球发病率和死亡率均最高的恶性肿瘤,其中又以非小细胞肺癌(non-small cell lung cancer,NSCLC)最为常见。过去十年,表皮生长因子受体(epidermal growth factor receptor,EGFR)-酪氨酸激酶抑制药(tyrosine kinase inhibitor,TKI)开启了晚期NSCLC的精准医学之路,晚期NSCLC的治疗效果得到显著提高。进一步优化3代EGFR-TKI的管理,扩大适应证,提升疗效,探索耐药机制及策略是未来发展的重要方向。

1 EGFR-TKI成为EGFR敏感突变晚期NSCLC的一线标准治疗

2002年,两项Ⅱ期临床研究(IDEAL1、IDEAL2)发现,EGFR-TKI在晚期NSCLC二、三线治疗中具有良好的抗肿瘤活性[1]。此后,大量临床研究探讨EGFR-TKI在晚期NCSLC中的应用。然而,在未经选择人群中进行的多项临床研究均以失败告终。直到2009年,IPASS研究首次发现EGFR-TKI在EGFR突变阳性NSCLC中的疗效及安全性均显著优于化学治疗(化疗),由此开启了以分子分型为基础的精准临床研究模式[2]。迄今,11项大型随机对照研究共同奠定了EGFR-TKI在EGFR敏感突变晚期NSCLC患者一线治疗中的地位。EGFR-TKI一线治疗EGFR敏感突变晚期NSCLC患者的缓解率(response rate,RR)约为70%,中位无进展生存(progression-free survival,PFS)为8~14个月[3]

2 3代EGFR-TKI的比较
2.1 第1代EGFR-TKI间的比较

CTONG 0901及WJOG 5108L两项大型随机对照临床研究均表明,在EGFR敏感突变的晚期NSCLC中,吉非替尼与厄洛替尼疗效无显著差异[4]。此外,ICOGEN研究结果显示,在既往接受过1或2次化疗的局部晚期或晚期NSCLC中,吉非替尼和埃克替尼的疗效与安全性相当[5]。既往汇总分析提示厄洛替尼的肝毒性小于吉非替尼,但皮疹反应较明显[6]。目前,3种第1代EGFR-TKI间疗效均未见显著差异,需根据安全性及药效经济学进行个体化选择。

2.2 第2代与第1代EGFR-TKI比较 LUX-Lung

7研究为全球首个多中心前瞻性、随机对照比较第2代和第1代EGFR-TKI的IIB期临床研究。结果表明,与吉非替尼比较,阿法替尼中位PFS差异有统计学意义,但仅延长0.1个月(11.0个月vs 10.9个月,P=0.017),总生存(overall survival,OS)差异无统计学意义(27.9个月vs 24.5个月,P=0.258)[7]。ARCHER 1050研究表明,在EGFR敏感突变晚期NSCLC的一线治疗中,达克替尼较吉非替尼显著延长中位PFS(14.7个月vs 9.2个月,P<0.000 1),但OS数据暂不成熟[8]。无论阿法替尼或达克替尼,作为不可逆性泛HER家族抑制药,在研究中均表现出更高的不良反应发生率和剂量调整率,制约其成为一线最优选择[7,8]。有疗效汇总分析发现,阿法替尼在罕见突变患者中有效率可达71%,显著优于第1代EGFR-TKI的历史数据,为这类患者治疗提供了新的思路,但仍需前瞻性临床研究证明[9]。目前,第2代阿法替尼与第1代EGFR-TKI均可作为EGFR敏感突变晚期NSCLC一线选择,而达克替尼仍有待更多数据证明。

2.3 第3代与第1代EGFR-TKI比较

FLAURA研究对比了第3代和第1代EGFR-TKI在EGFR敏感突变晚期NSCLC一线治疗中的疗效。结果表明,与第1代EGFR-TKI(厄洛替尼或吉非替尼)比较,奥西替尼显著延长中位PFS达8.7个月(18.9个月vs 10.2个月,P<0.000 1)。在脑转移亚组中,奥西替尼同样显示出更优的疗效,中位PFS显著延长(15.2个月vs 9.6个月,P=0.000 9),OS数据暂不成熟。基于以上结果,奥西替尼获批用于EGFR敏感突变晚期NSCLC一线治疗。然而,奥西替尼一线治疗后耐药机制及对策尚不明朗[10]。且AURA extension和AURA2的汇总分析显示,第1代EGFR-TKI一线治疗进展后,T790M突变的患者接受奥西替尼治疗,中位OS可达26.8个月[11]。因此,奥西替尼能否成为一线治疗最优选择,仍需进一步证明。

3 EGFR-TKI在特殊人群中的应用
3.1 EGFR-TKI在NSCLC患者手术后辅助治疗中的探索

NSCLC-CG及LACE两项大型荟萃分析结果显示NSCLC手术后辅助化疗可提升5年生存率4%~5%,奠定了NSCLC手术后辅助化疗的地位,但获益并不令人满意[12]。此后BR19、RADIANT等研究探索了EGFR-TKI在未经EGFR突变状态选择的NSCLC手术后辅助治疗中的疗效,均得出阴性结论[12]。直到SELECT研究选择性入组EGFR敏感突变NSCLC,手术后接受常规辅助化疗或放化疗后,接受厄洛替尼治疗2年。结果显示,2年无病生存期(disease-free survival,DFS)为89%,打破了手术后辅助治疗的僵局[12]。ADJUVANT研究进一步精准选择入组完全切除手术后Ⅱ~ⅢA期(N1~N2)伴EGFR敏感突变的NSCLC患者,对比吉非替尼持续2年与长春瑞滨联合顺铂化疗4周期的疗效。该研究中,与化疗组比较,吉非替尼组DFS显著延长(28.7个月vs 18.0个月,P=0.005)[13]。EVAN研究则仅纳入完全切除手术后ⅢA期伴EGFR敏感突变的NSCLC患者,结果显示手术后厄洛替尼组较手术后化疗组,中位DFS显著地延长(42.41个月vs 20.96个月,P<0.001)[14]。基于以上研究结果,EGFR-TKI在选择人群的NSCLC手术后辅助治疗中崭露头角。然而,仍存在很多问题亟待解决。首先,ADJUVANT及EVAN两项研究OS数据均未成熟,EGFR-TKI组的DFS获益能否转换为OS获益,仍需更多数据证实。其次,靶向药物使用时间、有效人群选择及辅助治疗进展后治疗策略仍需更多探讨。

3.2 EGFR-TKI在NSCLC脑转移患者中的地位

NSCLC患者30%~50%在病程中会出现脑转移,EGFR敏感突变患者中比例更高,且预后差。NSCLC脑转移患者经典治疗方式包括立体定向放射外科治疗(stereotactic radiosurgery,SRS)、全脑放疗(whole brain radiotherapy,WBRT)或两者结合,中位OS约6个月[15]。EGFR-TKI为EGFR敏感突变NSCLC脑转移患者的治疗提供更多选择。

BRAIN研究首次证实,与传统放化疗比较,单药埃克替尼可显著提升EGFR敏感突变多发脑转移NSCLC患者的颅内PFS(10.0个月vs 4.8个月,P=0.014),但并无OS获益[16]。AURA 3研究的亚组分析提示,在T790M突变NSCLC脑转移患者中,单药奥希替尼较化疗具有更好的颅内客观缓解率(objective response rate,ORR)(70% vs 31%,P=0.015)和颅内PFS(11.7个月vs 5.6个月,P=0.004)[17]。BLOOM研究结果表明,新型EGFR抑制药AZD3759也具有良好的颅内抗肿瘤活性(ORR=83%)。EGFR-TKI为NSCLC脑转移患者的治疗模式提供了新的选择[18]

