piperidines and alectinib

Immune checkpoint inhibitors (ICIs) have demonstrated marked efficacy in some cancer patients, but they may cause various severe immune-related adverse events. Alectinib is a second-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) approved for ALK-rearranged non-small-cell lung cancer (NSCLC). Alectinib is said to be safer than other TKIs. We conducted an investigator-initiated trial of alectinib, which also has RET kinase-inhibitory activity, against RET-rearranged NSCLC. Two RET-rearranged NSCLC patients experienced severe skin toxicity with alectinib after first undergoing anti-PD-1 antibody treatment with an ICI. These findings suggest that we should carefully follow patients for adverse effects of targeted drugs following ICI treatment.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Crizotinib and alectinib are the 2 most commonly used anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive non-small cell lung cancer (NSCLC). We compared their antitumor efficacies and adverse effects based on a pooled analysis of the ALEX, ALESIA, and J-ALEX clinical trials.. Seven databases were searched for eligible articles. The primary endpoints included overall survival (OS), progression-free survival (PFS), central nervous system (CNS)-PFS, drug responses, and adverse effects (AEs).. Seven articles on 3 randomized controlled clinical trials (ALEX, ALESIA, and J-ALEX) that included 697 patients were included. Compared with crizotinib, alectinib exhibited superior efficacy in PFS (HR [hazard ratio]: 0.35 [0.25-0.49], p < 0.00001), OS (HR: 0.66 [0.47-0.92], p = 0.02), CNS-PFS (HR: 0.17 [0.11-0.24], p < 0.00001), duration of response (HR: 0.31 [0.23-0.42], p < 0.00001), objective response rate (risk ratio [RR]: 0.87 [0.80-0.94], p = 0.0003), partial response (RR: 0.88 [0.81-0.96], p = 0.004), and grade 3-5 AEs (RR: 1.43 [1.09-1.87], p = 0.009). Additionally, compared with crizotinib, alectinib exhibited a survival advantage that increased with its prolongation of survival time. The disease control rate, complete response, and total AEs were comparable between the 2 groups. The crizotinib group reported higher rates of constipation, nausea, diarrhea, vomiting, peripheral edema, dysgeusia, visual impairment, and levels of alanine aminotransferase and aspartate aminotransferase as well as greater decreases in appetite and neutrophil count.. In both antitumor efficacy and safety, alectinib appears to be superior to crizotinib for the treatment of ALK-positive NSCLC.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic

Because of lacking of head-to-head comparison among lorlatinib, alectinib and brigatinib for patients with ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced non-small-cell lung cancer (NSCLC), the optimal option for these patients still remains undefined. We searched published reports that described the activity and safety of those novel ALK inhibitors (lorlatinib, alectinib and brigatinib) for ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. Five randomized controlled trials were identified, covering 1111 subjects. In the network meta-analysis, lorlatinib seemed to prolong progression free survival than brigatinib (Hazard Ratio: 0.57,

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lung Neoplasms; Network Meta-Analysis; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Lung cancer is a malignant tumor with high incidence rate and mortality rate in China and even the whole world, of which non-small cell lung cancer accounts for about 80%. Anaplastic lymphoma kinase (ALK) gene mutation accounts for about 5%. Alectinib, ALK-tyrosine kinase inhibitor (ALK-TKI), has great performance in clinical. The early detection and treatment of adverse drug reactions can greatly improve clinical benefits. This paper reports a patient of ALK positive non-small cell lung cancer was admited to Baotou Central Hospital in April 2020. The diagnosis and treatment was retrospectively analyzed, and the literature was reviewed.
.. 【中文题目：阿来替尼治疗ALK阳性非小细胞肺癌：
1例报告及文献复习】 【中文摘要：肺癌是我国乃至全球发病率及死亡率均较高的恶性肿瘤，其中非小细胞肺癌占80%左右，间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）基因突变的患者约占5%。ALK抑制剂阿来替尼的疗效优异，药物治疗不良反应的及时发现、及早治疗能极大地提高患者的临床获益。现报道包头市中心医院2020年4月收治的1例ALK阳性非小细胞肺癌的诊断、治疗及药物副反应处理，并文献复习。
】 【中文关键词：间变性淋巴瘤激酶；肺肿瘤；阿来替尼；不良反应】.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Piperidines; Pleural Neoplasms; Protein Kinase Inhibitors; Retrospective Studies; Tomography, X-Ray Computed

Anaplastic lymphoma kinase (ALK) fusion is a well-defined biomarker for ALK tyrosine kinase inhibitors (TKIs) treatment in non-small cell lung cancer (NSCLC). Alectinib, a second-generation ALK-TKI, has been shown to have significantly longer progression-free survival (PFS) than first-generation ALK inhibitors in untreated ALK-rearranged NSCLC patients. However, its clinical efficacy on rare ALK fusions remains unclear. Herein, two advanced NSCLC patients received first-line alectinib treatment, given their positive ALK fusion status as determined by immunohistochemistry (IHC) testing results. Patients showed limited clinical response (PFS: 4 months) and primary resistance to alectinib respectively. Molecular profiling using next-generation sequencing (NGS) further revealed a striatin (STRN)-ALK fusion in the first patient accompanied by MET amplification, and a LIM domain only protein 7 (LMO7)-ALK fusion in another patient without any other known oncogenic alterations. Both patients demonstrated improved survival after they switched to second-line crizotinib (PFS: 11 months) and ensartinib (PFS: 18 months), respectively, up till the last follow-up assessment. In conclusion, the clinical efficacy of ALK-TKIs including alectinib for lung cancer with uncommon ALK gene fusions is still under evaluation. This study and literature review results showed mixed responses to alectinib in NSCLC patients who harboured rare ALK fusions. Comprehensive molecular profiling of tumour is thus strongly warranted for precise treatment strategies.

Topics: Adult; Anaplastic Lymphoma Kinase; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Disease Management; Female; Genetic Testing; Humans; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Oncogene Proteins, Fusion; Piperidines; Prognosis; Protein Kinase Inhibitors; Tomography, X-Ray Computed; Treatment Outcome

The echinoderm microtubule-associated protein-like 4 gene (EML4) and anaplastic lymphoma kinase gene (ALK) fusion is the most common ALK rearrangements in non-small cell lung cancer (NSCLC). Herein, we firstly report that coexistence of a novel Neurobeachin (NBEA)-ALK, EML4-ALK double-fusion is sensitive to alectinib.. Hematoxylin-eosin staining (HE), fluorescent in situ hybridization (FISH), and next-generation sequencing (NGS) was performed on the biopsy sample.. The patient responded to alectinib as a second-line treatment and achieved stable disease for 11 months, without significant symptoms of toxicity. Significantly, the liquid biopsy also validated clinical benefit, with the disappearance of NBEA-ALK and EML4-ALK fusion variants. We also provided a comprehensive review of all 50 ALK fusion genes in NSCLC.. This is the first report on one patient with a novel NBEA-ALK, EML4-ALK double-ALK fusion beneficial from alectinib. Alectinib may be a viable therapeutic option for NSCLC patients with double-ALK fusion, and liquid biopsy could dynamically monitor clinical curative effect.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Carrier Proteins; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Nerve Tissue Proteins; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

Whereas there are many pharmacological interventions prescribed for patients with advanced anaplastic lymphoma kinase (ALK)- rearranged non-small cell lung cancer (NSCLC), comparative data between novel generation ALK-tyrosine kinase inhibitors (TKIs) remain scant. Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC.. We included all phase 2 and 3 randomised controlled trials (RCTs) comparing any two or three treatment options. Eligible studies reported at least one of the following outcomes: progression free survival (PFS), overall survival (OS), objective response rate (ORR), or adverse events of grade 3 or higher (Grade ≥ 3 AEs). Subgroup analysis was conducted according to central nervous system (CNS) metastases.. A total of 9 RCTs consisting of 2484 patients with 8 treatment options were included in the systematic review. Our analysis showed that alectinib (300 mg and 600 mg), brigatinib, lorlatinib and ensartinib yielded the most favorable PFS. Whereas there was no significant OS or ORR difference among the ALK-TKIs. According to Bayesian ranking profiles, lorlatinib, alectinib 600 mg and alectinib 300 mg had the best PFS (63.7%), OS (35.9%) and ORR (37%), respectively. On the other hand, ceritinib showed the highest rate of severe adverse events (60%).. Our analysis indicated that alectinib and lorlatinib might be associated with the best therapeutic efficacy in first-line treatment for major population of advanced NSCLC patients with ALK-rearrangement. However, since there is little comparative evidence on the treatment options, there is need for relative trials to fully determine the best treatment options as well as the rapidly evolving treatment landscape.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Gene Rearrangement; Humans; Lactams; Lung Neoplasms; Network Meta-Analysis; Organophosphorus Compounds; Piperazines; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Treatment Outcome

