克唑替尼在EML-4ALK阳性晚期非小细胞肺癌患者的靶向治疗中的疗效及安全性

目的观察探讨克唑替尼在EML-4ALK阳性晚期非小细胞肺癌患者的靶向治疗中的疗效及安全性,总结临床应用价值。方法回顾性分析在我院接受治疗的60例EML-4ALK阳性晚期NSCLC患者,根据随机数字表法平均分为2组,对照组给予多西他赛注射液,观察组服用克唑替尼胶囊,观察对比两组患者治疗12周后的治疗效果和不良反应情况。结果观察组总有效率显著高于对照组(P<0.05);观察组的视觉异常发生率显著高于对照组(P<0.05)。结论克唑替尼治疗EML-4ALK阳性晚期非小细胞肺癌患者的疗效确切,且不良反应较少,安全性较好,值得临床推广使用。     

克里唑替尼治疗ALK重排的非小细胞肺癌的研究进展

肺癌是严重威胁人类健康的重大疾病,而非小细胞肺癌(non-small cell lung cancer,NSCLC)则占所有类型肺癌的85％以上.目前,“个体化给药”是改善晚期NSCLC患者治疗效果的一条前景良好的途径.2011年8月,美国食品和药物管理局(FDA)批准了克里唑替尼(crizotinib),一种ALK/MET/ROS1抑制剂,用于治疗间变性淋巴瘤激酶(ALK)基因重排的非小细胞肺癌,同时还批准了一种ALK荧光原位杂交法检测试剂盒,作为伴侣诊断试剂,用于ALK重排的非小细胞肺癌的检测.随后,克里唑替尼被作为一种ALK和MET抑制剂开发,用于治疗由ALK和MET突变驱动的其他类型的肿瘤.最近已经证实在ROS1重排的非小细胞肺癌中克里唑替尼是一种有效的ROS1抑制剂,并且未来可能用于ROS1基因重排肿瘤的临床治疗.对克里唑替尼的设计开发、治疗ALK重排的NSCLC的的临床应用、药物不良反应以及相应的疾病诊断检测方法进行了回顾,以期为NSCLC的靶向治疗药物的研究和开发提供参考.     

ALK/ROS1抑制剂治疗晚期非小细胞肺癌的最新研究进展

目的综述ALK/ROS1抑制剂治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的最新研究进展。方法通过查阅文献,对治疗晚期NSCLC患者的ALK/ROS1抑制剂进行总结。结果克唑替尼被报道在NSCLC病人中抑制间变性淋巴瘤激酶(ALK)和ROS1重排高度有效和耐受性良好,但在初始治疗后的9~12个月出现了耐药问题,随后又有一些新的ALK抑制剂被研发出来。结论耐药基因的发现及新ALK/ROS1抑制剂的研发具有重要意义和广阔前景。     

小分子靶向药物治疗非小细胞肺癌的不良事件研究进展

目的:综述近年关于厄洛替尼和吉非替尼单用或合并用药研究中导致停药的主要不良反应及其用药的危险因素。方法:查阅、综述、分析近几年关于厄罗替尼和吉非替尼单用或合并用药在非小细胞肺癌治疗方面的研究文献。结果与结论:厄洛替尼和吉非替尼具有耐受性好且不良反应少等特点,但该类药物相关的不良事件依然应当受到关注。     

色瑞替尼治疗间变性淋巴瘤激酶阳性非小细胞肺癌的研究概况

目的:综述色瑞替尼治疗间变性淋巴瘤激酶(ALK)阳性非小细胞肺癌(NSCLC)的研究概况。方法:以"非小细胞肺癌""间变性淋巴瘤激酶抑制剂""色瑞替尼""Non-small cell lung cancer""Ceritinib"作为关键词,查阅中国知网、Pub Med数据库截止至2017年6月的文献,就色瑞替尼治疗ALK阳性NSCLC的药效学、药动学、临床疗效、安全性等的研究进行整理分析和归纳总结。结果与结论:共检索到英文文献1 464篇,中文文献127篇,其中有效文献27篇。色瑞替尼为ALK的高效抑制剂,能有效克服第一代ALK克唑替尼的部分耐药突变;其多次给药后呈非线性药动学特征,不建议与细胞色素P4503A的强抑制剂和诱导剂联用。与化疗和克唑替尼比较,色瑞替尼显著延长了患者的中位无进展生存期与总生存期,其透过颅内浓度高于克唑替尼;最常报道的不良事件是腹泻、恶心、呕吐、腹痛和食欲下降,通常为1~2级,可通过降低剂量减少不良事件的发生,较少引起治疗中止。色瑞替尼可作为ALK阳性、经克唑替尼治疗后疾病进展或不能耐受的晚期NSCLC患者的治疗方案。     