放疗仍为有临床症状的NSCLC脑转移患者首选治疗方式。然而,由于存在脑水肿、认知功能损伤等不良反应,能否在无症状的EGFR敏感突变NSCLC脑转移患者中延迟放疗,成为近期NSCLC脑转移治疗中的研究热点[19]。回顾性研究表明,对于无症状的EGFR突变NSCLC脑转移患者,接受EGFR-TKI单药治疗可延迟放疗的介入时间,且并未造成OS受损[20]。然而,也有回顾性研究提示,对于无症状或转移灶较少的EGFR敏感突变NSCLC脑转移患者,SRS联合EGFR-TKI为最优选择[21]。EGFR-TKI与放疗的最佳联合模式仍需前瞻性临床研究给出答案。

4 EGFR-TKI与其他治疗手段联合治疗晚期NSCLC
4.1 EGFR-TKI与化疗的联合

基础研究发现,在EGFR敏感突变的肺癌细胞中,化疗与EGFR-TKI具有协同抗肿瘤作用。目前,多个临床研究显示EGFR-TKI联合化疗具有较好的疗效。FASTACT II研究表明,在EGFR敏感突变晚期NSCLC患者中,化疗序贯EGFR-TKI较单用化疗能显著延长中位PFS(16.8个月vs 6.9个月,P<0.000 1)和OS(31.4月vs 20.6月,P=0.009 2)[22]。JMIT研究结果显示,EGFR-TKI同步化疗较EGFR-TKI单药可带来近5个月的PFS获益(15.8个月vs 10.9个月,P=0.029)[23]。此外,NEJ005研究对比了EGFR-TKI同步化疗和EGFR-TKI序贯化疗治疗晚期NSCLC的疗效,发现同步组的中位PFS和OS均优于序贯组[24]。然而,以上研究采用的化疗方案、选择的治疗人群及联合模式均不相同,且YANG等[25]Ⅲ期临床研究得出相反结论。因此,EGFR-TKI联合化疗虽在晚期NSCLC患者中具有前景,但目前的研究结果暂无法改变临床实践。

4.2 EGFR-TKI与抗血管治疗的联合

肿瘤的生长需要新生血管持续供能,抗血管生成已成为临床上常用的治疗策略。基础研究提示,EGFR突变肿瘤高度依赖VEGF等血管生成通路,因此这类患者接受EGFR-TKI联合抗血管治疗可能获得更好的疗效[26,27]。ATLAS研究结果显示,EGFR-TKI联合贝伐珠单抗可在晚期NSCLC患者的维持治疗和二线治疗中带来生存获益[28]。JO25567为首个探索EGFR-TKI联合贝伐珠单抗一线治疗EGFR敏感突变晚期NSCLC的前瞻性临床研究。结果显示,EGFR-TKI联合贝伐珠单抗可显著延长中位PFS(16.0个月vs 9.7个月,P=0.001 5)[29]。然而,JO25567仅为Ⅱ期临床研究,且联合治疗组3级以上不良反应显著多于EGFR-TKI单药。期待正在进行的NEJ026、ARTEMIS等Ⅲ期临床研究在未来对EGFR-TKI联合抗血管治疗的疗效给出最终答案。

4.3 EGFR-TKI与免疫治疗的联合

免疫治疗正在不断改写肿瘤治疗策略。临床前研究表明,活化的EGFR通路可提升动物模型对PD-1抑制药的敏感性。然而,临床研究中免疫检查点抑制药在EGFR突变患者中的疗效不尽人意[30]。GAINOR等[31]回顾性研究表明,在EGFR突变或ALK阳性NSCLC患者中,免疫治疗有效率仅为3.6%。KEYNOTE-010、CheckMate057和OAK等研究的亚组分析结果同样提示,EGFR突变患者未能从免疫治疗中获益。此外,严重的不良反应使得探索联合治疗的前瞻性临床研究遭遇瓶颈[32,33,34]。CheckMate012研究中,联合治疗3级以上不良反应发生率达19%[35]。奥西替尼联合durvalumab虽展现出不俗的临床疗效,但高达38%的间质性肺炎发生率使得研究提前终止。吉非替尼联合durvalumab则使得40%~70%患者出现3级以上转氨酶升高[30]。因此,目前研究数据暂不支持EGFR-TKI与免疫治疗的联合应用,明确联合治疗不良反应发生机制将有助于指导未来临床研究的开展。

5 EGFR-TKI耐药后的治疗策略
5.1 第3代EGFR-TKI

T790M突变约占EGFR-TKI获得性耐药的50%,为最常见的耐药机制[36]。第3代EGFR-TKI主要针对T790M突变研发,包括奥希替尼和诺司替尼等。AURAI研究结果表明,奥希替尼在第1代EGFR-TKI耐药且具有T790M突变患者中ORR为61%,中位PFS为9.6个月,且安全性良好。AURA II、AURA III及AURA 17研究均印证了以上结果,共同奠定了奥希替尼在EGFR T790M突变阳性患者治疗中的首选地位[17,37]。然而,再次耐药也是第3代EGFR-TKI面临的重要问题,其机制更为复杂。明确第3代EGFR-TKI的具体耐药机制,寻找个体化的解决方案是未来面临的重要挑战。

5.2 EGFR-TKI

联合其他靶点抑制药 MET扩增是第二常见(占5%~20%)的EGFR-TKI获得性耐药机制,第3代 EGFR-TKI奥希替尼亦受困于此[38,39]。一项Ib/Ⅱ期临床研究结果显示,在第1代EGFR-TKI进展的MET扩增且无T790M突变的NSCLC中,MET抑制药INC280联合吉非替尼显示出一定的疗效。在MET拷贝数>6的试验组中,ORR达到50%,DCR为84%[40]。YANG等[41]Ⅰb期临床研究结果表明,吉非替尼联合 MET抑制药Savolitinib在EGFR突变合并MET扩增的晚期NSCLC中的ORR为31%,DCR为66%。同期,另一项Ib期研究中,奥西替尼联合Savolitinib也展现出令人欣喜的临床疗效[42]。然而,以上结果均来自于Ⅰ/Ⅱ期临床试验,未来仍需Ⅲ期临床研究予以证实。

5.3 EGFR-TKI联合化疗或局部治疗

研究发现,肿瘤内部存在异质性,EGFR-TKI进展后仍有敏感克隆株存在,继续给予EGFR-TKI治疗可抑制敏感克隆株生长。ASPIRATION研究显示,EGFR-TKI耐药后继续EGFR-TKI治疗可将PFS延长3.1个月,且无新的不良事件发生[43]

化疗可以兼顾EGFR-TKI耐药的肿瘤细胞,因此耐药后使用EGFR-TKI联合化疗具备理论基础。然而,EGFR-TKI联合化疗的临床研究结果不理想。IMPRESS为对比EGFR-TKI治疗进展后使用EGFR-TKI联合化疗与单用化疗疗效的Ⅲ期临床,结果表明EGFR-TKI联合化疗可导致OS受损(13.4个月vs 19.5个月,P=0.016)[44]。因此,在临床实践中暂时不推荐EGFR-TKI耐药后使用EGFR-TKI联合化疗。单用化疗仍为EGFR-TKI耐药后NSCLC患者的标准治疗之一。