We aim to describe two cases of creatine phosphokinase (CPK) and liver enzymes elevation occurring as adverse effects of alectinib (Alecensa) treatment for anaplastic lymphoma kinase (ALK)-mutated metastatic nonsmall cell lung cancer (NSCLC). A 56-year-old female and a 59-year-old male diagnosed with NSCLC exhibiting ALK gene rearrangements were treated by alectinib administration. The former had a complete response of widespread metastatic disease within 3 months, and the latter also had a substantial response. Both patients initially experienced an episode of CPK elevation and neither had dose modifications. At the end of the treatment, CPK and liver enzymes returned to normal range despite the continuation of alectinib full dose. A transient elevation of CPK and liver enzymes may take place during the alectinib treatment, indicating a tumor tissue damage thus contributing to a significant response.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Creatine Kinase; Female; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Predictive Value of Tests; Protein Kinase Inhibitors

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Management; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mutation; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Actionable mutations are tested as standard of care for all new metastatic non-small cell lung cancers. Tumors harboring an anaplastic lymphoma kinase mutation respond to tyrosine kinase inhibitors targeting anaplastic lymphoma kinase pathway. Patients are monitored for common adverse effects, although we occasionally encounter unexpected side effects.. Prior to starting alectinib, our patient's triglyceride level was 420 mg/dL. While he consumed alcohol, he had no other traditional risk factor. To our knowledge, this is the first reported case of hypertriglyceridemia-induced acute pancreatitis related to treatment with an anaplastic lymphoma kinase inhibitor.

Topics: Acute Disease; Adenocarcinoma; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biopsy; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Hypertriglyceridemia; Lung Neoplasms; Male; Middle Aged; Pancreatitis; Piperidines; Protein Kinase Inhibitors

The treatment of patients with advanced non-small cell lung cancer with anaplastic lymphoma kinase chromosomal rearrangements has been revolutionized by the development of tyrosine kinase inhibitors (TKIs). Excellent progress has been made over the past decade, with 4 TKIs now approved in the front-line setting. Alectinib is the preferred first-line option based on its efficacy and side-effect profile. The central nervous system (CNS) activity of alectinib and brigatinib has allowed for treatment of CNS metastases with TKI therapy. Once resistance inevitably develops, newer therapies such as lorlatinib can be considered.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Pharmacogenomic Testing; Piperidines; Protein Kinase Inhibitors

Lung cancer is the most common malignant tumor, and it remains the major cause of cancerrelated death worldwide. Anaplastic lymphoma kinase fusion gene-rearrangement (ALK-positive) nonsmall cell lung cancer (NSCLC) is a unique subgroup that accounts for 3-7% of NSCLC cases. Over the last few years, the introduction of several ALK inhibitors has completely altered the treatment of advanced ALK-positive NSCLC and significantly improved the prognosis for patients. Crizotinib was the first ALK inhibitor developed, and it has demonstrated systemic efficacy and strongly improved outcomes in NSCLC patients with ALK-positive when compared with chemotherapy. Alectinib was designed specifically to be a more potent and selective anti-ALK therapeutic agent that could bypass crizotinib resistance. This study aims to evaluate the different efficacies of alectinib and crizotinib on progression-free survival (PFS), central nervous system (CNS) progression and adverse events (AEs) in NSCLC patients with ALK-positive.. We searched for relevant literature in four electronic databases: PubMed, EMBASE, Cochrane Library, and Web of Science. The hazard ratio (HR) was calculated, and the effect of alectinib and crizotinib on PFS was evaluated. The quality of the studies was assessed using the Cochrane Risk of Bias tool. Publication bias was assessed using the Begg rank correlation test and the Egger weighted linear regression test. We performed the sensitivity analysis using the method of "removing one study". All analyses were performed in STATA.. Ten studies were included, and the total sample size was 2,377. Alectinib showed significant PFS superiority over crizotinib. The pooled HR =0.41 (95% CI: 0.29-0.53) indicated that the alectinib therapy group did have significantly longer PFS than that of the crizotinib group. Based on 5 clinical trials, the cumulative incidence of CNS progression for patients treated with alectinib at 6 months (10%, 95% CI: 5-16%) and 12 months (16%, 95% CI: 9-24%) was calculated. Based on 7 clinical studies, the risk of AEs related to treatment with alectinib was determined: alectinib was associated with 28 cases of AE grade ≤2 and 9 cases of AE grade ≥3; among the top 4 incidences of AE grade ≥3, were blood creatine phosphokinase increased 5.6%, ALT increased 2.5%, AST increased 2.4% and Anemia 1.8%.. Alectinib significantly prolongs PFS and it better controls CNS metastases than crizotinib and good toxicity characteristics in the first-line treatment of NSCLC patients with ALK-positive.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System; Crizotinib; Humans; Lung Neoplasms; Piperidines; Progression-Free Survival

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Oncogene Proteins, Fusion; Piperidines; Prognosis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus-host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown.. We systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student's. As far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV.. May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, The Hong Kong Hainan Commercial Association South China Microbiology Research Fund, The Jessie & George Ho Charitable Foundation, Perfect Shape Medical, The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, The Theme-Based Research Scheme of the Research Grants Council, Sanming Project of Medicine in Shenzhen, and The High Level-Hospital Program, Health Commission of Guangdong Province, China.. Lower levels of total T3 were strongly correlated with in-hospital mortality in patients with SCMP. A low T3 level might suggest poor prognosis in patients with SCMP.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antibodies, Bacterial; Anxiety Disorders; Arecaceae; Arrhythmias, Cardiac; Autonomic Nervous System; Bacterial Proteins; Behavior Therapy; Burkholderia pseudomallei; Caco-2 Cells; Campylobacter; Campylobacter Infections; Carbazoles; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Chickens; Computer Simulation; Coumarins; COVID-19; Cross-Sectional Studies; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Diabetes Mellitus, Type 1; Diarrhea; Dietary Supplements; Echocardiography; Educational Measurement; Electrocardiography, Ambulatory; Endoribonucleases; Exercise; Exercise Therapy; Faculty, Dental; Farms; Fear; Female; Flame Retardants; Florida; Gene Expression Regulation, Plant; Halogenated Diphenyl Ethers; Hearing Loss, Sudden; Heart Rate; HIV Infections; Hospital Mortality; Humans; Hypertension; Hypoglycemia; Immunity; In Situ Hybridization; Japan; Kinetics; Kuwait; Lung Neoplasms; Macaca mulatta; Macrophages; Male; Masked Hypertension; Melioidosis; Methyltransferases; Mice; Mice, Inbred BALB C; Middle Aged; Molecular Docking Simulation; Molecular Dynamics Simulation; Myocardium; Oryza; Patient Education as Topic; Peptide Hydrolases; Phosphoric Monoester Hydrolases; Piperidines; Plant Extracts; Plant Proteins; Platelet Count; Poultry Diseases; Prevalence; Protease Inhibitors; Protein Kinase Inhibitors; Protein Kinases; Rabbits; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Resistance Training; Retrospective Studies; Risk Factors; SARS-CoV-2; Saudi Arabia; Severe acute respiratory syndrome-related coronavirus; Students; Substance-Related Disorders; Surveys and Questionnaires; Swine; Tachycardia, Ventricular; Takotsubo Cardiomyopathy; Thyroid Gland; Transcriptome; Transfection; Tropism; United Arab Emirates; Virulence; Virulence Factors; Writing

