克唑替尼联合化疗治疗间变性淋巴瘤激酶阳性晚期非小细胞肺癌的临床疗效及安全性

目的 探讨克唑替尼联合化疗治疗间变性淋巴瘤激酶(ALK)阳性晚期非小细胞肺癌(NSCLC)的临床疗效及安全性.方法 根据治疗方式的不同将90例ALK阳性晚期NSCLC患者分为对照组和观察组,每组45例,对照组予以单纯化疗,观察组予以化疗联合克唑替尼靶向治疗,两组患者均定期随访2年.比较两组患者的临床疗效、血清肿瘤标志物[癌胚抗原(CEA)、细胞角质蛋白19片段抗原21-1(CYFRA21-1)、神经元特异性烯醇化酶(NSE)]水平、不良反应发生率及生存情况.结果 治疗后,观察组患者的疾病控制率为82.22％,高于对照组的57.78％,差异有统计学意义(P﹤0.05);观察组患者的血清肿瘤标志物CEA、CYFRA21-1、NSE水平均低于对照组(P﹤0.05).治疗期间观察组患者的不良反应总发生率为42.22％(19/45),与对照组患者的48.89％(22/45)比较,差异无统计学意义(P﹥0.05).观察组患者的1年生存率和2年生存率均高于对照组(P﹤0.05).结论 克唑替尼联合化疗治疗ALK阳性晚期NSCLC的临床疗效显著,可降低血清肿瘤标志物水平,提高患者生存率,且安全性较高.     

克唑替尼治疗ALK阳性非小细胞肺癌脑转移的疗效观察

背景与目的：克唑替尼对间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)阳性非小细胞肺癌(non-small cell lung cancer,NSCLC)具有显著疗效,但在治疗中往往出现脑转移,本研究旨在探讨克唑替尼在ALK阳性NSCLC脑转移患者中的治疗疗效和治疗模式。方法：对2011年1月—2014年8月在解放军八一医院接受克唑替尼治疗的6例ALK阳性NSCLC脑转移患者的临床资料进行回顾性分析。结果：3例克唑替尼治疗前基线有脑转移患者,颅内疗效部分缓解(partial response,PR)1例、疾病稳定(stable disease,SD)2例;第1次服用克唑替尼治疗至第1次出现疾病进展(progressive disease,PD)的中位时间为5.7个月,且第1次疾病进展的部位均为脑。6例患者脑病灶进展接受放疗后继续服用克唑替尼治疗,中位无进展生存期(progression free survival,PFS)为4.0个月,其中1例患者继续接受克唑替尼治疗的PFS达23.3个月,颅内病灶疗效完全缓解(complete response,CR)。结论：克唑替尼治疗ALK阳性NSCLC脑转移患者有效,且对于单纯颅内病灶进展放疗后,继续接受克唑替尼治疗仍然有效,是临床上可以选择的治疗方式。     

克唑替尼治疗间变大细胞淋巴瘤激酶阳性间变大细胞淋巴瘤获长期缓解1例并文献复习

间变大细胞淋巴瘤(ALCL)是一种侵袭性非霍奇金淋巴瘤,部分患者初期临床症状表现不明显,容易误诊.确诊的间变大细胞淋巴瘤激酶阳性(ALK+)ALCL患者对化疗(CHOP或ECHOP方法)敏感.而对于功能状态评分差,不能耐受化疗的患者,部分显示了对克唑替尼良好的耐受性和临床疗效.对于复发和难治的ALK+ALCL患者,克唑...     

克里唑替尼在非小细胞肺癌中的研究进展

肺癌中的一大部分为非小细胞肺癌(NSCLC)。克里唑替尼作为ALK和MET的酪氨酸激酶抑制剂,是一种小分子靶向ALK突变的治疗药物,可以通过抑制ALK突变而产生抗NSCLC的作用。克里唑替尼通过抑制NSCLC中ALK激酶与ATP的结合及结合后的自身磷酸化而抑制激酶的激活,进而降低激酶活性,起到抗肿瘤作用。克里唑替尼以其高有效率已经获得FDA批准进行III期临床试验,是目前最早也是唯一一个进行III期临床试验的ALK酪氨酸激酶抑制剂。大多数的不良反应如一过性视觉障碍、胃肠道反应、疲惫等多处于比较轻微的1-2级水平。耐药情况的出现严重限制了其临床应用,因此,对于其耐药机制的研究有助于尽早研制出二代ALK抑制剂,取得更好的临床疗效。目前ALK突变的3种主要检测方法为:Break-apart FISH,RT-PCR,免疫组织化学方法(IHC)。     