根据疾病控制时间、肿瘤负荷变化和临床症状将EGFR-TKI治疗失败分为快速进展(疾病控制时间≥3个月,肿瘤负荷快速增加,症状评分达到2分)、缓慢进展(疾病控制时间≥6个月,肿瘤负荷轻微增加,症状评分≤1分)和局部进展(疾病控制时间≥3个月,孤立性颅外进展或颅内进展,症状评分≤1分)3种临床进展模式。局部进展者可从原EGFR-TKI联合局部治疗(如放疗、手术)中获益[45]。此后,多项回顾性临床研究均得出相似结果[46,47]。期待前瞻性临床研究进一步验证以上结果。

目前,EGFR-TKI耐药问题仍是其临床应用中所面临的最大挑战。明确分子耐药机制及进展模式为制定耐药后治疗策略的关键。第2代基因测序及液体活检等技术的飞速进步将推动精准治疗的发展。

6 展望

过去十多年,EGFR-TKI在EGFR敏感突变的晚期NSCLC治疗中独领风骚。如今,EGFR-TKI在EGFR突变阳性晚期NSCLC患者一线治疗中的地位已稳。EGFR-TKI的药物研发也进展迅速,已进入“三代同堂”时期。但因治疗适应证较窄、有效时间短暂、耐药机制及策略不明等原因,EGFR-TKI在NSCLC中遭遇疗效瓶颈。如何实现第3代EGFR-TKI的全程管理、扩大适应证、提升疗效及克服耐药,让NSCLC患者最大程度获益于EGFR-TKI,是未来面临的诸多挑战。

The authors have declared that no competing interests exist.