克唑替尼联合紫杉醇和顺铂治疗ALK阳性非小细胞肺癌的疗效观察

目的探究克唑替尼联合紫杉醇和顺铂治疗间变淋巴瘤激酶(ALK)阳性非小细胞肺癌(NSCLC)的临床疗效。方法选取2012年1月—2014年3月在榆林市第一医院接受治疗的ALK阳性NSCLC患者67例,随机分为对照组(33例)和治疗组(34例)。对照组静脉滴注紫杉醇注射液175 mg/m2,1次/d;并于停药30 min后静脉滴注顺铂注射液75 mg/m2,1次/d。治疗组在对照组基础上口服克唑替尼胶囊,1粒/次,2粒/d。两组均治疗2个月,并随访24个月。观察两组的临床疗效,比较两组的血清肿瘤标志物、不良反应和生存率。结果治疗后,对照组和治疗组的有效率分别为27.27%、61.76%,两组比较差异有统计学意义(P0.05)。治疗后,两组癌胚抗原(CEA)、糖类抗原(CA125)和细胞角蛋白19片段(CYFRA21-1)水平均显著降低,同组治疗前后比较差异有统计学意义(P0.05、0.01);且治疗组这些观察指标的下降程度明显优于对照组,两组比较差异具有统计学意义(P0.05)。随访后,对照组和治疗组的死亡率分别为24.24%、14.71%,中位无进展生存期(PFS)分别为13、17个月,两组比较差异有统计学意义(P0.05)。结论克唑替尼联合紫杉醇和顺铂治疗ALK阳性NSCLC具有较好的临床疗效,可降低血清肿瘤标志物水平,延长中位PFS,提高患者的生存率,具有一定的临床推广应用价值。     

非小细胞肺癌的靶向治疗策略

在世界范围内,肺癌位居所有癌症致死的首位,且其中大部分为非小细胞肺癌。尽管大量有关含铂化疗或联合其他药物的临床研究不断涌现,非小细胞肺癌患者的预后仍然差强人意。晚期非小细胞肺癌患者的5年生存率约为15%,在过去几年中未有明显提高。目前,肺癌治疗领域的主要成就在于靶向治疗的出现,例如针对表皮生长因子受体(EGFR)靶点的吉非替尼和厄罗替尼,以及针对抗血管内皮生长因子(VEGF)的贝伐珠单抗,均广泛运用于临床。     

克唑替尼治疗EML4-ALK阳性晚期非小细胞肺癌的临床疗效观察

目的：观察克唑替尼治疗EML4-ALK阳性晚期非小细胞肺癌的临床疗效。方法30例既往化疗失败的中晚期非小细胞肺癌（NSCLC）患者,随机分为实验组和对照组,实验组患者15例,给予克唑替尼治疗,克唑替尼胶囊250 mg,口服,1粒/次,2次/d,早晚确定时间各服1粒,1 d剂量为500 mg。对照组15例,给予多西他赛单药化疗,多西他赛75 mg/m2,于第1天静脉滴注,21 d为1个治疗周期,化疗前1 d给予口服地塞米松8 mg,2次/d常规预处理,避免患者出现过敏反应。对比两组患者的疗效,不良反应及生存期。结果克唑替尼用于二线治疗NSCLC与化疗相比,实验组和对照组有效率分别为60.0%、20.0%;控制率分别为93.3%、53.3%,实验组具有更好的疗效及安全性。结论能否将克唑替尼应用于EML4-ALK基因阳性NSCLC患者的一线治疗,有待于大样本的临床试验进一步确定。     