艾乐替尼治疗ALK阳性非小细胞肺癌的研究进展

克唑替尼作为第一代间变性淋巴瘤激酶酪氨酸激酶抑制剂(anaplastic lymphoma kinase-tyrosine kinase inhibitors, ALKTKIs), 在间变性淋巴瘤激酶(ALK)阳性晚期非小细胞肺癌(non-small cell lung cancer, NSCLC)患者的治疗中有着举足轻重的地位, 但其和所有的TKI一样, 也不可避免地遇到了耐药的问题。于是第二代ALK-TKIs (艾乐替尼、色瑞替尼、布加替尼等)应运而生, 本文就其中的研究热点之一艾乐替尼治疗ALK阳性NSCLC的研究进展进行综述。      

ALK阳性非小细胞肺癌患者克唑替尼耐药的机制和治疗措施

肺癌是全球发病率和致死率最高的疾病之一。非小细胞肺癌(non-small cell lung cancer,NSCLC)是肺癌最为常见的组织学类型。近些年,分子生物学的发展让我们对NSCLC的认识从组织水平深入到分子水平。表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变和间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)融合基因是NSCLC患者最为重要的两个肿瘤驱动基因。针对它们的酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)显著改善了带有这类分子特征的NSCLC患者的生存。不幸的是,目前几乎所有针对这两种突变的初始靶向治疗都会不可避免地出现耐药问题。有关EGFR-TKIs的耐药机制及其应对策略已经有很多文章进行阐述,而对于ALK TKIs治疗后出现耐药问题的机制和相应的治疗策略还未曾有过详细的综述。因此,本文针对一代ALK TKI(克唑替尼)治疗ALK融合基因阳性的NSCLC患者(ALK+NSCLC)后引起耐药问题的机制和有关后续治疗策略做一综述。     

阿来替尼治疗三线及以上ALK阳性晚期非小细胞肺癌的疗效和安全性

目的 探讨阿来替尼治疗三线及以上ALK阳性晚期非小细胞肺癌的疗效和安全性。方法 回顾性分析自2018年1月至2020年12月在河南大学淮河医院接受阿来替尼三线及以上治疗的25例晚期非小细胞肺癌患者的临床资料,所有患者均经过病理学检查确诊为非小细胞肺癌,且经免疫组化检查确诊为ALK阳性,均接受二线及以上化疗后病情进展,ECOG评分0～2分,年龄45～70岁。结果 阿来替尼三线及以上治疗ALK阳性晚期非小细胞肺癌的客观缓解率和疾病控制率分别为36.0%和88.0%,中位疾病无进展生存时间为11.5个月。且安全性高,不良反应发生率低。常见不良反应为Ⅰ、Ⅱ度便秘、恶心、口腔炎、肌痛、皮疹、转氨酶升高、胆红素升高等。Ⅲ、Ⅳ度不良反应包括高血压2例、贫血1例、肝损伤1例,经对症治疗后均有好转,仅1例患者因出现重度肝损伤导致停药。结论 阿来替尼治疗三线及以上ALK阳性晚期非小细胞肺癌疗效显著,安全性好。     

克唑替尼治疗 ALK 融合基因阳性的晚期非小细胞肺癌患者的疗效分析

目的：探讨克唑替尼治疗中国 ALK 融合基因阳性的非小细胞肺癌（NSCLC）患者的疗效和安全性。方法14名患者接受至少4周的克唑替尼（250 mg,q12h）治疗,以评价治疗后的近期疗效、生活质量、不良反应。结果12例患者口服克唑替尼治疗后,11例（91.67%）获得部分缓解,1例（8.33%）获得疾病稳定,客观缓解率为91.67%;在生活质量评估中,患者的疲乏、气短、睡眠等均得到改善;不良反应主要为消化道症状,其次是谷丙转氨酶升高（64.29%）,视觉障碍（57.14%）,大部分为1～2级。结论克唑替尼作为 ALK 融合基因阳性的 NSCLC 患者的靶向治疗,具有良好的疗效及安全性,不良反应轻微。     

克唑替尼治疗进展期ALK阳性非小细胞肺癌的临床疗效研究

目的 探讨克唑替尼对治疗进展期ALK阳性非小细胞肺癌的临床治疗效果.方法 选取60例进展期ALK阳性非小细胞肺癌(NSCLC)患者,随机分为实验组和对照组,实验组和对照组患者分别应用克唑替尼和多西他赛进行治疗.对比两组治疗效果、不良反应及生存期.结果 实验组和对照组有效率分别为76.7%,20.0%;控制率分别为93.3%、60.0%,实验组较对照组具有更好的安全性和疗效.结论 克唑替尼对进展期ALK阳性非小细胞肺癌有着良好的治疗效果,其能否成为一线治疗药物,有待大样本临床试验研究.     