The identification of anaplastic lymphoma kinase rearrangements in 2-5% of patients with non-small-cell lung cancer led to rapid advances in the clinical development of oral tyrosine kinase inhibitors. Anaplastic lymphoma kinase inhibitors are an effective treatment in preclinical models and patients with anaplastic lymphoma kinase-translocated cancers. Four anaplastic lymphoma kinase inhibitors (crizotinib, ceritinib, alectinib, and brigatinib) have recently been approved. Post-marketing studies provided additional pharmacokinetic information on their pharmacokinetic parameters. The pharmacokinetic properties of approved anaplastic lymphoma kinase inhibitors have been reviewed herein. Findings from additional studies on the effects of drug-metabolizing enzymes, drug transporters, and drug-drug interactions have been incorporated. Crizotinib, ceritinib, and alectinib reach their maximum plasma concentrations after approximately 6 h and brigatinib after 1-4 h. These drugs are primarily metabolized by cytochrome P450 3A with other cytochrome P450 enzymes. They are mainly excreted in the feces, with only a minor fraction being eliminated in urine. Crizotinib, ceritinib, and brigatinib are substrates for the adenosine triphosphate binding-cassette transporter B1, whereas alectinib is not. The different substrate specificities of the transporters play a key role in superior blood-brain barrier penetration by alectinib than by crizotinib and ceritinib. Although the absorption, distribution, and excretion of anaplastic lymphoma kinase inhibitors are regulated by drug transporters, their transporter-mediated pharmacokinetics have not yet been elucidated in detail in patients with non-small-cell lung cancer. Further research to analyze the contribution of drug transporters to the pharmacokinetics of anaplastic lymphoma kinase inhibitors in patients with non-small-cell lung cancer will be helpful for understanding the mechanisms of the inter-individual differences in the pharmacokinetics of anaplastic lymphoma kinase inhibitors.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Interactions; Humans; Lung Neoplasms; Membrane Transport Proteins; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Activation of the anaplastic lymphoma kinase (ALK) gene has been found in several human cancers, including non-small-cell lung cancer (NSCLC). Currently, novel drugs targeting ALK gene have been extensively investigated in NSCLC. However, concerns about ALK inhibitors-induced liver toxicities have been increasing.. Eligible prospective clinical studies have been searched in several databases. Primary outcomes of interest were incidence rates of liver toxicities, relative risks (RRs), and 95% confidence intervals (CIs).. Data from 2418 patients (1873 in the experimental arm; 545 in the control arm) were included. The incidences of all-grade alanine transaminase (ALT) and aspartate aminotransferase (AST) elevation were 26.0% (95% CI: 17.4%-37%), and 23.2% (95% CI, 16.7%-31.4%), respectively. The incidences of high-grade ALT and AST elevation were 8.4% (95% CI, 5.1%-13.4% and 7.0% (95% CI: 5.4%-9.0%), respectively. Sub-group analysis according to the ALK inhibitors found that pooled incidence of liver toxicities associated with ceritinib was higher than that of crizotinib and alectinib. In comparison with chemotherapy, ALK inhibitors significantly increased the all-grade and high-grade ALT elevation (RR 2.37, 95% CI, 1.97-2.86; P < .001; RR 7.34, 95% CI, 3.95-13.63; P < .001) and AST elevation (RR 3.27, 95% CI, 2.47-4.34; P < .001; RR 11.54, 95% CI, 4.33-30.7; P < .001), respectively. No publication bias was detected for RR of ALT and AST.. The findings of the present study offer substantial evidence that ALK inhibitors treatment in advanced NSCLC significantly increases the risk of developing all-grade and high-grade liver toxicities in comparison with controls. Clinicians should recognize liver toxicities promptly as early interventions may alleviate future complications.

Topics: Alanine Transaminase; Anaplastic Lymphoma Kinase; Aspartate Aminotransferases; Carbazoles; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Crizotinib; Female; Humans; Incidence; Liver; Lung Neoplasms; Male; Middle Aged; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Pyrimidines; Risk Factors; Sulfones

Topics: Carbazoles; Dose-Response Relationship, Drug; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and extend the survival benefit with crizotinib. The role of whole brain irradiation in the treatment of brain metastases diminishes, as this technique is associated with the risk of neurocognitive decline. Stereotactic radiotherapy represents an alternative technique that delivers ablative doses of ionizing radiation to the limited volume of oligometastatic brain disease, offering sparing of the adjacent brain parenchyma and reduced neurotoxicity. The next generation ALK inhibitors were designed to cross the blood-brain barrier more efficiently than crizotinib and achieve higher concentration in the cerebrospinal fluid, offering prominent ability to control central nervous system spread. In the phase III ALEX trial the intracranial control was significantly better with alectinib as compared to crizotinib and it translated into survival benefit. Other next generation ALK inhibitors (i.e. ceritinib, brigatinib, lorlatinib) also demonstrated promising activity in the central nervous system.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Cranial Irradiation; Crizotinib; Disease Management; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Meningeal Neoplasms; Mice; Molecular Targeted Therapy; Neoplasm Proteins; Neurocognitive Disorders; Observational Studies as Topic; Oncogene Proteins, Fusion; Pemetrexed; Piperidines; Protein Kinase Inhibitors; Radiosurgery

Topics: Acrylamides; Aniline Compounds; Antibodies, Monoclonal; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Immunotherapy; Molecular Targeted Therapy; Nivolumab; Piperazines; Piperidines; Progression-Free Survival

Anaplastic lymphoma kinase (ALK) gene activation is involved in the carcinogenesis process of several human cancers such as anaplastic large cell lymphoma, lung cancer, inflammatory myofibroblastic tumors and neuroblastoma, as a consequence of fusion with other oncogenes (NPM, EML4, TIM, etc) or gene amplification, mutation or protein overexpression. ALK is a transmembrane tyrosine kinase receptor that, upon ligand binding to its extracellular domain, undergoes dimerization and subsequent autophosphorylation of the intracellular kinase domain. When activated in cancer it represents a target for specific inhibitors, such as crizotinib, ceritinib, alectinib etc. which use has demonstrated significant effectiveness in ALK-positive patients, in particular ALK-positive non- small cell lung cancer. Several mechanisms of resistance to these inhibitors have been described and new strategies are underway to overcome the limitations of current ALK inhibitors.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Sulfones

The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosage and administration, and place in therapy of alectinib for treatment of patients with non-small-cell lung cancer (NSCLC) are reviewed.. In patients with NSCLC driven by mutations of. Alectinib appears to be effective and safe for use in patients with metastatic

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors

Despite significant advancements in the treatment of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) since the advent of crizotinib, the development of acquired resistance and poor CNS efficacy have necessitated the search for novel and more robust therapies. Ensartinib (X-396) is a novel second-generation ALK-tyrosine kinase inhibitor (TKI) that holds much clinical promise. Preclinical data have demonstrated increased potency of the drug as compared with crizotinib and other second-generation ALK-TKI therapies such as alectinib and ceritinib. This review highlights the first- and second-generation ALK inhibitors approved for the treatment of ALK-positive NSCLC and discusses the clinical trial protocol for the eXalt3 trial (NCT02767804) comparing the efficacy and safety of ensartinib to crizotinib in patients diagnosed with ALK-positive NSCLC who are naive to prior ALK-TKI treatment.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Piperazines; Piperidines; Protein Kinase Inhibitors; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Research Design; Sulfones; Treatment Outcome

Anaplastic lymphoma kinase (ALK) gene rearrangements as driver genetic alterations occur in approximately 2-4% of non-small-cell lung cancer (NSCLC) patients. Alectinib, a next generation ALK inhibitor, recently demonstrated, in two separate Phase III trials, superior efficacy to crizotinib, the first ALK inhibitor to demonstrate clinical efficacy in ALK-positive NSCLC patients. Alectinib also demonstrated superior efficacy in the CNS. The data from these two Phase III studies suggest that the efficacy of starting with alectinib is superior to the overall clinical efficacy of starting with crizotinib followed by switching to alectinib at the time of disease progression. These results have changed the standard of care to alectinib as front-line therapy for advanced ALK-positive NSCLC patients. Areas covered: this paper reviews the available data on alectinib as front-line therapy in patients with ALK-positive NSCLC patients including its activity against brain metastases. In addition, the paper will review the data with other ALK inhibitors as front-line therapy.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Survival Rate; Treatment Outcome

