恩沙替尼治疗间变性淋巴瘤激酶阳性非小细胞肺癌专家共识

非小细胞肺癌患者间变性淋巴瘤激酶(ALK)突变率为3%～7%。与表皮生长因子受体阳性非小细胞肺癌患者比较, ALK突变非小细胞肺癌患者更易获得长期生存, 因此, ALK突变被称为钻石突变。目前, 在全球范围内, ALK-酪氨酸激酶抑制剂(TKI)药物已经有三代药物。中国已获批的ALK-TKI第一代药物为克唑替尼, 第二代药物为阿来替尼、塞瑞替尼和恩沙替尼。恩沙替尼为中国自主原研的ALK-TKI, 其疗效与阿来替尼相似, 耐受性表现为一过性皮疹, 从患者长期生存的角度而言, 顺应性更好。恩沙替尼引起的皮疹表现与其他ALK-TKI药物不同, 为了便于临床应用和为患者提供更多的治疗选择, 在中国抗癌协会肿瘤康复与姑息治疗专业委员会的指导下, 专家收集汇总了恩沙替尼常见的不良反应, 并结合临床实践制定了明确的不良分级及具体处理方案, 以期为临床医师提供相应的参考依据。     

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基因抑制剂治疗非小细胞肺癌脑转移的研究进展

间变性淋巴瘤激酶(ALK)重排是非小细胞肺癌(NSCLC)强有力的致癌驱动基因之一,伴ALK重排的NSCLC患者应用第一代ALK抑制剂如克唑替尼的治疗疗效要远远优于化疗.同时越来越多的研究报道了ALK抑制剂在伴有脑转移的NSCLC患者中的颅内有效率.然而尽管第一代ALK抑制剂治疗ALK阳性NSCLC脑转移有初步的临床数据,但在获得性耐药后,肿瘤出现不同程度的复发,给肿瘤患者的后续治疗带来新的挑战.新一代ALK抑制剂如艾乐替尼、色瑞替尼、AP26113和PF-06463922的相继出现解决了这一问题.     

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)。     

克唑替尼治疗肺癌的疗效及其耐药后的治疗

以棘皮动物微管相关蛋白4-间变性淋巴瘤激酶（EML4-ALK）融合基因突变为靶点的酪氨酸激酶抑制剂（TKI）克唑替尼能够显著延长晚期 ALK 阳性非小细胞肺癌（NSCLC）患者的无进展生存期（PFS）,一线、二线单药治疗的中位 PFS 分别为10．9个月和7．7个月。尽管克唑替尼的初始疗效良好,但大部分患者于治疗1年内出现耐药并显示疾病复发,其原因是 ALK 融合基因扩增和二次突变。临床试验证实二代 ALK 抑制剂、联合热休克蛋白等能有效克服克唑替尼耐药。     

克唑替尼治疗晚期NSCLC患者单中心回顾性分析

背景与目的 克唑替尼是针对间变淋巴瘤激酶(anaplastic lymphoma kinase,ALK)融合基因、ROS-1重排等靶点的药物.本文观察克唑替尼治疗ALK/ROS1重排阳性的晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的近远期疗效.方法 对2013年6月-2014年12月于北京肿瘤医院开始接受克唑替尼治疗的40例相应靶点阳性的NSCLC患者进行回顾性分析.结果 本组40例,39例为腺癌或腺鳞癌,包括印戒细胞癌、腺泡型、乳头状腺癌等特点.中位年龄49.5岁,治疗总有效率62.5％,疾病控制率为95.0％.全组中位随访14.6个月,中位无进展生存时间(progression free survival,PFS) 7.5个月,中位生存期(overall survival,OS)尚未到达,1年生存率77.4％.第一、二线较二线后治疗者中位PFS、OS有延长趋势,但无统计学意义(PFS:9mo vs 6mo,P=0.06; OS:21.5 mo vs 14.6 mo,P=0.12).20例进展者以脑转移为进展部位.进展后接受二代/三代ALK-酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)的患者表现出疾病控制、生存延长的疗效.不良反应主要为消化道反应、转氨酶升高、特征性的视觉异常等.结论 本组克唑替尼治疗相应靶点阳性晚期NSCLC临床特点、疗效及不良反应与国际报道相近.脑转移进展是克唑替尼治疗后进展的常见形式,克唑替尼耐药者给予二代/三代ALK-TKI可延迟进展.     