克唑替尼在ALK阳性晚期NSCLC患者中的疗效和安全性评价及其预后影响因素

目的 探讨克唑替尼在间变性淋巴瘤激酶(ALK)阳性晚期非小细胞肺癌(NSCLC)患者中的疗效和安全性,并重点分析其预后影响因素.方法 收集2013年1月至2016年9月在北京协和医院就诊且经细胞学或组织学证实的晚期(ⅢB ～Ⅳ期)ALK阳性NSCLC患者50例,记录相关临床信息、治疗方案并随访疗效和安全性,分析预后影响因素.结果 截至随访结束,进展患者(24例)中位无进展生存期(PFS)为9.6个月(95％ CI为8.3 ～10.9个月),其中5例死亡;未进展患者(26例)中位随访时间为10.7个月.最常见的不良反应为肝功能异常(48.0％,24/50);在Kaplan-Meier单因素分析中,≤40岁的患者拥有更长的PFS(P =0.017),且COX回归多因素分析(Enter法)也有意义(HR =6.1,95％ CI为1.4～27.5,P=0.018);而性别(HR =0.8,95％ CI为0.2～2.6,P=0.697)、吸烟史(HR=1.5,95％ CI为0.4 ～5.6,P=0.524)、病理类型(HR=1.1,95％ CI为0.3 ～4.2,P=0.922)、分期(HR=1.7,95％ CI为0.4 ～8.4,P=0.502)、表皮生长因子受体(EGFR)突变型(HR =0.4,95％ CI为0.4 ～4.3,P=0.461)、EGFR未知(HR=1.3,95％ CI为0.3～6.1,P=0.727)、美国东部肿瘤协作组体能状态评分(HR =2.0,95％ CI为0.6 ～6.8,ECOG PS评分,P=0.290)、既往治疗情况(HR =0.6,95％ CI为0.2～1.8,P=0.385)和脑转移情况(HR =0.7,95％ CI为0.1 ～3.2,P=0.628)均与疾病进展时间无关.结论 克唑替尼对晚期ALK阳性NSCLC患者有良好的疗效,安全可耐受,年龄是其预后的独立影响因素.     

Anaplastic lymphoma kinase inhibitors in elderly patients with advanced non-small cell lung cancer

Introduction: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the USA and worldwide. At diagnosis, half of the patients are over 70 years of age, and most present with advanced disease for which chemotherapy provides modest benefit with significant toxicity. Older patients often have more comorbidities than their younger counterparts and tend to be excluded from clinical trials.

Areas covered: A small percentage (less than 7%) of patients with NSCLC have the anaplastic lymphoma kinase (ALK) rearrangement. Compared to the general NSCLC population, this clinically distinct group has a relatively younger median age of 51 years at diagnosis. As such, elderly patients with ALK-positive disease are both a minority within this group and are expected to be underrepresented in clinical trials.

Expert commentary: Despite promising results in the general population, data about the efficacy and safety of ALK inhibitors in the elderly population remains scarce. In our review, we briefly discuss the current evidence of ALK inhibitors in the general population and we shed light on this subgroup of elderly patients with advanced ALK-positive disease.     

Targeted therapies in non-small cell lung cancer: a focus on ALK/ROS1 tyrosine kinase inhibitors

Introduction: Anaplastic lymphoma kinase (ALK) and ROS1 rearrangements define important molecular subgroups of advanced non-small cell lung cancer (NSCLC). The identification of these genetic driver alterations created new potential for highly active therapeutic interventions. After discovery of ALK rearrangements in NSCLC, it was recognized that these confer sensitivity to ALK inhibition.

Areas covered: Crizotinib, the first-in-class ALK/ROS1/MET inhibitor, was initially approved as second-line treatment of ALK-positive advanced NSCLC but after this, it was firmly established as the standard first-line therapy for advanced ALK-positive NSCLC. After initial response to crizotinib, tumors inevitably relapse. Next-generation ALK inhibitors, more potent and brain-penetrable than crizotinib, may be effective in re-inducing remissions when cancers are still addicted to ALK. Ceritinib and alectinib are approved for metastatic ALK positive NSCLC patients, while brigatinib received granted accelerated approval by the United States Food and Drug Administration. Regarding ROS1 rearrangement, to date crizotinib is the only ALK-tyrosine kinase inhibitor receiving indication as treatment of ROS1 positive advanced NSCLC.