Alectinib (Alecensa

Topics: Administration, Oral; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Approval; Drug Resistance, Neoplasm; Europe; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Treatment Outcome

Anaplastic lymphoma kinase (ALK) rearrangements were first implicated as driving mutations in non-small cell lung cancer in 2007. Since then, a number of novel, small-molecule inhibitors directed against the ALK receptor have demonstrated superiority over standard chemotherapies in the treatment of ALK rearrangement-positive lung cancer. Of considerable importance when considering such therapies is the ability of each to overcome mutations conferring acquired resistance, as well as penetrate the central nervous system (CNS), the most common site of metastasis and traditionally the most difficult to breach. Herein is a review of the efficacy, indications, and degree of CNS penetration for the ALK-targeting agents crizotinib, ceretinib, alectinib, brigatinib, and lorlatinib, as well as a summary of ongoing clinical trials comparing these drugs.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Crizotinib; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Organophosphorus Compounds; Piperidines; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Small Molecule Libraries

Lung cancer is among the top causes of cancer-related mortality in men and is the second most common cancer after breast cancer in women. There are approximately 234,030 new cases of lung cancer and 154,050 deaths from lung cancer in 2018 as per the latest American Cancer Society's report. Alectinib, a more potent orally active tyrosine kinase inhibitor which was approved by the US Food & Drug Administration for anaplastic lymphoma kinase-positive lung adenocarcinoma, has been shown to have a reasonable safety profile when compared with other anaplastic lymphoma kinase-targeted therapy. As per research studies, grade 1 or 2 renal impairment has been reported but grade 4 renal toxicity due to alectinib has not been reported so far. We report a case of acute renal failure caused by alectinib which necessitated emergency dialysis. This is the first case report describing the severe renal toxicity of alectinib.. We describe a case of 72-year-old Taiwanese man diagnosed with stage IV anaplastic lymphoma kinase-positive adenocarcinoma of the lung initially treated with crizotinib for over a year, which was switched to alectinib due to disease progression with brain metastasis. Within 6 weeks of starting alectinib, he developed acute renal failure needing emergency dialysis support. His renal failure was secondary to acute tubular necrosis and had a complete reversal within 7-10 days on withdrawing the medication. When he was re-challenged with alectinib, his creatinine started to worsen again which confirmed the renal toxicity of alectinib.. This case emphasizes the uncommon adverse effect of the anaplastic lymphoma kinase-targeted therapy alectinib causing acute renal failure manifesting as acute tubular necrosis. Recognition of alectinib nephropathy requires a thorough drug history and knowledge of risk factors that lessen its margin of safety at therapeutic ingestions. Frequent monitoring of renal functions and early nephrology referral significantly reduce the mortality and morbidity of these patients.

Topics: Acute Kidney Injury; Adenocarcinoma; Aged; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Piperidines

The discovery of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved-ceritinib and alectinib-and others that are in development-brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms. Ceritinib gained US Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK-positive (ALK+) metastatic NSCLC who have progressed on or are intolerant to crizotinib. In pre-clinical studies, it demonstrated more potent inhibition of ALK than crizotinib in enzymatic assays, more durable responses in xenograft models and the ability to potently overcome crizotinib resistance mutations in vitro (including the gatekeeper mutation). There is also evidence for ceritinib penetration across the blood-brain barrier. In clinical trials, ceritinib has demonstrated durable responses and progression-free survival in ALK-inhibitor-pre-treated and -naïve NSCLC patients, including high overall and intracranial response rates in those with central nervous system metastases. Selective gastrointestinal toxicity of ceritinib, such as diarrhea, nausea and vomiting is generally manageable with prophylactic medication and prompt dose reduction or interruption. Future progress in treating ALK+ NSCLC will focus on determining the optimal sequencing of therapies and strategies to overcome acquired resistance, an ongoing challenge in treating ALK-mutation-driven tumors.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Pyrazoles; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

The anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have been administered to patients with ALK-positive non-small cell lung cancer for a long period of time and show a promising response. However, the differences in the toxicity profiles among these drugs are still unclear.. We performed a comprehensive search of the MEDLINE, EMBASE, WEB OF SCIENCE and COCHRANE databases from the drugs' inception to May 2016 to identify clinical trials. Severe adverse events (AEs) (grade ≥ 3) based on the ALK-TKI type were analysed.. Seventeen trials published between 2011 and 2016, including a total of 1826 patients, were eligible for analysis. Patients in 10 trials (n = 1000) received crizotinib, patients in 5 trials (n = 601) received ceritinib and patients in 2 trials (n = 225) received alectinib. The overall frequencies of treatment-related death and AEs due to treatment withdrawal were 0.9% (12/1365) and 5.5% (85/1543), respectively. Moreover, the frequency of severe AEs in patients treated with ceritinib was significantly higher than patients treated with crizotinib or alectinib, especially for hepatotoxicity, fatigue and some of gastrointestinal symptoms. Additionally, significant difference in the elevated lipase and amylase levels (grade ≥ 3) were detected between ceritinib and crizotinib/alectinib, whereas neutropenia was less frequent.. ALK-TKIs were safe for ALK-positive patients. Moreover, statistically significant differences in some severe AEs among ceritinib, crizotinib and alectinib were detected in present study.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Crizotinib; Female; Humans; Lung Neoplasms; Male; Patient Safety; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Although anaplastic lymphoma kinase (ALK) fusion genes are generally identified in lung adenocarcinoma patients, they are relatively rare in patients with squamous cell carcinoma (SqCC). Metastatic ALK-rearranged lung adenocarcinoma patients treated with ALK inhibitors demonstrate higher response rates, improved progression-free survival, and reduced toxicity relative to those treated with conventional chemotherapy regimens. However, the efficacy of treatment with ALK inhibitors in patients with ALK-rearranged lung SqCC remains unknown.. We discuss a 52-year-old Japanese-Brazilian woman without a history of smoking who was referred to our hospital for evaluation of severe left back pain and a left hilar mass observed on a chest radiograph. The patient was eventually diagnosed on the basis of computed tomography, pathological, and immunohistochemical findings as having Stage IV lung SqCC. First-line treatment with palliative radiotherapy and systemic chemotherapy with cisplatin plus vinorelbine was administered, but was not effective. ALK testing was subsequently performed, revealing positive ALK expression and gene rearrangement. Alectinib therapy was then initiated, which resulted in a gradual, but substantial reduction in tumor size.. To the best of our knowledge, this is the first case report to discuss the successful management of ALK-rearranged lung SqCC with alectinib. We propose that molecular testing for driver mutations should be considered in young patients with a light or no smoking history, even if the histological findings correspond with SqCC, and alectinib therapy represents a reasonable option in cases of ALK-rearranged lung SqCC.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biopsy; Carbazoles; Carcinoma, Squamous Cell; Female; Gene Rearrangement; Humans; Immunohistochemistry; Lung Neoplasms; Middle Aged; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Tomography, X-Ray Computed; Translocation, Genetic; Treatment Outcome