克唑替尼一线治疗ALK阳性非小细胞肺癌的成本-效果分析

摘要：目的:比较克唑替尼和培美曲塞联合顺铂一线治疗间变淋巴瘤激酶(ALK)阳性非小细胞肺癌(NSCLC)的成本-效果。方法:从医疗保健系统角度出发,构建三状态Markov模型模拟疾病病程,根据Ⅲ期临床试验数据获得各状态之间的转移概率,从已发表文献获得成本数据,效果指标为质量调整生命年(QALY);采用成本-效果分析法比较两方案的经济性,并进行敏感性分析。结果:克唑替尼组和培美曲塞联合顺铂化疗组的两年总成本分别为554 322.4元和293 622.8元,分别获得1.48QALYs和1.33 QALYs,克唑替尼组的收益较化疗组更高,但成本也高于化疗组,增量成本-效果比(ICER)为1 698 291元/QALY,高于支付意愿阈值161 805元(3倍人均GDP)。结论:短期分析结果提示,与培美曲塞联合顺铂化疗相比,克唑替尼治疗ALK阳性晚期NSCLC不具有经济性,克唑替尼组效用值为主要决定因素。     

Pharmacotherapeutic advances with anaplastic lymphoma kinase inhibitors for the treatment of non-small cell lung cancer

ABSTRACT

Introduction

Anaplastic lymphoma kinase (ALK) inhibitors are potent oral anti-cancer agents acting as tyrosine kinase inhibitors (TKIs), which are approved for the treatment of ALK+ non-small cell lung cancer (NSCLC). Over the last years, several new molecules have been developed and are currently under clinical investigation.     

Evolution in the treatment landscape of non-small cell lung cancer with ALK gene alterations: from the first- to third-generation of ALK inhibitors

ABSTRACT

Introduction: The medical treatment of non-small cell lung cancer (NSCLC) has radically changed over the last 10 years thanks to new molecular-targeted drugs able to act on biological mechanisms involved in tumor development. One such mechanism is the aberrant anaplastic lymphoma kinase (ALK) activation: patients with ALK-driven NSCLC benefit from treatments that selectively inhibit its pathogenetic mechanism.

Areas covered: The first-generation ALK inhibitor is crizotinib, initially used in Europe as second-line treatment for ALK-positive metastatic NSCLC patients, then approved as the standard first-line (already approved in the USA as front-line therapy). However, most patients eventually experience disease progression due to the emergence of secondary resistance, partly linked to ALK-dependent mechanisms, hence the development of second- and third-generation ALK inhibitors: ceritinib, alectinib, and brigatinib are approved for ALK-positive NSCLC, lorlatinib is currently being evaluated while others are under development.

Expert opinion: Despite the considerable responses to these new inhibitors, however, resistance mechanisms are described. Thus, while the therapeutic scenario of NSCLC has been soon revolutionized introducing next-generation ALK inhibitors in the first-line setting, future research should identify combined therapies or new generation drugs overcoming resistance in pretreated patients.     

晚期非小细胞肺癌靶向治疗的研究进展

生物标志物检测使得许多晚期非小细胞肺癌(NSCLC)患者获益。近年来,针对表皮生长因子受体(EGFR)和间变性淋巴瘤激酶(ALK)突变呈阳性的NSCLC患者,以吉非替尼、厄洛替尼、阿法替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)和以克唑替尼为代表的ALK-TKI取得了卓越的疗效。但是,大多数第一代EGFR-TKI和ALK-TKI的疗效因为不可避免的继发性耐药而被减弱。目前,第三代EGFR-TKI正是基于第二代EGFR-TKI的耐药机制研发而成。除此之外,还有许多针对其他突变位点的晚期NSCLC维持治疗的靶向抑制剂。遗憾的是,针对突变比例最大的K-RAS突变,尚无疗效确切的靶向药物。因此,基于肿瘤驱动基因突变机制的探索和靶向药物的开发是目前NSCLC的研究热点。     

非小细胞肺癌分子靶向治疗的研究进展

肺癌作为对人类健康与生命造成威胁的一种常见恶性肿瘤,具有较高的发病率与死亡率。肺癌临床属性分为非小细胞肺癌与小细胞肺癌,其中非小细胞肺癌在全部肺癌发病中的占比高达80%~85%,且多数肺癌患者在确诊阶段已处于中晚期,加剧了临床治疗的难度。在医疗技术的不断发展下,手术、放疗、化疗、靶向治疗以及免疫治疗等方式的出现与发展为非小细胞肺癌患者的临床治疗带来新的希望,而分子靶向治疗药物的涌现,为非小细胞肺癌患者的治疗提供了新的选择。     