Expert commentary: Although novel ALK-inhibitors are under clinical investigation compared to crizotinib as front-line treatment for ALK-positive NSCLC, nowadays the current standard first-line therapy for these patients is crizotinib. Further research will clarify the best management of ALK-positive NSCLC, above all who progress on first-line crizotinib.     

Development of crizotinib,a rationally designed tyrosine kinase inhibitor for non‐small cell lung cancer

Non‐small cell lung cancer (NSCLC) is the number one cause of global mortality. Despite aggressive treatment, the prognosis is dismal. Patients with advanced NSCLC have a median survival of 4 months from the time of diagnosis. Fortunately, molecularly based approaches to drug discovery have yielded a tyrosine kinase inhibitor, crizotinib, which significantly prolongs median progression‐free survival in a subset of patients. Although initial clinical trial results demonstrate crizotinib has a promising role to play in NSCLC treatment, development of resistance leaves much to be elucidated about how to effectively combat this deadly disease. In this review, we follow the discovery and development of crizotinib from bench to bedside and provide an example of successful bottom‐up drug design. Then, we explore the clinical trial results that fast‐tracked its eventual use as a frontline therapy for sensitive NSCLC patients and the development of resistance. Lastly, we discuss the potential for future uses of crizotinib both within and beyond NSCLC.     

Rapid‐onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer

BACKGROUND:

The objective of this study was to document the differences in testosterone (T) levels between crizotinib‐treated and noncrizotinib‐treated patients with metastatic nonsmall cell lung cancer (NSCLC).

METHODS:

Testosterone levels were measured in 19 men with metastatic NSCLC who received crizotinib and in 19 men with metastatic NSCLC who did not receive crizotinib. Clinical characteristics of the patients were compared, and additional hormone assays were performed as appropriate. Two patients who began crizotinib and 4 patients who had dose interruptions or who stopped crizotinib therapy had serial hormone measurements, permitting the documentation of dynamic hormone changes on and off crizotinib treatment.

RESULTS:

Total T levels were low (<241 ng/dL) in 19 of 19 (100%) crizotinib‐treated men and in 6 of 19 men (32%) with metastatic NSCLC who did not receive crizotinib (mean T levels, 131 ng/dL and 311 ng/dL, respectively; P = .0002). Only 1 in 5 patients who had anaplastic lymphoma kinase (ALK) gene rearrangements and had not yet received crizotinib had low T. The initiation of crizotinib in 2 patients who had previously normal T levels was associated with a rapid decreases in T and in luteinizing hormone and follicle stimulating hormone levels within 14 to 21 days. Discontinuation of crizotinib led to increases back to normal T levels.

CONCLUSIONS:

Crizotinib therapy caused rapid suppression of T levels in men. The current results indicated that the site of action must include a central (hypothalamic or pituitary) effect, but additional direct testicular effects could not be excluded. Further work is required to assess the correlation between low T levels and crizotinib side effects as well as the exact molecular mechanism and site of drug toxicity. Cancer 2012. © 2012 American Cancer Society.     

ALK融合基因阳性的晚期非小细胞肺癌靶向治疗进展

近十年来，晚期非小细胞肺癌（non-small cell lung cancer，NSCLC）在治疗方面出现重大的模式转变。关键致癌性突变（如驱动基因突变和染色体重排）的存在，使得靶向治疗相比传统的细胞毒性化学疗法显示出更高的敏感性。2007年间变性淋巴瘤激酶（anaplastic lymphoma kinase，ALK）基因与棘皮动物微管相关蛋白样-4（echinoderm microtubule-associated protein-4，EML4）基因融合突变首次在NSCLC患者中被发现。随后研究证实，ALK-EML4融合突变阳性的NSCLC（ALK+NSCLC）显示出对克唑替尼治疗的敏感性。随着后续一系列靶向治疗新药的研发，将ALK+NSCLC靶向治疗推向高潮。本综述回顾ALK+NSCLC的分子生物学发病机制、流行病学特征及检测方法，汇总其抑制剂的重要临床试验结果，并解读ALK+NSCLC抑制剂耐药机制及合并脑转移的最新研究进展。     

Diagnostic assays for identification of anaplastic lymphoma kinase‐positive non–small cell lung cancer