ALK translocation is the 3rd most frequent genetic aberration in lung adenocarcinoma, and several inhibitors are now clinically available in first and second line settings. Accordingly, molecular diagnostics of ALK-positive lung cancer is very important and can be done with the rational combination of several methods. All international recommendations suggest that, except for cytological samples, screening technology for ALK-positive tumors is immunohistochemistry using a validated test. It is highly recommended that in case of ALK protein positive samples gene translocation must be confirmed by fluorescent in situ hybridization (FISH). In case of cytological samples FISH technique must be used as ALK diagnostics. In equivocal cases the genetic alteration of ALK can be confirmed by alternative molecular techniques such as next generation sequencing or RNAbased PCR methods. Upon administration of ALK inhibitors, acquired resistance is frequent which is mostly due to ALK amplification and/or mutation. It is evident that the diagnostics of these secondary ALK gene alterations must be done from recurrent tumors or circulating nucleic acids.. Az ALK gén transzlokációja a harmadik leggyakoribb, terápiás szempontból hasznosítható genetikai eltérés a tüdõ adenokarcinómáiban, és manapság már elsõ- és másodvonalú terápiákban több inhibitor áll rendelkezésre. Ezen okoknál fogva nagy jelentõsége van az ALK-pozitív tüdõrák molekuláris diagnosztikájának, amit több módszer racionális kombinációjával lehet végezni. A nemzetközi ajánlások megegyeznek abban, hogy a citológiai minták kivételével más típusú formalinfixált, paraffinos anyagok esetében az ALK-pozitív esetek szûrése a protein kimutatásának validált immunhisztokémiai módszerével történik. Az ALK proteinre pozitív esetekben a géntranszlokáció jelenlétét fluoreszcens in situ hibridizációval (FISH) célszerû megerõsíteni. Citológiai minták esetében az ALK gén transzlokációját elsõdlegesen FISH-módszerrel kell végezni. A kérdéses eredményû esetekben a genetikai eltérés tisztázására újgenerációs szekvenálást vagy RNS-alapú PCR-technikákat lehet alkalmazni. Az ALK-inhibitorok klinikai alkalmazása során gyakran alakul ki rezisztencia, aminek leggyakoribb oka az ALK gén amplifikációja és/vagy mutációi. Ezek molekuláris diagnosztikájának alapja a recidív daganatszövet vagy a vérben keringõ nukleinsav kell, hogy legyen.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Biopsy, Needle; Carbazoles; Crizotinib; Early Detection of Cancer; Gene Expression Regulation, Neoplastic; Humans; Hungary; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Molecular Targeted Therapy; Piperidines; Polymerase Chain Reaction; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Risk Assessment; Sulfones; Survival Analysis; Translocation, Genetic; Treatment Outcome

Alectinib is a highly selective second-generation ALK inhibitor that is active against most crizotinib ALK resistance mutations, with a good penetration in CNS and a good safety profile. Thanks to the positive results of Phase II trials, alectinib was approved in Japan and by the US FDA for ALK-positive non-small-cell lung cancer (NSCLC) patients pretreated with crizotinib. Recently, the Phase III J-ALEX study demonstrated superiority of alectinib over crizotinib in crizotinib naive ALK-positive NSCLC, with an impressive improvement of progression-free survival. From the results and those expected of Phase III ALEX study, alectinib might become the frontline treatment of ALK-positive NSCLC. This article summarizes the therapeutic options in ALK-positive advanced NSCLC, and the chemical, pharmacodynamics, pharmacokinetics, metabolism and clinical efficacy of alectinib.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Discovery; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Signal Transduction; Treatment Outcome

Anaplastic lymphoma kinase (ALK) gene rearrangements occur in a small portion of patients with non-small cell lung cancer (NSCLC). These gene rearrangements lead to constitutive activation of the ALK kinase and subsequent ALK-driven tumor formation. Patients with tumors harboring such rearrangements are highly sensitive to ALK inhibitors, such as crizotinib, ceritinib, and alectinib. Resistance to these kinase inhibitors occurs through several mechanisms, resulting in ongoing clinical challenges. This review summarizes the biology of ALK-positive lung cancer, methods for diagnosing ALK-positive NSCLC, current FDA-approved ALK inhibitors, mechanisms of resistance to ALK inhibition, and potential strategies to combat resistance.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Gene Rearrangement; Humans; Lung Neoplasms; Neoplasm Proteins; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) may derive significant clinical benefit from targeted therapies against this driver mutation, but progression is virtually inevitable. Alectinib is a next-generation ALK inhibitor that provides a novel treatment option for this group of patients. Areas covered: In this review, we summarize the overall safety and tolerability of alectinib. Specifically, we cover cardiovascular, gastrointestinal, hepatic, musculoskeletal, and respiratory adverse events. The safety profile of alectinib is also described in special populations and in comparison with other ALK inhibitors. Expert opinion: Alectinib is a well-tolerated tyrosine kinase inhibitor and should be considered for patients with ALK-rearranged NSCLC. The question then arises as to how to choose a next-generation ALK inhibitor in the second-line setting. Understanding acquired resistant mechanisms has become essential. Whether or not to use alectinib in the first-line setting is extremely controversial, but we anticipate its approval for this indication and availability in more countries in the near future.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Disease Progression; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Crizotinib is an anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) that represents the standard first-line treatment of patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer (NSCLC). In this setting, crizotinib has demonstrated a response rate of roughly 75% and a median progression-free survival just under one year. However, acquired resistance will emerge in virtually all crizotinib-treated patients, whose management may require a diversified approach according to the pace of the disease and/or the site(s) of disease progression. Crizotinib beyond disease progression is an option in patients with oligoprogressive disease, especially in presence of isolated central nervous system (CNS) relapse, provided that local ablative therapy (mainly radiotherapy) to the brain is administered. On the other hand, novel more potent and highly selective ALK-TKIs with demonstrated anti-tumor activity (CNS included) in crizotinib-refractory patients have been made available in recent years. Therefore, clinicians may well consider switching to a second-generation ALK-TKI as treatment option in case of progression on crizotinib. Therapeutic chances are more limited for patients who progress after crizotinib and a second-generation ALK-TKI, for whom both a third-generation ALK-TKI or pemetrexed-based chemotherapy could prove beneficial, while evidence in support of the use of immunotherapy in patients pretreated with ≥1 ALK-TKI is lacking.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Immunotherapy; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Prevalence; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Crizotinib as the first-generation ALK inhibitor has shown significant activity in ALK-mutated non-small cell lung cancer (NSCLC). Second- and third-generation ALK inhibitors are entering clinical applications for ALK+ NSCLC. In addition, a third-generation ALK inhibitor, lorlatinib (PF-06463922), was reported to resensitize NSCLC to crizotinib. This review provided a summary of clinical development of alectinib, ceritinib, brigatinib (AP26113), and lorlatinib.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Kaplan-Meier Estimate; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

: The advent of crizotinib, the first small molecule inhibitor against anaplastic lymphoma kinase (ALK), has led to impressive advances in the care of patients with advanced ALK-rearranged non-small cell lung cancer. The development of second-generation ALK inhibitors, starting with the recent U.S. Food and Drug Administration approval of ceritinib, promises to expand the therapeutic landscape for this cohort of patients. With increasing use of molecularly targeted therapy options, it has been observed that disease progression in patients receiving targeted agents has a heterogeneous biology, manifesting as either oligoprogressive or widely progressive disease, which may require development of innovative treatment strategies. This review discusses the first- and second-generation ALK inhibitors approved or in clinical development, as well as the novel challenges and approaches to disease progression in patients on targeted agents.. The identification of driver mutations in non-small cell lung cancer (NSCLC), most prominently epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), has expanded treatment options for a significant cohort of patients. However, the success of targeted agents has brought new challenges, particularly regarding management of progression. Progression manifests heterogeneously, and management of oligoprogression may differ from diffusely progressive disease. Multiple options for treatment at progression exist, and it is becoming evident that selecting the best avenue of care requires understanding the biology and potential drivers of disease progression. This review discusses the array of treatment options available for patients with ALK-positive NSCLC, as well as evaluation and treatment of progressive disease.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; Humans; Lung Neoplasms; Piperidines; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Secondary anaplastic lymphoma kinase (ALK) mutation may occur in patients with advanced ALK-positive non-small cell lung cancer treated with ALK inhibitors, but its nature is not well-known.. We analyzed tumor specimens after the failure of treatment with ALK inhibitor(s) (crizotinib, alectinib, and ceritinib) for secondary ALK kinase domain mutation, EGFR, K-ras, and PIK3CA mutations. The literature regarding acquired ALK-inhibitor(s) resistance was also reviewed.. Among 59 patients who received ALK inhibitor(s) during the period of December 2010 to April 2015, 7 had re-biopsied tumor specimens for analyses following ALK inhibitor(s) failure. One had G1202R after crizotinib and alectinib failure, and 6 were wild type. No EGFR, K-ras, or PIK3CA mutations were found. In our review of the literature and taken together with our patients, 25 of the 88 (28%) patients with crizotinib failure had secondary ALK mutation; L1196M mutation was most common (n = 11). Patients with secondary ALK mutation other than L1196M had a longer progression-free survival after crizotinib than patients with L1196M (median, 12.0 vs. 7.0 months; P = .04). Of the 9 patients with alectinib failure, 5 had I1171 mutation and 2 had G1202R. Of the 11 patients with ceritinib failure, 2 had G1202R, 1 had F1174C, and 1 had both G1202R and F1174V. I1171 mutation, G1202R, and F1174 mutations were also found in crizotinib-failed patients.. Some acquired ALK mutations may cause co-resistance to other ALK inhibitors. Re-biopsy for ALK mutation analysis might be suggested prior to choosing a second-line ALK inhibitor treatment.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Failure