Alectinib在非小细胞肺癌治疗中的研究进展

目前,分子靶向治疗在非小细胞肺癌( Non-small cell lung cancer,NSCLC)的治疗中占据着重要地位. 克唑替尼是第一代ALK酪氨酸激酶抑制剂,于2011年在美国批准上市,用于治疗ALK重排阳性的非小细胞肺癌. 然而,克唑替尼仅在治疗的早期阶段有效,长期使用后由于肿瘤出现二次突变而产生耐药. 近年来,Alectinib作为第二代ALK激酶抑制剂已经在日本批准上市用于治疗ALK重排阳性的NSCLC患者. 本文综述Alectinib在非小细胞肺癌治疗中的研究进展.     

新型ALK抑制剂在晚期非小细胞肺癌治疗中的研究进展

克唑替尼作为第一代间变性淋巴瘤激酶(ALK)抑制剂,对于治疗ALK阳性晚期非小细胞肺癌疗效显著,但耐药问题限制了其临床应用.二代ALK抑制剂色瑞替尼和艾乐替尼等也相继被美国食品药品监督管理局(FDA)批准上市,而更多安全有效的新型ALK抑制剂正处于研发阶段.本文就新型ALK抑制剂的研究进展作一系统性综述,以期为新型ALK抑制剂的临床应用提供选择依据.     

伊鲁阿克治疗间变性淋巴瘤激酶融合基因阳性局部晚期或转移性非小细胞肺癌中国专家共识(2024版)

间变性淋巴瘤激酶(ALK)融合基因是非小细胞肺癌(NSCLC)常见的驱动基因之一。流行病学数据显示, 在中国晚期NSCLC患者中ALK融合基因的阳性率为9.06%。ALK酪氨酸激酶抑制剂(TKIs)已经成为ALK融合基因阳性晚期NSCLC患者的标准治疗选择。目前中国国家药品监督管理局已经批准7种ALK-TKIs上市, 分别是克唑替尼、塞瑞替尼、阿来替尼、恩沙替尼、布格替尼、洛拉替尼和伊鲁阿克。伊鲁阿克是中国自主研发的新型ALK-TKI, 2023年6月27日, 国家药品监督管理局批准伊鲁阿克上市, 用于既往接受过克唑替尼治疗后疾病进展或对克唑替尼不耐受的ALK融合基因阳性局部晚期或转移性NSCLC患者的治疗, 2024年1月16日, 国家药品监督管理局批准伊鲁阿克用于ALK融合基因阳性局部晚期或转移性NSCLC患者的一线治疗。为了帮助广大医师更好地了解伊鲁阿克的疗效和安全性, 使伊鲁阿克得到更合理的临床应用, 中国医疗保健国际交流促进会肿瘤内科学分会和中国医师协会肿瘤医师分会组织专家编写了《伊鲁阿克治疗间变性淋巴瘤激酶融合基因阳性局部晚期或转移性非小细胞肺癌中国专家共识(2024版)》...     

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。     

Drug resistance mechanisms in Japanese anaplastic lymphoma kinase‐positive non–small cell lung cancer and the clinical responses based on the resistant mechanisms

The treatment for anaplastic lymphoma kinase (ALK)‐positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK‐TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK‐positive lung cancer during multiple ALK‐TKI treatments to reveal the resistance mechanisms to ALK‐TKI. Among 32 patients, 24 patients received more than two ALK‐TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P‐gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK‐TKI treatment duration was longer in the on‐target treatment group than that in the off‐target group (13.0 vs 1.2 months). In conclusion, resistance to ALK‐TKI based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. Understanding the appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK‐TKI treatment strategies.     

The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers

The ALK kinase inhibitor crizotinib (PF-02341066) is clinically effective in patients with ALK-translocated cancers, but its efficacy will ultimately be limited by acquired drug resistance. Here we report the identification of a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harboring a RANBP2-ALK translocation who progressed while on crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth, and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib-mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. A chemically distinct ALK inhibitor, TAE684, and the HSP90 inhibitor 17-AAG are both effective in models harboring the F1174L ALK mutation. Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK-translocated cancers.     