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Abstract Recent advances in cancer therapy have resulted in the development of drugs that target mechanisms involved in neoplastic change and angiogenesis. One example is gefitinib ('Iressa', ZD1839), an orally-active epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that blocks EGFR signaling in vitro, thereby inhibiting the growth, proliferation and survival of many solid tumors. Clinical trial data show that gefitinib monotherapy is generally well tolerated in patients with a wide range of tumor types (including lung, head and neck, colon, breast, and prostate cancers). The most common adverse events (AEs) were mild and reversible skin and gastrointestinal disorders (National Cancer Institute common toxicity criteria grade 1/2). Few drug-related grade 3/4 skin and gastrointestinal disorders were observed, and drug-related hematologic AEs were uncommon. The clinical benefit of gefitinib in non-small-cell lung cancer (NSCLC), head and neck, colon, breast, and prostate cancer is being investigated, as antitumor activity has been observed in a range of solid tumors, including NSCLC. In two large phase II NSCLC trials (IDEAL ['Iressa' Dose Evaluation in Advanced Lung Cancer] 1 and 2) objective tumor responses of 18.4% and 11.8%, and disease control rates (complete and partial responses plus stable disease) of 54.4% and 42.2%, respectively, were seen in patients given 250 mg/day gefitinib. Additionally, disease-related symptoms improved in 40.3% and 43.1% of patients, and improved quality of life was experienced by 23.9% and 34.3% patients in IDEAL 1 and 2, respectively. Furthermore, the majority of patients who had an objective response also experienced symptom improvement. Gefitinib has been approved for the treatment of advanced NSCLC in Japan, the USA, and other countries. This review discusses the potential of gefitinib in a wide range of solid tumors. 'Iressa' is a trademark of the AstraZeneca group of companies.
DOI:10.1038/162137b0      PMID:15582898      URL    
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[2] FUKUOKA M,WU Y L,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].J Clin Oncol,2011,29(21):2866-2874.
DOI:10.1200/JCO.2010.33.4235      URL    
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[3] NAN X,XIE C,YU X,et al.EGFR TKI as first-line treat-ment for patients with advanced EGFR mutation-positive non-small-cell lung cancer[J].Oncotarget,2017,8(43):75712-75726.
After the discovery of activating mutations in EGFR, EGFR tyrosine kinase inhibitors (TKIs) have been introduced into the first-line treatment of non-small-cell lung cancer (NSCLC). A series of studies have shown that EGFR TKI monotherapy as first-line treatment can benefit NSCLC patients harbouring EGFR mutations. Besides, combination strategies based on EGFR TKIs in the first line treatment have also been proved to delay the occurrence of resistance. In this review, we summarize the scientific literature and evidence of EGFR TKIs as first-line therapy from the first-generation EGFR TKIs to conceptually proposed fourth-generation EGFR TKI, and also recommend the application of monotherapy and combination therapies of the EGFR-based targeted therapy with other agents such as chemotherapy, anti-angiogenic drugs and immunecheckpoint inhibitors.
DOI:10.18632/oncotarget.20095      PMID:29088904      URL    
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[4] URATA Y,KATAKAMI N,MORITA S,et al.Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma:WJOG 5108L[J].J Clin Oncol,2016,34(27):3248-3257.
Abstract PURPOSE: The epidermal growth factor receptor (EGFR) tyrosine kinase has been an important target for non-small-cell lung cancer. Several EGFR tyrosine kinase inhibitors (TKIs) are currently approved, and both gefitinib and erlotinib are the most well-known first-generation EGFR-TKIs. This randomized phase III study was conducted to investigate the difference between these two EGFR-TKIs. PATIENTS AND METHODS: Previously treated patients with lung adenocarcinoma were randomly assigned to receive gefitinib or erlotinib. This study aimed to investigate the noninferiority of gefitinib compared with erlotinib. The primary end point was progression-free survival (PFS). RESULTS: Five hundred sixty-one patients were randomly assigned, including 401 patients (71.7%) with EGFR mutation. All baseline factors (except performance status) were balanced between the arms. Median PFS and overall survival times for gefitinib and erlotinib were 6.5 and 7.5 months (hazard ratio [HR], 1.125; 95% CI, 0.940 to 1.347; P = .257) and 22.8 and 24.5 months (HR, 1.038; 95% CI, 0.833 to 1.294; P = .768), respectively. The response rates for gefitinib and erlotinib were 45.9% and 44.1%, respectively. Median PFS times in EGFR mutation-positive patients receiving gefitinib versus erlotinib were 8.3 and 10.0 months, respectively (HR, 1.093; 95% CI, 0.879 to 1.358; P = .424). The primary grade 3 or 4 toxicities were rash (2.2% for gefitinib v 18.1% for erlotinib) and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation (6.1%/13.0% for gefitinib v 2.2%/3.3% for erlotinib). CONCLUSION: The study did not demonstrate noninferiority of gefitinib compared with erlotinib in terms of PFS in patients with lung adenocarcinoma according to the predefined criteria. 2016 by American Society of Clinical Oncology.
DOI:10.1200/JCO.2015.63.4154      PMID:27022112      URL    
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[5] SHI Y,ZHANG L,LIU X,et al.Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN):a randomised,double-blind phase 3 non-inferiority trial[J].Lancet Oncol,2013,14(10):953-961.
Abstract BACKGROUND: Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer. METHODS: In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18-75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 100·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780 , and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506. FINDINGS: 400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 000·84, 95% CI 000·67-100·05; median progression-free survival 400·6 months [95% CI 300·5-600·3] vs 300·4 months [200·3-300·8]; p=000·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=000·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=000·033). INTERPRETATION: Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer. Copyright 0008 2013 Elsevier Ltd. All rights reserved.
DOI:10.1016/S1470-2045(13)70355-3      PMID:23948351      URL    
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[6] YANG Z,HACKSHAW A,FENG Q,et al.Comparison of gefitinib,erlotinib and afatinib in non-small cell lung cancer:A meta-analysis[J].Int J Cancer,2017,140(12):2805-2819.
Gefitinib, erlotinib and afatinib are three widely used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) for treating advanced non-small cell lung cancer (NSCLC) with proven efficacy. We undertook a systematic review and meta-analysis to synthesize existing studies with direct comparisons of EGFR TKIs in NSCLC in terms of both efficacy and safety. Eight randomized trials and 82 cohort studies with a total of 17,621 patients were included for analysis. Gefitinib and erlotinib demonstrated comparable effects on progression-free survival (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.95 to 1.04), overall survival (HR, 0.99; 95% CI, 0.93 to 1.06), overall response rate (risk ratio [RR], 1.05; 95% CI, 1.00 to 1.11), and disease control rate (RR, 0.98; 95% CI, 0.96 to 1.01), which did not vary considerably with EGFR mutation status, ethnicity, line of treatment, and baseline brain metastasis status. Gefitinib was associated with more grade 3/4 liver dysfunction, but tended to cause lower rates of dose reduction, treatment discontinuation, total grade 3/4 adverse events (RR, 0.78; 95% CI 0.65 to 0.94), and a number of specific adverse events such as rash and diarrhea. No solid evidence was found that afatinib had greater efficacy than gefitinib or erlotinib in first-line treatment of EGFR-mutant NSCLC. However, afatinib was more effective than erlotinib as second-line treatment of patients with advanced squamous cell carcinoma. The grade 3/4 adverse events rate of afatinib was comparable to that of erlotinib but higher than that of gefitinib.
DOI:10.1002/ijc.30691      PMID:28295308      URL    
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[7] PARK K,TAN E H,O'BYRNE K,et al.Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7):a phase 2B,open-label,randomised controlled trial[J].Lancet Oncol,2016,17(5):577-589.
Boehringer Ingelheim.
DOI:10.1016/S1470-2045(16)30033-X      PMID:27083334      URL    
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[8] RAMALINGAM S S,O'BYRNE K,BOYER M,et al.Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC):pooled subset analyses from two randomized trials[J].Ann Oncol,2016,27(3):423-429.
Background: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases.Methods: The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib.Results: One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0–18.2] with dacomitinib and 9.6 months (95% CI 7.4–12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458–1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6–41.5) with dacomitinib versus 23.2 months (95% CI 16.0–31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431–1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib.Conclusions: Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721).Clinical trials number: ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).
DOI:10.1093/annonc/mdv593      PMID:26768165      URL    