Anaplastic lymphoma kinase (ALK) rearrangements are present in about 5% of advanced non-small-cell lung cancer (NSCLC) patients. Despite the initial response, after a median of 1-2 years, ALK-positive patients developed an acquired resistance to the ALK-inhibitor crizotinib. Among the most promising second-generation ALK-inhibitors, alectinib is being investigated in crizotinib-naïve and -resistant ALK-positive NSCLC patients.. The current state-of-the-art of ALK-inhibitors treatment, and in particular the role of alectinib in this setting, is reviewed and discussed. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken. Expert commentary: Alectinib reports promising results with a good safety profile, becoming a potentially very important option for ALK-translocated NSCLC patients. The preliminary results from the J-ALEX phase III randomized trial performed in ALK-rearranged NSCLC Japanese patients showed a better activity and tolerability of alectinib versus crizotinib.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases

The treatment of patients with ALK-rearranged non-small-cell lung cancer was completely revolutionized by the introduction of Crizotinib, a small molecule inhibiting ALK, MET and ROS1. Given that resistance occurs within approximately 12 months, in order to develop more potent inhibitors and to increase drug penetration to CNS, innovative ALK-inhibitors were developed. Second-generation ALK inhibitors Ceritinib (LDK378), Alectinib (CH5424802/RO5424802) and Brigatinib (AP26113) have shown significant clinical activity, and were rapidly approved by regulatory agencies. In addition, early clinical data demonstrated that 3

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Piperidines; Precision Medicine; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

The identification of anaplastic lymphoma kinase (ALK) gene rearrangements in subsets of non-small cell lung cancer patients has provided with unparalleled opportunities to hinder the progression of this disease through targeting the activity of these specific molecules. Unfortunately most patients develop disease progression in less than a year of treatment with crizotinib, the first-generation ALK-inhibitor. Areas covered: We review the resistance mechanisms to ALK inhibitors as well as an overview of the clinical activity of the alectinib, a second generation ALK inhibitor. Expert commentary: Second generation ALK inhibitors as alectinib and ceritinib can overcome crizotinib-resistant mutations and improve central nervous system control. Novel third-generation inhibitors and combination of agents give hope of achieving an even longer disease control in the next decade.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Carcinoma, Non-Small-Cell Lung; Disease Progression; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Alectinib (Alecensa(®)) is a second-generation, orally active, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK). Alectinib is approved for the treatment of ALK fusion-gene positive, unresectable, advanced or recurrent non-small cell lung cancer (NSCLC) in Japan, where it has been given orphan drug designation. Approval was based on a phase 1-2 study in ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC who received twice-daily alectinib 300 mg. In the phase 2 portion, 93.5 % of patients achieved an objective response. Treatment response was rapid, with a partial response achieved in two-thirds of patients within 3 weeks (cycle 1). Patient follow-up is ongoing, and after approximately 2 years, 19.6 % of patients had achieved a complete response, and the 2-year progression-free survival rate is 76 %. During treatment with alectinib (median follow-up approximately 8 months), there was no progression of CNS lesions among patients with known CNS metastases at baseline (although prior radiation therapy may have confounded results). In preclinical models, alectinib was active against most ALK fusion-gene mutations related to crizotinib resistance, and preliminary results from clinical trials indicate efficacy in crizotinib-refractory NSCLC. Alectinib was generally well tolerated in clinical trials, and there were no treatment-related grade 4 adverse events or deaths. The most common grade 3 treatment-related adverse events were decreased neutrophil counts and increased creatinine phosphokinase. While more data are needed to confirm the efficacy of alectinib and to evaluate its activity in crizotinib-resistant disease, the drug provides a very promising option for the treatment of ALK-rearranged advanced NSCLC.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines; Receptor Protein-Tyrosine Kinases

The identification of the EML4-ALK rearrangement in 5% of NSCLC enhanced the development of 1st generation ALK inhibitors such as crizotinib. Two phase III trials demonstrated crizotinib efficacy in second line metastatic (PROFILE 1007) and more recently first line metastatic (PROFILE 1014) NSCLC in terms of progression-free survival and also objective response. However, within 12 to 16 months, patients will progress due to the emergence of acquired resistance mechanisms such as mutation (L1196M) or amplification of the ALK gene, as well as activation of alternative signaling pathways (EGFR, KRAS). Second generation ALK inhibitors have been developed such as ceritinib, alectinib, and AP26113. This review will present those new drugs, summarize the results of their ongoing trials, and discuss the best way to treat ALK+ NSCLC patients.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Our increased understanding of the molecular subsets of non-small cell lung cancer (NSCLC) has led to the development of highly effective targeted therapies. In particular, the outcomes of patients with advanced NSCLC driven by the EML4-ALK fusion protein, which comprise 3-5% of cases, have remarkably improved with the use of crizotinib, an oral multi-tyrosine kinase inhibitor that targets ALK. However, patients inevitably develop progression while on crizotinib due to various mechanisms of resistance. Alectinib is a novel oral small molecule that inhibits ALK with high potency and selectivity, and demonstrates promising antitumor effects in NSCLC. Preclinical studies have shown that it is also active against several mutant forms of ALK that confer resistance to crizotinib, including the gatekeeper mutation L1196M. Moreover, an objective response rate of over 90% was observed in a phase I trial. Due to the impressive results of early phase studies, alectinib was approved for the treatment of advanced ALK-positive NSCLC in Japan, while it has been granted a breakthrough therapy designation by the FDA. A phase III trial is currently ongoing. This review will describe the biology and significance of ALK rearrangements in NSCLC, ALK inhibition by crizotinib and mechanisms of resistance, as well as the preclinical and clinical evidence for the novel ALK inhibitor alectinib.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Discovery; Humans; Lung Neoplasms; Piperidines; Receptor Protein-Tyrosine Kinases; Treatment Outcome; Xenograft Model Antitumor Assays

With therapeutic approaches based on oncogene addiction offering significant anticancer benefit, the identification of anaplastic lymphoma kinase (ALK) rearrangements is a key aspect of the management of lung cancers. The EML4-ALK gene fusion is detected in 4-8% of all lung cancers, predominantly in light smokers or nonsmokers. Crizotinib, the first agent to be approved in this indication, is associated with a median progression-free survival of 10.9 months when given as first-line treatment and 7.7 months when administered after chemotherapy. Median overall survival with crizotinib in the second-line setting is 20.3 months. Second-generation ALK inhibitors are currently being evaluated, with early studies giving impressive results, notably in patients resistant to crizotinib or with brain metastases. Among available chemotherapies, pemetrexed appears to be particularly active in this population. Despite this progress, several questions remain unanswered. What detection strategies should be favoured? What underlies the mechanisms of resistance and what options are available to overcome them? What are the best approaches for progressing patients? This review provides an overview of current data in the literature and addresses these questions.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Crizotinib; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Neoplasm Metastasis; Piperidines; Predictive Value of Tests; Prognosis; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Smoking; Sulfones