晚期非小细胞肺癌个体化化疗的研究进展

非小细胞肺癌(NSCLC)全球发病率高、死亡病例多。第三代化疗药物(长春瑞滨、吉西他滨、紫杉醇、多西他赛)联合铂类的两药化疗方案仍是目前NSCLC一线治疗的常规方案。与化疗疗效相关的新靶标基因(切除修复交叉互补基因1与铂类耐药、核苷酸还原酶调节因子1与吉西他滨耐药、β微管蛋白与紫杉类耐药等)有可能作为预测化疗反应的生物标记。本文结合分子病理分型综述临床个体化化疗方案研究。     

New systemic strategies for overcoming resistance to targeted therapies in non-small cell lung cancer

Introduction: Although the achievements in the treatment of advanced non-small cell lung cancer (NSCLC) have been translated in improved disease control, response rate and survival, especially in the case of patients with targetable oncogenic drivers, acquired resistance is common after initial benefit; furthermore, primary resistance can occasionally be observed. Due to its clinical implications, the management of treatment-resistant NSCLC is a top topic of the current research, and many efforts are being put in the study of the mechanisms at the base of resistance and in the development of effective therapeutic countermeasures.

Areas covered: This review aims at identifying the most relevant novel chemical therapies designed to overcome resistance in NSCLC, including recently approved agents, as well as compounds in clinical development.

Expert opinion: An improved knowledge of the mechanisms causing resistance to treatments in NSCLC translates into effective innovative chemical therapies able to overcome such occurrence, and the paradigms of this progress are represented by novel inhibitors of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK); however, the study of novel systemic therapies in this setting is challenging, and further efforts in this setting are highly needed.     

Anaplastic lymphoma kinase inhibitors in phase I and phase II clinical trials for non-small cell lung cancer

Introduction: Crizotinib is a first-in-class ALK tyrosine kinase inhibitor (TKI), which has proven its superiority over standard platinum-based chemotherapy for the first-line therapy of ALK-rearranged non-small cell lung cancer (NSCLC) patients. The development of acquired resistance to crizotinib represents an ongoing challenge with the central nervous system being one of the most common sites of relapse. Ceritinib and alectinib are approved second-generation ALK TKIs. Several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib, are currently in development.

Areas covered: This review will focus on new ALK inhibitors, currently in phase 1 or 2 clinical studies. We will also comment on the mechanisms of resistance to ALK inhibition and the strategies to delay or overcome resistance.

Expert opinion: The therapeutic management of ALK-rearranged NSCLC has been greatly improved. Next-generation ALK inhibitors have shown differential potency against ALK rearrangements and ALK resistance mutations. The molecular profile of the tumor at the time of disease progression to crizotinib is crucial for the sequencing of novel ALK TKIs. Ongoing clinical studies will address key issues, including the optimal therapeutic algorithm and whether combinational approaches are more effective than single ALK inhibition for the outcome of ALK-rearranged NSCLC patients.     

非小细胞肺癌EGFR-T790M突变药物的研究进展

原发性肺癌(简称肺癌)是常见的恶性肿瘤之一,发生率居恶性肿瘤首位。非小细胞肺癌(NSCLC)约占所有肺癌的80%。近年来,表皮生长因子受体–酪氨酸激酶抑制(EGFR-TKI)在NSCLC治疗中起到重要作用;随着EGFR-TKI在临床上的广泛应用,耐药问题日益加剧;T790M基因突变是导致EGFR-TKI获得性耐药最主要的机制。全球新批准并上市的治疗NSCLC EGFR-T790M突变的药物有brigatinib、奥莫替尼、atezolizumab等;处于上市申请阶段的有丁磺氨酸、阿拉莫林盐酸盐、ABP-215;处于研发阶段的主要有naquotinib、TG-4010等。对近年来处于研发后期的NSCLC治疗药物进行详细介绍,同时对抗NSCLC药物的未来发展方向进行了展望,以期为抗NSCLC药物的研发提供参考。     

基于多元回归-灰色模型的非小细胞肺癌靶向药物用量预测分析

目的 建立非小细胞肺癌(NSCLC)常用靶向药物的用量预测模型,为指导医疗机构抗肿瘤靶向药物的采购和库存管理提供数据支撑.方法 参考天津市肿瘤医院2019年各月的靶向药物用量数据,以4种临床常用的NSCLC靶向药物(吉非替尼、埃克替尼、奥希替尼和克唑替尼)为例,建立多元回归模型、GM(1,1)灰色模型以及多元回归-灰色...