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[9] YANG J C,SEQUIST L V,GEATER S L,et al.Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations:a combined post-hoc analysis of LUX-Lung 2,LUX-Lung 3,and LUX-Lung 6[J].Lancet Oncol,2015,16(7):830-838.
Abstract BACKGROUND: Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21, or both (ie, common mutations). However, a subset of patients (10%) with mutations in EGFR have tumours that harbour uncommon mutations. There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors. Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have tumours harbouring uncommon EGFR mutations. METHODS: In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR mutation-positive advanced (stage IIIb-IV) lung adenocarcinomas who were given afatinib in a single group phase 2 trial (LUX-Lung 2), and randomised phase 3 trials (LUX-Lung 3 and LUX-Lung 6). Analyses were done in the intention-to-treat population, including all randomly assigned patients with uncommon EGFR mutations. The type of EGFR mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs non-Asian) were pre-specified stratification factors in the randomised trials. We categorised all uncommon mutations as: point mutations or duplications in exons 18-21 (group 1); de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations (group 2); or exon 20 insertions (group 3). We also assessed outcomes in patients with the most frequent uncommon mutations, Gly719Xaa, Leu861Gln, and Ser768Ile, alone or in combination with other mutations. Response was established by independent radiological review. These trials are registered with ClinicalTrials.gov, numbers NCT00525148 , NCT00949650 , and NCT01121393 . FINDINGS: Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon EGFR mutations (38 in group 1, 14 in group 2, 23 in group 3). 27 (7100·1%, 95% CI 5400·1-8400·6) patients in group 1 had objective responses, as did two (1400·3%, 100·8-4200·8) in group 2 and two (800·7%, 100·1-2800·0) in group 3. Median progression-free survival was 1000·7 months (95% CI 500·6-1400·7) in group 1, 200·9 months (100·2-800·3) in group 2; and 200·7 months (100·8-400·2) in group 3. Median overall survival was 1900·4 months (95% CI 1600·4-2600·9) in group 1, 1400·9 months (800·1-2400·9) in group 2, and 900·2 months (400·1-1400·2) in group 3. For the most frequent uncommon mutations, 14 (7700·8%, 95% CI 5200·4-9300·6) patients with Gly719Xaa had an objective response, as did nine (5600·3%, 2900·9-8000·2) with Leu861Gln, and eight (10000·0%, 6300·1-10000·0) with Ser768Ile. INTERPRETATION: Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations, especially Gly719Xaa, Leu861Gln, and Ser768Ile, but less active in other mutations types. Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations. These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon EGFR mutations. FUNDING: Boehringer Ingelheim. Copyright 0008 2015 Elsevier Ltd. All rights reserved.
DOI:10.1016/S1470-2045(15)00026-1      PMID:26051236      URL    
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[10] SORIA J C,OHE Y,VANSTEENKISTE J,et al.Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer[J].N Engl J Med,2018,378(2):113-125.
DOI:10.1056/NEJMoa1713137      URL    
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[11] KHOZIN S,WEINSTOCK C,BLUMENTHAL G M,et al.Osimertinib for the treatment of metastatic EGFR T790M mutation-positive non-small cell lung cancer[J].Clin Cancer Res,2017,23(9):2131-2135.
On November 13, 2015, FDA granted accelerated approval to osimertinib (TAGRISSO鈩; AstraZeneca), a breakthrough therapy-designated drug for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, with progression on or after EGFR tyrosine kinase inhibitor therapy. Approval was based on durable tumor response rates in two single-arm, multicenter trials: the dose extension cohort of a first-in-human trial (AURA extension; n=201) and a fixed-dose, activity-estimating trial (AURA2; n=210). Osimertinib was administered at 80 mg orally once daily. The objective response rates (ORR) per blinded independent committee review were 57% (95% CI: 50%, 64%) in AURA extension and 61% (95% CI: 54%, 68%) in AURA2. Median duration of response (DOR) could not be estimated. Supportive efficacy data from 63 patients in the dose-finding part of the FIH trial demonstrated ORR of 51% (95% CI: 38%, 64%) with median DOR of 12.4 months. Common adverse events (AEs) evaluated in 411 patients included diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%). Grade 3-4 AEs occurred in 28% of patients and 6% discontinued treatment due to AEs.
DOI:10.1158/1078-0432.CCR-16-1773      PMID:27923840      URL    
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[12] ZHAI H,ZHONG W,YANG X,et al.Neoadjuvant and adjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy for lung cancer[J].Transl Lung Cancer Res,2015,4(1):82-93.
Abstract The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis and the meta-analysis of individual participant data reported by non-small cell lung cancer (NSCLC) Meta-analysis Collaborative Group in neo-adjuvant setting validated respectively that adjuvant and neoadjuvant chemotherapy would significantly improve overall survival (OS) and recurrence-free survival for resectable NSCLC. However, chemotherapy has reached a therapeutic plateau. It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeting therapy provides a dramatic response to patients with advanced EGFR-mutation positive NSCLC. Researchers have paid more attention to exploring applications of TKIs to early resectable NSCLCs. Several studies on adjuvant TKI treatment concluded its safety and feasibility. But there existed certain limitations of these studies as inference factors to interpret data accurately: the BR19 study recruited patients among which almost 52% had stage IB and only 15 (3.0%, 15/503) had been confirmed with EGFR-mutant type; retrospective studies performed at Memorial Sloan Kettering Cancer Center (MSKCC) selected EGFR mutant-type NSCLC patients but couldn't avoid inherent defects inside retrospective researches; the RADIANT study revised endpoints from targeting at EGFR immunohistochemistry (IHC)+ and/or fluorescence in situ hybridization (FISH)+ mutation to only EGFR IHC+ mutation, leading to selective bias; despite that the SELECT study validated efficacy of adjuvant TKI and second round of TKI after resistance occurred, a single-arm clinical trial is not that persuasive in the absence of comparison with chemotherapy. Taking all these limitations into account, CTONG1104 in China and IMPACT in Japan have been conducted and recruiting patients to offer higher level of evidences to explore efficacy of preoperative TKI therapy for early resectable EGFR mutation positive NSCLC patients (confirmed by pathological results of tumor tissue or lymph node biopsy). On the other hand, case reports and several phase II clinical trials with small sample size tried to elbow their way on respect of preoperative TKI treatment and advised that TKI tended to improve response rate. However, no data on survival rate was present. The first phase II study of biomarker-guided neoadjuvant therapy for stage IIIA-N2 NSCLC patients stratified by EGFR mutation status, sponsored by CSLC0702, showed erlotinib tended to improve response rate, but failed to show benefits of disease-free survival (DFS) or OS. Subsequently, CTONG1103 was designed to investigate efficacy of erlotinib vs. combination of gemcitabine/cisplatin (GC) as neoadjuvant treatment in stage IIIA-N2 NSCLC with sensitizing EGFR mutation in exon 19 or 21. All these ongoing trials should be worthy of our expect to provide convincing evidences for customized therapy for patients with resectable NSCLC.
DOI:10.3978/j.issn.2218-6751.2014.11.08      PMID:25806348      URL    
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[13] ZHONG W Z,WANG Q,MAO W M,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[J].Lancet Oncol,2018,19(1):139-148.
DOI:10.1016/S1470-2045(17)30729-5      URL    
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[14] YUE D,XU S,LI Q,et al.A prospective,open-labeled,randomized,multicenter phase II study to evaluate efficacy and safety of erlotinib vs np chemotheraoy as adjuvant therapy ub post radical operation stage ⅢA NSCLC patients with EGFR 19 or 21 EXON mutation (EVAN,ML28280,NCT01683175)[J].J Thorac Oncol,2013,8(Suppl):S888.
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[15] ZHU Q,SUN Y,CUI Y,et al.Clinical outcome of tyrosine kinase inhibitors alone or combined with radiotherapy for brain metastases from epidermal growth factor receptor (EGFR) mutant non small cell lung cancer (NSCLC)[J].Oncotarget,2017,8(8):13304-13311.
This study compared treatment outcomes between TKI monotherapy and TKI administration combined with brain radiotherapy (TKI + RT) in 133 non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). We also evaluated the association of different epidermal growth factor receptor (EGFR) mutation subtypes with treatment outcome. To screen for potential variables affecting cranial progression free survival (PFS) and overall survival (OS), we performed univariate and multivariate analysis based on Cox proportional-hazards models. Median cranial PFS and OS were longer for the TKI + RT group (n = 67) than TKI alone group (n = 66). Intracranial metastasis correlated with a better median OS than extracranial metastasis. For patients with exon 21 mutations, TKI + RT yielded a better median OS and cranial PFS than TKI alone. However, there were no significant differences in median OS and cranial PFS between the two treatment groups for patients with exon 19 deletions. Thus EGFR-mutant NSCLC patients with BM could benefit more from TKI + RT than from TKI monotherapy, especially when they suffer from exon 21 mutations. However, TKI + RT confers no advantage over TKI treatment alone for patients with exon 19 deletions. These results underscore the urgent need to develop individualized disease management strategies in clinical practice.