In series dominated by adenocarcinoma histology, approximately 5% of non–small cell lung cancers (NSCLCs) harbor an anaplastic lymphoma kinase (ALK) gene rearrangement. Crizotinib, a tyrosine kinase inhibitor with significant activity against ALK, has demonstrated high response rates and prolonged progression‐free survival in ALK‐positive patients enrolled in phase 1/2 clinical trials. In 2011, crizotinib received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of proven ALK‐positive NSCLC using an FDA‐approved diagnostic test. Currently, only break‐apart fluorescence in situ hybridization testing is FDA approved as a companion diagnostic for crizotinib; however, many other assays are available or in development. In the current review, the authors summarize the diagnostic tests available, or likely to become available, that could be used to identify patients with ALK‐positive NSCLC, highlighting the pros and cons of each. Cancer 2013. © 2012 American Cancer Society.     

Targeting autophagy enhances the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma

Anaplastic Lymphoma Kinase-positive Anaplastic Large Cell Lymphomas (ALK+ ALCL) occur predominantly in children and young adults. Their treatment, based on aggressive chemotherapy, is not optimal since ALCL patients can still expect a 30% 2-year relapse rate. Tumor relapses are very aggressive and their underlying mechanisms are unknown. Crizotinib is the most advanced ALK tyrosine kinase inhibitor and is already used in clinics to treat ALK-associated cancers. However, crizotinib escape mechanisms have emerged, thus preventing its use in frontline ALCL therapy. The process of autophagy has been proposed as the next target for elimination of the resistance to tyrosine kinase inhibitors. In this study, we investigated whether autophagy is activated in ALCL cells submitted to ALK inactivation (using crizotinib or ALK-targeting siRNA). Classical autophagy read-outs such as autophagosome visualization/quantification by electron microscopy and LC3-B marker turn-over assays were used to demonstrate autophagy induction and flux activation upon ALK inactivation. This was demonstrated to have a cytoprotective role on cell viability and clonogenic assays following combined ALK and autophagy inhibition. Altogether, our results suggest that co-treatment with crizotinib and chloroquine (two drugs already used in clinics) could be beneficial for ALK-positive ALCL patients.     

Correlations between the percentage of tumor cells showing an anaplastic lymphoma kinase (ALK) gene rearrangement, ALK signal copy number, and response to crizotinib therapy in ALK fluorescence in situ hybridization-positive nonsmall cell lung cancer

BACKGROUND:

Fluorescence in situ hybridization (FISH), using break‐apart red (3′) and green (5′) ALK (anaplastic lymphoma kinase) probes, consistently shows rearrangements in <100% of tumor cells in ALK‐positive (ALK+) nonsmall cell lung cancer (NSCLC). Increased copy numbers of fused and rearranged signals also occur. Here, correlations are explored between the percentage of ALK+ cells and signal copy number and their association with response to ALK inhibition.

METHODS:

Ninety ALK+ NSCLC cases were evaluated. The percentage of positive cells, pattern of positivity (split, single red, or both), and copy number of fused, isolated red and green signals were recorded. Thirty patients had received crizotinib.

RESULTS:

Increased isolated red signal copy number (contributing to both single red and split patterns of positivity) correlated with a higher percentage of ALK+ cells (r = 0.743, P < .0001). Mean fused copy number was negatively associated with isolated red signal copy number (r = ?0.409, P < .0001). Neither percentage of positive cells (r = 0.192, P = .3), nor copy number of isolated red signal (r = 0.274, P = .195) correlated with maximal tumor shrinkage with crizotinib.

CONCLUSIONS:

The strong association between increased copy number of key ALK signals and percentage of positive cells suggests that the <100% rate of cellular positivity in ALK+ tumors is due to technical factors, not biological factors. In ALK+ tumors, neither the percentage of positive cells nor signal copy number appear to be informative variables for predicting benefit from ALK inhibition. The inverse relationship between fused and isolated red copy number suggests ALK+ may be a distinct “near‐diploid” subtype of NSCLC that develops before significant chromosomal aneusomy occurs. Cancer 2012. © 2012 American Cancer Society.     

Efficacy of crizotinib inhibiting specific molecular pathways in non-small-cell lung carcinoma

The US FDA granted approval for crizotinib as the first-line treatment for patients with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase rearranged metastatic non-small-cell lung cancer, on November 20, 2013. Crizotinib is a customized and improved therapeutic option for patients with non-small-cell lung cancer that enhances overall survival without increasing toxicity. In the future, new targeted therapies may achieve additional indications for treating patients with lung cancer. This article summarizes data from crizotinib studies.