NPM/ALK mutants resistant to ASP3026 display variable sensitivity to alternative ALK inhibitors but succumb to the novel compound PF-06463922

ALK is involved in the onset of several tumors. Crizotinib (Xalkori^TM), a potent ALK inhibitor, represents the current front-line treatment for ALK+ NSCLC and shows great clinical efficacy. However, resistant disease often develops after initial response. ASP3026 is a novel second-generation ALK inhibitor with activity on crizotinib-resistant ALK-L1196M gatekeeper mutant. As resistance is likely to be a relevant hurdle for any drug, we sought to determine the resistance profile of ASP3026 in the context of NPM/ALK+ ALCL. We selected six ASP3026-resistant cell lines by culturing human ALCL cells in the presence of increasing concentrations of drug. The established resistant cell lines carry several point mutations in the ALK kinase domain (G1128S, C1156F, I1171N/T, F1174I, N1178H, E1210K and C1156F/D1203N were the most frequent) that are shown to confer resistance to ASP3026 in the Ba/F3 cell model. All mutants were profiled for cross-resistance against a panel of clinically relevant inhibitors including ceritinib, alectinib, crizotinib, AP26113 and PF-06463922. Finally, a genetically heterogeneous ASP3026-resistant cell line was exposed to second-line treatment simulations with all inhibitors. The population evolved according to relative sensitivity of its mutant subclones to the various drugs. Compound PF-06463922 did not allow the outgrowth of any resistant clone, at non-toxic doses.     

Brigatinib in Japanese Patients With ALK-Positive NSCLC Previously Treated With Alectinib and Other Tyrosine Kinase Inhibitors: Outcomes of the Phase 2 J-ALTA Trial

IntroductionThis phase 2 trial evaluated the efficacy and safety of brigatinib in patients with advanced ALK-positive NSCLC refractory to alectinib or other ALK tyrosine kinase inhibitors (TKIs).MethodsThis single-arm, multicenter, open-label study in Japanese patients consisted of a safety lead-in followed by an expansion stage in patients refractory to ALK TKI or those naive for ALK TKI. Patients received brigatinib 180 mg once daily with 7-day lead-in at 90 mg once daily. Primary end point was independent review committee (IRC)–assessed confirmed objective response rate per the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsWe report the results of the lead-in and expansion in the patients refractory to ALK TKI. Of 72 patients enrolled, 47 had alectinib as most recent ALK TKI (with or without previous crizotinib). At analysis cutoff, 14 of the 47 remained on brigatinib (median follow-up: 12.4 mo). In the alectinib-refractory population, IRC-assessed confirmed objective response rate was 34% (95% confidence interval [CI]: 21%–49%) with median duration of response of 11.8 months (95% CI: 5.5–16.4). Disease control rate was 79% (95% CI: 64%–89%). Median IRC-assessed progression-free survival was 7.3 months (95% CI: 3.7–9.3). Two of eight patients with measurable brain lesions at baseline had confirmed intracranial partial response. Brigatinib has been found to have antitumor activity in patients with G1202R, I1171N, V1180L, and L1196M secondary mutations. The safety profile in Japanese patients was consistent with that in previous reports in broader populations.ConclusionsBrigatinib has been found to have clinically meaningful efficacy in Japanese patients with ALK+ NSCLC refractory to alectinib (with or without previous crizotinib).     

A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALK TKI (TAE684)-sensitive H3122 cell line. The crizotinib-resistant DFCI076 cell line harbored a unique L1152R ALK secondary mutation and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent coactivation of epidermal growth factor receptor (EGFR) signaling. In contrast, the TAE684-resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harbored coactivation of EGFR signaling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naive NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signaling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients.     

Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of ALK-Rearranged Lung Cancer

IntroductionLeptomeningeal carcinomatosis (LMC) occurs frequently in anaplastic lymphoma kinase (ALK)–rearranged NSCLC and develops acquired resistance to ALK tyrosine kinase inhibitors (ALK TKIs). This study aimed to clarify the resistance mechanism to alectinib, a second-generation ALK TKI, in LMC and test a novel therapeutic strategy.MethodsWe induced alectinib resistance in an LMC mouse model with ALK-rearranged NSCLC cell line, A925LPE3, by continuous oral alectinib treatment, established A925L/AR cells. Resistance mechanisms were analyzed using several assays, including Western blot and receptor tyrosine kinase array. We also measured amphiregulin (AREG) concentrations in cerebrospinal fluid from patients with ALK-rearranged NSCLC with alectinib-refractory LMC by enzyme-linked immunosorbent assay.ResultsA925L/AR cells were moderately resistant to various ALK TKIs, such as alectinib, crizotinib, ceritinib, and lorlatinib, compared with parental cells in vitro. A925L/AR cells acquired the resistance by EGFR activation resulting from AREG overexpression caused by decreased expression of microRNA-449a. EGFR TKIs and anti-EGFR antibody resensitized A925L/AR cells to alectinib in vitro. In the LMC model with A925L/AR cells, combined treatment with alectinib and EGFR TKIs, such as erlotinib and osimertinib, successfully controlled progression of LMC. Mass spectrometry imaging showed accumulation of the EGFR TKIs in the tumor lesions. Moreover, notably higher AREG levels were detected in cerebrospinal fluid of patients with alectinib-resistant ALK-rearranged NSCLC with LMC (n = 4), compared with patients with EGFR-mutated NSCLC with EGFR TKI–resistant LMC (n = 30), or patients without LMC (n = 24).ConclusionsThese findings indicate the potential of novel therapies targeting both ALK and EGFR for the treatment of ALK TKI–resistant LMC in ALK-rearranged NSCLC.     

Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer

Introduction

The multitargeted tyrosine kinase inhibitor (TKI) crizotinib is active against ALK translocated non-small-cell lung cancer (NSCLC); however acquired resistance invariably develops over time. ALK mutations have previously been implicated in only a third of resistant tumors. We sought to evaluate alternative mechanisms of resistance and preclinical strategies to overcome these in a cell line driven by EML4-ALK.

Methods

We selected the NSCLC cell line NCI-H3122 (H3122: EML4-ALK E13;A20) and derived resistant variants that were able to grow in the presence of 1 μM crizotinib. These were analyzed for ALK mutations, sensitivity to crizotinib in combination with other TKIs, and for activation of alternative tyrosine kinases.

Results

All H3122 crizotinib resistant (CR) clones lacked amplification or mutations in the kinase domain of ALK. To evaluate if possible alternative kinases functioned as “bypass” tracks for downstream signaling activation in these resistance cells, we performed of phosho-receptor tyrosine kinase array that demonstrated that CR clones had higher phospho-EGFR signals than H3122 cells before and after exposure to crizotinib. A functional approach of dual ALK TKI (with crizotinib) with combinatory TKI inhibition was used as a secondary screen for possible targets. Crizotinib + erlotinib (reversible EGFR TKI) and crizotinib + afatinib (irreversible EGFR/ERBB2 TKI) were able to inhibit the growth of H3122 CR clones, confirming EGFR activation as a mechanism of resistance. The removal of crizotinib from the culture media re-sensitized CR cells to crizotinib.

Conclusions

We identified activation of EGFR as a mechanism of resistance to crizotinib in preclinical models of ALK translocated NSCLC. If EGFR activation is confirmed as a predominant mechanism of ALK TKI-induced resistance in patient-derived tumors, the use of ALK plus EGFR TKIs could be explored for this important cohort of NSCLCs.     

Detection of ALK and KRAS Mutations in Circulating Tumor DNA of Patients With Advanced ALK-Positive NSCLC With Disease Progression During Crizotinib Treatment

BackgroundIn patients with anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC), disease progression occurs after a median of 9 to 10 months of crizotinib treatment. Several mechanisms of resistance have been identified and include ALK mutations and amplification or the activation of bypassing signaling pathways. Rebiopsy in NSCLC patients represents a critical issue and the analysis of circulating cell-free DNA (cfDNA) has a promising role for the identification of resistance mechanisms.Patients and MethodsTwenty patients with advanced ALK-positive NSCLC were enrolled after disease progression during crizotinib treatment; cfDNA was analyzed using digital droplet polymerase chain reaction (BioRad, Hercules, CA) for ALK (p.L1196M, p.G1269A, and p.F1174L) and Kirsten rat sarcoma (KRAS) (codons 12 and 13) mutations.ResultsALK secondary mutations (p.L1196M, p.G1269A, and p.F1174L) were identified in 5 patients; 1 patient had 2 ALK mutations (p.L1196M and p.G1269A). Overall, 10 patients presented KRAS mutations (7 p.G12D, 2 p.G12V, and 1 p.G12C mutations, respectively). In 3 patients KRAS mutations were associated with ALK mutations. cfDNA was monitored during the treatment with second-generation ALK inhibitors and the amount of ALK as well as KRAS mutations decreased along with tumor regression.ConclusionALK and KRAS mutations are associated with acquired resistance to crizotinib in ALK-positive NSCLC. In particular, ALK acquired mutations can be detected in plasma and could represent a promising tumor marker for response monitoring.