DOI:10.18632/oncotarget.14515      PMID:28076323      URL    
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[16] YANG J J,ZHOU C,HUANG Y,et al.Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN):a multicentre,phase 3,open-label,parallel,randomised controlled trial[J].Lancet Respir Med,2017,5(9):707-716.
DOI:10.1016/S2213-2600(17)30262-X      URL    
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[17] MOK T S,WU Y,AHN M,et al.Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer[J].N Engl J Med,2017,376(7):629-640.
Abstract BACKGROUND: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown. METHODS: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival. RESULTS: The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%). CONCLUSIONS: Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).
DOI:10.1056/NEJMoa1612674      PMID:27959700      URL    
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[18] AHN M J,KIM D W,CHO B C,et al.Activity and safety of AZD3759 in EGFR-mutant non-small-cell lung cancer with CNS metastases (BLOOM):a phase 1,open-label,dose-escalation and dose-expansion study[J].Lancet Respir Med,2017,5(11):891-902.
Abstract BACKGROUND: CNS metastases-including brain and leptomeningeal metastases-from epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) are associated with poor prognosis. AZD3759 is a novel EGFR tyrosine kinase inhibitor with high capability to penetrate the blood-brain barrier. We aimed to assess the safety, tolerability, pharmacokinetics, and efficacy of AZD3759 in patients with EGFR-mutant NSCLC with brain and leptomeningeal metastases. METHODS: This open-label, multicentre, phase 1 study was undertaken at 11 centres and hospitals in Australia, South Korea, Taiwan, and the USA. Eligible patients included those with histologically confirmed, advanced-stage, EGFR-mutant NSCLC. The study was done in two parts, with dose-escalation and dose-expansion phases. In the dose-escalation phase, patients who had progressed after treatment with an EGFR tyrosine kinase inhibitor received AZD3759 at 50 mg, 100 mg, 200 mg, 300 mg, or 500 mg twice a day. In the dose-expansion phase, AZD3759 at 200 mg or 300 mg twice a day was administered to patients with either brain or leptomeningeal metastases who had never received an EGFR tyrosine kinase inhibitor and patients with leptomeningeal metastases who had been pretreated with an EGFR tyrosine kinase inhibitor. The primary objective was safety and tolerability, with severity of adverse events assessed with the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03. This trial is registered with ClinicalTrials.gov, number NCT02228369 . FINDINGS: Between Nov 18, 2014, and Sept 7, 2016, 67 patients with NSCLC were enrolled into the study, 29 to the dose-escalation phase and 38 to the dose-expansion phase. At data cutoff (Dec 12, 2016), three (10%) patients in the dose-escalation phase and 20 (53%) in the dose-expansion phase were still receiving treatment. Dose-limiting toxic effects occurred in two (67%) of three patients who received 500 mg twice a day in the dose-escalation phase (grade 3 acne [n=1] and intolerable grade 2 mucosal inflammation [n=1]); hence, doses of 200 mg and 300 mg twice a day were selected for further assessment in the dose-expansion phase. Drug-related skin and gastrointestinal disorders of any grade occurred in 35 (92%) and 29 (76%) patients in the dose-expansion phase, respectively, and led to treatment discontinuation in one (4%) patient treated with 200 mg twice a day (grade 3 increase of alanine aminotransferase and aspartate aminotransferase) and two (13%) patients given 300 mg twice a day (grade 3 diarrhoea [n=1] and grade 3 skin rash [n=1]). Grade 3 skin and gastrointestinal disorders occurred in four (17%) and two (9%) patients, respectively, at a dose of 200 mg twice a day, and in six (40%) and four (27%) patients, respectively, at a dose of 300 mg twice a day. No grade 4 disorders arose. Other grade 3 disorders included hepatobiliary and renal disorders (three [13%] at 200 mg twice a day), asthenia (one [7%] at 300 mg twice a day), infections and infestations (one [7%] at 300 mg twice a day), and metabolism and nutrition disorders (one [4%] at 200 mg twice a day and one [7%] at 300 mg twice a day). INTERPRETATION: AZD3759 at a dose of 200 mg twice daily showed a tolerable safety profile in patients with NSCLC and CNS metastases who had either never received a tyrosine kinase inhibitor or who had been pretreated with a tyrosine kinase inhibitor. The good penetration of the blood-brain barrier by AZD3759, and its promising clinical activity, support further assessment of this compound in studies. FUNDING: AstraZeneca. Copyright 2017 Elsevier Ltd. All rights reserved.
DOI:10.1016/S2213-2600(17)30378-8      PMID:29056570      URL    
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[19] DOHERTY M K,KORPANTY G J,TOMASINI P,et al.Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer[J].Radiother Oncol,2017,123(2):195-202.
DOI:10.1016/j.radonc.2017.03.007      URL    
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[20] JIANG T,SU C,LI X,et al.EGFR TKIs plus WBRT demonstrated No survival benefit other than that of TKIs alone in patients with NSCLC and EGFR mutation and brain metastases[J].J Thorac Oncol,2016,11(10):1718-1728.
The addition of WBRT to EGFR TKIs did not appear to have survival benefit superior to that of EGFR TKIs alone in with EGFR -mutant NSCLC with BM. WBRT also did not bring additional benefit to chemotherapy in patients with BM and EGFR of wild-type or unknown status.
DOI:10.1016/j.jtho.2016.05.013      PMID:27237825      URL    
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[21] MAGNUSON W J,LESTER-COLL N H,WU A J,et al.Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naive Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer:A Retrospective Multi-Institutional Analysis[J].J Clin Oncol,2017,35(10):1070-1077.
Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.
DOI:10.1200/JCO.2016.69.7144      PMID:28113019      URL    
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[22] ZHOU T,ZHENG L,HU Z,et al.The effectiveness of RECIST on survival in patients with NSCLC receiving chemotherapy with or without target agents as first-line treatment[J].Sci Rep,2015(5):7683.
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[23] 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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[24] 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    
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[25] YANG J C,SRIMUNINNIMIT V,AHN M J,et al.First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in east asian never-smoker patients with locally advanced or metastatic nonsquamous non-small cell lung cancer:final overall survival results from a randomized phase 3 study[J].J Thorac Oncol,2016,11(3):370-379.
DOI:10.1016/j.jtho.2015.11.008      URL    
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[26] HARARI P M,ALLEN G W,BONNER J A.Biology of interactions:antiepidermal growth factor receptor agents[J].J Clin Oncol,2007,25(26):4057-4065.
Epidermal growth factor receptor (EGFR) signaling inhibition represents a highly promising arena for the application of molecularly targeted cancer therapies. Evolving from several decades of systematic research in cancer cell biology, a series of EGFR inhibitors from both the monoclonal antibody (mAb) and tyrosine kinase inhibitor (TKI) class have been developed and promoted into clinical application. Several EGFR inhibitors have recently gained US Food and Drug Administration approval for cancer therapy in the United States (and many other countries), including the mAbs cetuximab and panitumumab, and the small molecule TKIs gefitinib, erlotinib, and lapatinib. The rapidly expanding preclinical and clinical data contributing to these US Food and Drug Administration drug registrations validates a central role of the EGFR as an important molecular target in epithelial malignancies. In this review, we focus primarily on the biology of EGFR interactions. Through improved understanding of EGFR biology in human cancers, there is anticipation that more tumor-selective therapy approaches with diminished collateral normal tissue toxicity can be advanced. Many questions remain to be answered, particularly with regard to how best combine EGFR inhibitors with conventional cancer therapies, and how to select those patients (tumors) most likely to benefit from EGFR inhibition strategies.
DOI:10.1200/JCO.2007.11.8984      PMID:17827454      URL    
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[27] CLARKE K,SMITH K,GULLICK W J,et al.Mutant epidermal growth factor receptor enhances induction of vascular endothelial growth factor by hypoxia and insulin-like growth factor-1 via a PI3 kinase dependent pathway[J].Br J Cancer,2001,84(10):1322-1329.