Topics: Animals; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Design; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Anaplastic lymphoma kinase (ALK) has been identified to exert a potent transforming activity through its rearrangement in non-small cell lung cancer (NSCLC), and patients (pts) with ALK rearrangement can be treated more successfully with ALK inhibitors, such as crizotinib, alectinib, and ceritinib, than with chemotherapy. Despite the excellent efficacy of ALK inhibitors, resistance to these drugs is inevitably encountered in most ALK-rearranged pts. Cases of resistance are subtyped into three groups, i.e., systemic, oligo, and central nervous system (CNS) types, with the CNS being used to be considered a sanctuary. With regard to the management of CNS lesions in pts with ALK+ NSCLC, a growing body of evidence has gradually demonstrated the intracranial (IC) efficacy of ALK inhibitor (ALKi) in ALK+ NSCLC pts with brain metastases (BMs). Although the efficacy of crizotinib for the CNS lesions remains controversial, a recent retrospective investigation of ALK+ pts with BM enrolled in PROFILE 1005 and PROFILE 1007 demonstrated that crizotinib is associated with a high disease control rate for BM. However, BM comprises the most common site of progressive disease in pts with or without baseline BMs, which is a serious problem for crizotinib. Furthermore, alectinib can be used to achieve strong and long-lasting inhibitory effects on BM. In addition to alectinib, the IC efficacy of other next-generation ALK inhibitors, such as ceritinib, AP26113 and PF-06463922, has been demonstrated. In this article, we review the latest evidence regarding the BM and IC efficacy of ALK inhibitors in pts with ALK+ NSCLC.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Anaplastic lymphoma kinase (ALK) has been found to fuse with other partners, such as echinoderm microtubule-associated protein-like 4 (EML4), leading to potent malignant transformation in lung cancer, specifically non-small-cell lung cancer (NSCLC). The frequency of the ALK rearrangement in patients with NSCLC is reported to be 4-7%, and the rearrangement is frequently observed in relatively younger patients, non- or light smokers and those with adenocarcinoma histology without other genetic disorders, such as mutations of the epidermal growth factor receptor gene. Crizotinib, which is a first-in-class ALK tyrosine kinase inhibitor (TKI), was shown to be effective and well tolerated in ALK-positive NSCLC patients by a single-arm phase I study. Furthermore, a phase III randomized study demonstrated the superiority of crizotinib to standard chemotherapy (pemetrexed or docetaxel) in the treatment of NSCLC patients harboring the ALK rearrangement who had received one prior platinum-based chemotherapy. However, the mechanisms of resistance to crizotinib are major concerns when administering crizotinib to ALK-positive NSCLC patients, and they include second mutations and a gain in the copy number of the ALK gene, activation of other oncogenes, etc. Treatment strategies to overcome these mechanisms of resistance have been developed, including the use of second-generation ALK inhibitors, such as alectinib and ceritinib, heat shock protein 90 inhibitors and so on. In this article, we review the pre-clinical and clinical data regarding the biologal and clinical significance of the ALK rearrangement in lung cancer.

Topics: Age Factors; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Transformation, Neoplastic; Crizotinib; ErbB Receptors; Gene Fusion; Gene Rearrangement; Humans; Lung Neoplasms; Microtubule-Associated Proteins; Molecular Targeted Therapy; Mutation; Oncogene Proteins, Fusion; Piperidines; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Serine Endopeptidases; Smoking; Sulfones

The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase represents a potential therapeutic target. Specially, a variety of alterations in the ALK gene including mutations, overexpression, amplification, translocations and structural rearrangements, are involved in human cancer tumorigenesis. The second-generation ALK inhibitor CH5424802 (development code: AF802; Chugai Pharmaceutical, a subsidiary of Roche) achieves tumor regression with excellent tolerance and shows promising efficacy in patients with ALK-positive non-small cell lung cancer. CH5424802 shows good kinase selectivity, has a promising pharmacokinetics profile, and has strong antiproliferative activity in several ALK-driven tumor models. CH5424802 has also shown anti-tumor activity in mouse xenograft studies. Here, we summarize recent advances and the evidence that CH5424802 acts as an ALK inhibitor. We also discuss its potential for further development as an anticancer drug in clinical trials.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Drugs, Investigational; Humans; Lung; Lung Neoplasms; Molecular Targeted Therapy; Neoplasm Proteins; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Tumor Burden

Alectinib, a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is highly effective in advanced ALK-rearranged non-small-cell lung cancer and represents a standard first-line therapy. New strategies are needed, however, to delay resistance. We conducted a phase I/II study to assess the safety and efficacy of combining alectinib with bevacizumab, a monoclonal antibody against vascular endothelial growth factor.. Patients with advanced ALK-rearranged non-squamous non-small-cell lung cancer were enrolled. The phase I portion employed a dose de-escalation strategy with alectinib and bevacizumab starting at the individual standard doses. The primary objective was to determine the recommended phase II dose (RP2D). In phase II, the primary objective was to evaluate the safety of the combination at the RP2D; the secondary objective was to determine extracranial and intracranial efficacy.. Eleven patients were enrolled between September 2015 and February 2020. Most patients (82%) had baseline brain metastases. Six patients (55%) were treatment-naive; five (46%) had received prior ALK TKIs (crizotinib, n = 3; ceritinib, n = 1; crizotinib then brigatinib, n = 1). No dose-limiting toxicities occurred. RP2D was determined as alectinib 600 mg orally twice daily plus bevacizumab 15 mg/kg intravenously every 3 weeks. Three patients experienced grade 3 treatment-related adverse events: pneumonitis related to alectinib, proteinuria related to bevacizumab, and hypertension related to bevacizumab. Treatment-related intracranial hemorrhage was not observed. Six (100%) of six treatment-naive patients and three (60%) of five ALK TKI-pretreated patients had objective responses; median progression-free survival was not reached (95% confidence interval, 9.0 months-not reached) and 9.5 months (95% confidence interval, 4.3 months-not reached), respectively. Intracranial responses occurred in four (100%) of four treatment-naive and three (60%) of five TKI-pretreated patients with baseline brain metastases. The study was stopped prematurely because of slow accrual.. Alectinib plus bevacizumab was well tolerated without unanticipated toxicities or dose-limiting toxicities.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines; Receptor Protein-Tyrosine Kinases; Vascular Endothelial Growth Factor A

Mature progression-free survival (PFS) data from the phase III J-ALEX study showed superiority for alectinib versus crizotinib [hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.26-0.52; median PFS 34.1 versus 10.2 months, respectively] in advanced ALK (anaplastic lymphoma kinase)-positive non-small-cell lung cancer (NSCLC). Overall survival (OS) data were immature (HR 0.80, 99.8799% CI 0.35-1.82) at the time of data cut-off (30 June 2018). We report final OS data after ≥5 years of follow-up.. ALK inhibitor naive Japanese patients who were chemotherapy naive or had received one prior chemotherapy regimen were enrolled. Patients were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was independent review facility-assessed PFS, with OS (not fully powered) as a secondary endpoint.. Median duration of OS follow-up was 68.6 months with alectinib and 68.0 months with crizotinib. Treatment with alectinib did not prolong OS relative to crizotinib (HR 1.03, 95.0405% CI 0.67-1.58; P = 0.9105). Five-year OS rates were 60.9% (95% CI 51.4-70.3) with alectinib and 64.1% (95% CI 54.9-73.4) with crizotinib. In total, 91.3% (n = 95/104) of crizotinib-treated patients and 46.6% (n = 48/103) of alectinib-treated patients received at least one subsequent anticancer therapy. After study drug discontinuation, 78.8% of patients in the crizotinib arm switched to alectinib, while 10.7% of patients in the alectinib arm switched to crizotinib as a first subsequent anticancer therapy. Patients randomized to crizotinib tended to switch treatment earlier than those randomized to alectinib.. Final OS analysis from J-ALEX did not show superiority of alectinib to crizotinib; this result was most likely confounded by treatment crossover. Alectinib remains a standard of care for the treatment of patients with advanced ALK-positive NSCLC.