Abstract Over-expression of truncated epidermal growth factor receptor (EGFR) occurs in a variety of malignancies including glioblastoma multiforme, breast and lung cancer. The truncation deletes an extracellular domain and results in constitutive activation of the receptor. NIH3T3 cells were transfected with full length or truncated human EGFR and differences in growth rates in vivo and in vitro analysed. A growth advantage was seen for cells expressing mutant receptor compared to full length EGFR in vivo only. Administration of an anti-mutant EGFR antibody to mice transiently reduced the growth rates of mutant tumours, confirming that the mutant receptor itself was important in this enhanced tumorigenicity. This showed that stimuli present in vivo and not in vitro may be contributing to growth. We therefore analysed the regulation of the angiogenic factor vascular endothelial growth factor (VEGF). Although levels of secreted VEGF did not differ significantly between wild-type and mutant EGFR cell lines when grown in vitro under normoxic conditions, following exposure to 0.1% hypoxia levels of VEGF produced by mutant cells increased 3.5-6.6 fold compared to 2 or less for full length EGFR cells. The fold induction was influenced by experimental conditions, including cell confluence and percentage of fetal bovine serum, but was consistently higher for mutant cell lines. The increase in VEGF under hypoxic conditions was blocked by the addition of PI3 kinase inhibitors, indicating that the latter pathway is important in the hypoxic stress response. Basal levels were not affected. Addition of insulin-like growth factor-1 also increased levels of VEGF under normoxic conditions in the mutant cells and no further increase was seen when added to cells exposed to 0.1% oxygen, indicating that levels of VEGF were already maximally stimulated. These results show that the mutant EGFR interacts with other growth factors and hypoxia to regulate VEGF via a PI3 kinase pathway, and suggests a specific role for anti-mutant EGFR antibodies and PI3 kinase inhibitors as therapy of this specific tumour target. Copyright 2001 Cancer Research Campaign.
DOI:10.1054/bjoc.2001.1805      PMID:11355942      URL    
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[28] JOHNSON B E,KABBINAVAR F,FEHRENBACHER L,et al.ATLAS:randomized,double-blind,placebo-controlled,phase IIIB trial comparing bevacizumab therapy with or without erlotinib,after completion of chemotherapy,with bevacizumab for first-line treatment of advanced non-small-cell lung cancer[J].J Clin Oncol,2013,31(31):3926-3934.
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[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[J].Lancet Oncol,2014,15(11):1236-1244.
DOI:10.1016/S1470-2045(14)70381-X      URL    
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[30] AHN M J,SUN J M,LEE S H,et al.EGFR TKI combina-tion with immunotherapy in non-small cell lung cancer[J].Expert Opin Drug Saf,2017,16(4):465-469.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) has significantly improved clinical outcomes compared with chemotherapy in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR gene mutation. Areas covered: Almost all patients treated with EGFR TKIs eventually develop acquired resistance. It has been reported that activation of the oncogenic EGFR pathway enhances susceptibility of the lung tumors to PD-1 blockade in mouse model, suggesting combination of PD1 blockade with EGFR TKIs may be a promising therapeutic strategy. Nivolumab combined with erlotinib was associated with 19% of grade 3 toxicities. The combination of osimertinib plus durvalumab in pretreated or chemo nave NSCLC patients showed encouraging clinical activity, however, this combination was associated with high incidence of interstitial lung disease (38%), leading to termination of further enrollment. The combination of gefitinib plus durvalumab demonstrated encouraging activity but higher incidence of grade 3/4 liver enzyme elevation (40-70%). The treatment related Grade 3-4 adverse events were observed in 39% of patients when treated with atezolizumab plus erlotinib. Expert opinion: Given the relatively high incidence of treatment-related toxicities associated with combination of EGFR TKI and immunotherapy, further development of this approach remains controversial. Until now, the combination of EGFR TKI and immunotherapy should be investigational.
DOI:10.1080/14740338.2017.1300656      PMID:28271729      URL    
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[31] GAINOR J F,SHAW A T,SEQUIST L V,et al.EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway bockade in non-small cell lung cancer:a retrospective analysis[J].Clin Cancer Res,2016,22(18):4585-4593.
PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma kinase (ALK)-positive, and EGFR wild-type/ALK-negative patients. We identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORR) were assessed using RECIST v1.1. PD-L1 expression and CD8(+) tumor-infiltrating lymphocytes (TIL) were evaluated by IHC. Objective responses were observed in 1 of 28 (3.6%) EGFR-mutant or ALK-positive patients versus 7 of 30 (23.3%) EGFR wild-type and ALK-negative/unknown patients (P = 0.053). The ORR among never- or light- (≤10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (P = 0.123). In an independent cohort of advanced EGFR-mutant (N = 68) and ALK-positive (N = 27) patients, PD-L1 expression was observed in 24%/16%/11% and 63%/47%/26% of pre-tyrosine kinase inhibitor (TKI) biopsies using cutoffs of ≥1%, ≥5%, and ≥50% tumor cell staining, respectively. Among EGFR-mutant patients with paired, pre- and post-TKI-resistant biopsies (N = 57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression (≥5%) and high levels of CD8(+) TILs (grade ≥2) were observed in only 1 pretreatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens and was not observed in any ALK-positive, pre- or post-TKI specimens. NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8(+) TILs within the tumor microenvironment may underlie these clinical observations. Clin Cancer Res; 22(18); 4585-93. 082016 AACRSee related commentary by Gettinger and Politi, p. 4539.
DOI:10.1158/1078-0432.CCR-15-3101      PMID:27225694      URL    
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[32] HERBST R S,BAAS P,KIM D W,et al.Pembrolizumab versus docetaxel for previously treated,PD-L1-positive,advanced non-small-cell lung cancer (KEYNOTE-010):a randomised controlled trial[J].Lancet,2016,387(10027):1540-1550.
DOI:10.1016/S0140-6736(15)01281-7      URL    
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[33] HORN L,SPIGEL D R,VOKES E E,et al.Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer:two-year outcomes from two randomized,open-label,phase III trials (CheckMate 017 and CheckMate 057)[J].J Clin Oncol,2017,35(35):3924-3933.
Purpose Nivolumab, a programmed death-1 inhibitor, prolonged overall survival compared with docetaxel in two independent phase III studies in previously treated patients with advanced squamous (CheckMate 017; ClinicalTrials.gov identifier: NCT01642004) or nonsquamous (CheckMate 057; ClinicalTrials.gov identifier: NCT01673867) non-small-cell lung cancer (NSCLC). We report updated results, including a pooled analysis of the two studies. Methods Patients with stage IIIB/IV squamous (N = 272) or nonsquamous (N = 582) NSCLC and disease progression during or after prior platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks). Minimum follow-up for survival was 24.2 months. Results Two-year overall survival rates with nivolumab versus docetaxel were 23% (95% CI, 16% to 30%) versus 8% (95% CI, 4% to 13%) in squamous NSCLC and 29% (95% CI, 24% to 34%) versus 16% (95% CI, 12% to 20%) in nonsquamous NSCLC; relative reductions in the risk of death with nivolumab versus docetaxel remained similar to those reported in the primary analyses. Durable responses were observed with nivolumab; 10 (37%) of 27 confirmed responders with squamous NSCLC and 19 (34%) of 56 with nonsquamous NSCLC had ongoing responses after 2 years' minimum follow-up. No patient in either docetaxel group had an ongoing response. In the pooled analysis, the relative reduction in the risk of death with nivolumab versus docetaxel was 28% (hazard ratio, 0.72; 95% CI, 0.62 to 0.84), and rates of treatment-related adverse events were lower with nivolumab than with docetaxel (any grade, 68% v 88%; grade 3 to 4, 10% v 55%). Conclusion Nivolumab provides long-term clinical benefit and a favorable tolerability profile compared with docetaxel in previously treated patients with advanced NSCLC.
DOI:10.1200/JCO.2017.74.3062      PMID:29023213      URL    
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[34] RITTMEYER A,BARLESI F,WATERKAMP D,et al.Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK):a phase 3,open-label,multicentre randomised controlled trial[J].Lancet,2017,389(10066):255-265.
Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/mevery 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8-15·7] vs 9·6 months [8·6-11·2]; hazard ratio [HR] 0·73 [95% CI 0·62-0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6-18·0] with atezolizumab vs 10·3 months [8·8-12·0] with docetaxel; HR 0·74 [95% CI 0·58-0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59-0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54-0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60-0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. F. Hoffmann-La Roche Ltd, Genentech, Inc.
DOI:10.1016/S0140-6736(16)32517-X      PMID:27979383      URL    
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[35] HELLMANN M D,RIZVI N A,GOLDMAN J W,et al.Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012):results of an open-label,phase 1,multicohort study[J].Lancet Oncol,2017,18(1):31-41.
Bristol-Myers Squibb.
DOI:10.1016/S1470-2045(16)30624-6      PMID:27932067      URL    
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[36] SORIA J C,OHE Y,VANSTEENKISTE J,et al.Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer[J].N Engl J Med,2018,378(2):113-125.
DOI:10.1056/NEJMoa1713137      URL    
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[37] YANG J C,AHN M J,KIM D W,et al.Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer:AURA study phase II extension component[J].J Clin Oncol,2017,35(12):1288-1296.
Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg. T790M status was confirmed by central testing from a tumor sample taken after the most recent disease progression. Patients with asymptomatic, stable CNS metastases that did not require corticosteroids were allowed to enroll. The primary end point was objective response rate (ORR) by independent radiology assessment. Secondary end points were disease control rate, duration of response, progression-free survival (PFS), and safety. Patient-reported outcomes comprised an exploratory objective. Results In total, 201 patients received treatment, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015). In evaluable patients (n = 198), ORR was 62% (95% CI, 54% to 68%), and the disease control rate was 90% (95% CI, 85 to 94). Median duration of response in 122 responding patients was 15.2 months (95% CI, 11.3 to not calculable). Median PFS was 12.3 months (95% CI, 9.5 to 13.8). The most common possibly causally related adverse events (investigator assessed) were diarrhea (43%; grade 3, < 1%) and rash (grouped terms; 40%; grade 3, < 1%). Interstitial lung disease (grouped terms) was reported in eight patients (4%; grade 1, n = 2; grade 3, n = 3; grade 5, n = 3). Conclusion In patients with EGFRm T790M advanced NSCLC who progress after EGFR-TKI treatment, osimertinib provides a high ORR, encouraging PFS, and durable response.
DOI:10.1200/JCO.2016.70.3223      PMID:28221867      URL    
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[38] WU Y L,SOO R A,LOCATELLI G,et al.Does c-Met remain a rational target for therapy in patients with EGFR TKI-resistant non-small cell lung cancer?[J].Cancer Treat Rev,2017,61:70-81.
react-text: 104 Einleitung: Die Identifizierung und Charakterisierung von Tumorstammzellen ist von zentraler Bedeutung, da diese Subpopulation als potentiell Tumor-initiierend bzw. Chemotherapie-resistent betrachtet wird. Podoplanin (D2–40), ein 40kDa Sialoglykoprotein, der Transkriptionsfaktor Sox10 und das Intermediarfilament Nestin gelten als Stammzellmarker. In dieser Studie wurde die Korrelation der... /react-text react-text: 105 /react-text [Show full abstract]
DOI:10.1016/j.ctrv.2017.10.003      PMID:29121501      URL    
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[39] MARTINEZ-MARTI A,FELIP E,MATITO J,et al.Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC)[J].Ann Oncol,2017,28(10):2451-2457.
Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance. For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at-80C. In a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs. Acquired resistance to subsequent EGFR-TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation.
DOI:10.1093/annonc/mdx396      PMID:28961841      URL    
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[40] WU Y L,YANG C H,KIM D W,et al.Safety and efficacy of inc280 in combination with gefitinib (gef) in patients with EGFR-mutated (mut),MET-positive NSCLC:a single-arm phase lb/ll study[J].J Clin Oncel,2014,15(Suppl):8017.
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[41] YANG J J,YANG L,FARNSWORTH A,et al.Preliminary results of a phase Ⅰb trial of savolitinib combined with gefitinib in EGFR-mutant lung cancer[C].ASCO Annual Meeting,2016.
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[42] AHN M J,YANG J,YU H,et al.136O:Osimertinib com-bined with durvalumab in EGFR-mutant non-small cell lung cancer:results from the TATTON phase Ib trial[J].J Thor Oncol,2016,11(4 Suppl):S115.
react-text: 440 Although several antibodies developed to target programmed cell death-1 (PD-1) and its ligand (PD-L1) have demonstrated great promise for the treatment of non-small cell lung cancer (NSCLC), and other malignancies, these therapeutic antibodies can cause pneumonitis. Furthermore, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-induced pneumonitis was reported after... /react-text react-text: 441 /react-text [Show full abstract]
DOI:10.1016/S1556-0864(16)30246-5      PMID:27198274      URL    
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[43] PARK K,YU C J,KIM S W,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[J].JAMA Oncol,2016,2(3):305-312.
Abstract Importance: Continuing molecularly targeted treatment beyond disease progression in non-small-cell lung cancer (NSCLC) has appeared promising in retrospective analyses, highlighting the challenge to identify whether progression is the optimal time to switch treatment. Objective: To study the efficacy of first-line erlotinib therapy in patients with NSCLC with activating EGFR mutations and postprogression erlotinib therapy. Design, Setting, and Participants: ASPIRATION (Asian Pacific trial of Tarceva as first-line in EGFR mutation) was a phase 2, open-label, single-arm study conducted from 2011 to 2012 in 23 centers in Hong Kong, Korea, Taiwan, and Thailand of adults with stage IV, EGFR mutation-positive NSCLC, with ECOG performance status 0 to 2. Interventions: Patients received erlotinib 150 mg/d orally until disease progression, after which erlotinib therapy could be continued at patient and/or investigator discretion. Main Outcomes and Measures: The primary end point was progression-free survival (PFS1; time to Response Evaluation Criteria in Solid Tumours 1.1 progression or death). Secondary end points included PFS2 (time to off-erlotinib progression if erlotinib therapy was extended beyond progression at patient and/or investigator discretion), objective response rate, disease control rate, overall survival, and safety. The use of plasma-based assessment of EGFR mutations was also investigated. Results: Of 359 patients screened, 208 were enrolled. Median follow-up was 11.3 (95% CI, 10.9-13.0) months. Of the 207 intent-to-treat patients (62.3% female; median age, 60.8 [range, 28-89] y), 176 had a PFS1 event (171 progression and 5 deaths); of these, 78 discontinued and 93 continued erlotinib therapy following progression. Median PFS1 was 10.8 (95% CI, 9.2-11.1) months. Median PFS1 and PFS2 in the 93 continuing patients was 11.0 (95% CI, 9.2-11.1) and 14.1 (95% CI, 12.2-15.9) months, respectively. Median PFS1 and PFS2 was 11.0 (95% CI, 9.3-12.0) and 14.9 (95% CI, 12.2-17.2) months in patients with exon 19 deletions or L585R mutations. Overall response rate was 66.2%; disease control rate was 82.6%. Median overall survival was 31.0 months (95% CI, 27.3 months to not reached). In the safety population (n=207) serious adverse events were reported in 27.1%, with events of at least grade 3 experienced by 50.2%. Sensitivity and specificity of plasma-based EGFR mutation analysis was 77% and 92%, respectively. Conclusions and Relevance: ASPIRATION supports the efficacy of first-line erlotinib therapy in patients with EGFR mutation-positive NSCLC and that treatment beyond progression is feasible and may delay salvage therapy in selected patients. Trial Registration: clinicaltrials.gov Identifier: NCT01310036.
DOI:10.1001/jamaoncol.2015.4921      PMID:26720423      URL    
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[44] SORIA J C,WU Y L,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[J].Lancet Oncol,2015,16(8):990-998.
DOI:10.1016/S1470-2045(15)00121-7      URL    
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[45] YANG J J,CHEN H J,YAN H H,et al.Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer[J].Lung Cancer,2013,79(1):33-39.
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[46] YU H A,SIMA C S,HUANG J,et al.Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors[J].J Thorac Oncol,2013,8(3):346-351.
DOI:10.1097/JTO.0b013e31827e1f83      URL    
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[47] MATIKAS A,MISTRIOTIS D,GEORGOULIAS V,et al.Current and future approaches in the management of non-small-cell lung cancer patients with resistance to EGFR TKIs[J].Clin Lung Cancer,2015,16(4):252-261.
Abstract Metastatic non-small-cell lung cancer carries a dismal prognosis. However, the recognition of the predictive value of activating epidermal growth factor receptor (EGFR) mutations and the availability of tyrosine kinase inhibitors has markedly improved the prognosis of these patients, because treatment with these inhibitors induces rapid and robust responses. Unfortunately, the responses are not durable and resistance inevitably occurrs after a median of 9 to 14/months. Although the management of resistant patients who harbor EGFR mutations is rapidly evolving, there are no conclusive guidelines regarding this issue. However, palliative cytotoxic chemotherapy is considered the standard of care for these patients. The elucidation of the mechanisms of acquired resistance has led to efforts to personalize the treatment approach. Promising results from early clinical trials using the third-generation inhibitors that specifically target the most common mechanism of resistance, the gatekeeper T790M mutation, provide the basis to look to the future with cautious optimism. Moreover, it has been shown that in some cases of oligoprogressive disease, aggressively treating all metastatic sites while continuing the targeted treatment could improve outcomes. Herein, we review the treatment strategies being evaluated that will shape the future management of these patients. Copyright 2015 Elsevier Inc. All rights reserved.
DOI:10.1016/j.cllc.2014.12.013      PMID:25700775      URL    
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关键词(key words)
表皮生长因子受体
酪氨酸激酶抑制药
非小细胞

Epidermal growth factor r...
Tyrosine kinase inhibitor
Cancer
lung
non-small cell

作者
彭敏
宋启斌

PENG Min
SONG Qibin