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Japan; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Survival Analysis

Alectinib, a highly selective next generation ALK-inhibitor, has exhibited potent anti-tumour activity in RET-rearranged NSCLC in the preclinical stage.. ALERT-lung is a single-arm, phase II trial evaluating the activity of alectinib for the treatment of pretreated RET-rearranged advanced NSCLC. Alectinib was administered orally, 600 mg, twice per day until progression, refusal or unacceptable toxicity (treatment could continue beyond progression, if patient was deriving clinical benefit). Patient recruitment closed prematurely due to discouraging results for alectinib in a phase I/II study in the same indication.. All 14 patients who enrolled until the premature accrual closure, received at lease one dose of alectinib. Among them, median age was 61 years, majority (71 %) was female, never smokers, of ECOG PS 1. No objective response (complete or partial response) was recorded. Of the 13 evaluable patients, three (23 %) achieved and maintained disease stabilisation for 24 weeks. Up to 31 March 2021 (median follow-up 15.9 months), 12 PFS-events (92 %) were observed, with median PFS of 3.7 months (95 % C.I.: 1.8 - 7.3 months). Overall, three deaths (23 %) were reported. Seven patients (50 %) experienced grade ≥ 3 adverse events, while three discontinued treatment due to erythema multiforme of grade 3, related to alectinib. No treatment-related serious adverse event was reported.. Accrual into our trial was terminated early in response to other reports of limited activity of alectinib in patients with RET-fusion NSCLC and the emergence of more potent selective RET-inhibitors. Also in our trial, alectinib did not show the expected potential for anti-tumour activity in NSCLC.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Receptor Protein-Tyrosine Kinases

This 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).. This 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.. We 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.. Brigatinib has been found to have clinically meaningful efficacy in Japanese patients with ALK+ NSCLC refractory to alectinib (with or without previous crizotinib).

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Humans; Japan; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrimidines

The efficacy of crizotinib treatment for recurring EML4-ALK-positive non-small cell lung cancer (NSCLC) previously treated with alectinib is unclear. Based on our preclinical findings regarding hepatocyte growth factor/mesenchymal epithelial transition (MET) pathway activation as a potential mechanism of acquired resistance to alectinib, we conducted a phase II trial of the anaplastic lymphoma kinase/MET inhibitor, crizotinib, in patients with alectinib-refractory, EML4-ALK-positive NSCLC.. Patients with ALK-rearranged tumors treated with alectinib immediately before enrolling in the trial received crizotinib monotherapy. The objective response rate was the primary outcome of interest.. Nine (100%) patients achieved a partial response with alectinib therapy with a median treatment duration of 6.7 months. Crizotinib was administered with a median treatment interval of 50 (range, 20-433) days. The overall response rate was 33.3% (90% confidence interval [CI]: 9.8-65.5 and 95% CI: 7.5-70.1), which did not reach the predefined criteria of 50%. Two (22%) patients who achieved a partial response had brain metastases at baseline. Progression-free survival (median, 2.2 months) was not affected by the duration of treatment with alectinib. The median survival time was 24.1 months. The most common adverse events were an increased aspartate transaminase/alanine transaminase (AST/ALT) ratio (44%) and appetite loss (33%); one patient developed transient grade 4 AST/ALT elevation, resulting in treatment discontinuation. Other adverse events were consistent with those previously reported; no treatment-related deaths occurred.. Although the desired response rate was not achieved, crizotinib monotherapy following treatment with alectinib showed efficacy alongside previously described adverse events.

Topics: Adult; Aged; Aged, 80 and over; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

Theranostic translocations may be difficult to detect by routine techniques, especially when specimens are exiguous. We recently demonstrated in a series of translocated lung adenocarcinomas that LD-RT-PCR (ligation-dependent reverse transcription polymerase chain reaction) assay could identify ALK, ROS1 and RET rearrangements with 64% sensitivity and 100% specificity. Here, we report an upgraded version of this assay used in a routine prospective cohort of lung carcinomas. Newly diagnosed lung carcinomas referred to the Rouen molecular platform between 15/05/2018 and 15/05/2019 for ALK and ROS1 IHC, genotyping (SNaPshot© +/- high-throughput genotyping) and sometimes FISH (standard routine process) were tested prospectively in parallel with the LD-RT-PCR assay designed to detect at one go ALK, ROS1 and RET translocations and MET exon 14 skipping. 413 tumors from 396 patients were included. LD-RT-PCR had a global sensitivity of 91.43% (standard routine process: 80%), with a specificity of 100%. It detected 15/18 ALK and 4/4 ROS1 translocated tumors, but also 6/6 tumors with MET exon 14 skipping retrieved by genotyping. In addition, it retrieved 7 alterations missed by the routine process, then confirmed by other means: 5 MET exon 14 skipping and 2 RET translocated tumors. Finally, it allowed to deny an effect on MET exon 14 skipping for 8 mutations detected by routine genotyping. We successfully implemented LD-RT-PCR in routine analysis. This technique is cheap, fast, sensitive, specific, and easily upgradable (e.g., NTRK translocations), but still requires IHC to be performed in parallel. Owing to its advantages, we recommend considering it, in parallel with IHC and genotyping, as an excellent cost-effective alternative, for the systematic testing of lung adenocarcinoma, to FISH and to more expensive and complex assays such as RNA-seq.

Topics: Adenocarcinoma; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Crizotinib; Exons; Humans; Lung Neoplasms; Molecular Targeted Therapy; Piperidines; Precision Medicine; Prospective Studies; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-met; Proto-Oncogene Proteins c-ret; Translocation, Genetic

Lay abstract Tyrosine kinase inhibitor medications (like crizotinib, alectinib or ceritinib) may work as the first treatment for people with non-small-cell lung cancer (NSCLC) that has spread to other parts of the body and has the ALK+ mutation (ALK+ NSCLC) in tumor testing. However, after a while, many people stop responding to treatment with one of these medicines. Brigatinib is a tyrosine kinase inhibitor medicine that may be effective in people with ALK+ NSCLC who have stopped responding to alectinib or ceritinib treatment. We describe the need for and design of a study of brigatinib in people with ALK+ NSCLC whose disease got worse on alectinib or ceritinib.

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Middle Aged; Organophosphorus Compounds; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Quality of Life; Response Evaluation Criteria in Solid Tumors; Sulfones

Alectinib is a potent anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) which is currently used in the first-line setting of advanced ALK. Patients with potentially resectable stage III ALK. Our case report supports the feasibility of alectinib as neoadjuvant treatment. ALNEO study will further explore the activity and safety of this novel treatment strategy.

Topics: Adolescent; Adult; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Male; Middle Aged; Neoadjuvant Therapy; Patient Safety; Piperidines; Young Adult

Crizotinib is highly efficacious and more tolerable than chemotherapy for ALK. Lay abstract Tyrosine kinase inhibitor medications like crizotinib may work as a first treatment for people with non-small-cell lung cancer (NSCLC) that has spread to other parts of the body and has the ALK

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Organophosphorus Compounds; Piperidines; Pyrimidines

A pooled analysis of two open-label phase II studies of alectinib (NP28673 [NCT01801111] and NP28761 [NCT01871805]) demonstrated clinical activity in patients with advanced, anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) previously treated with crizotinib. Longer-term and final pooled analyses of overall survival (OS) and safety data from the two studies are presented here.. The pooled population totaled 225 patients (NP28673: n = 138, NP28761: n = 87) who received 600 mg oral alectinib twice daily until disease progression, death, or withdrawal. OS was defined as the time from date of first treatment to date of death, regardless of cause. OS was estimated using Kaplan-Meier methodology, with 95% confidence intervals (CIs) determined using the Brookmeyer-Crowley method. Safety was assessed through adverse event (AE) reporting.. Baseline characteristics were generally comparable between the studies. At final data cutoff (October 27, 2017 [NP28673], October 12, 2017 [NP28761]; median pooled follow-up time, ∼21 months), 53.3% of patients had died, 39.1% were alive and in follow-up, and 7.6% had withdrawn consent or were lost to follow-up. Alectinib demonstrated a median OS of 29.1 months (95% CI 21.3-39.0). No new or unexpected safety findings were observed. The most common all-grade AEs included constipation (39.1%), fatigue (35.1%), peripheral edema (28.4%), myalgia (26.2%), and nausea (24.0%).. Updated results from this pooled analysis further demonstrate that alectinib has robust clinical activity and a manageable safety profile in patients with advanced, ALK+ NSCLC pretreated with crizotinib.

Topics: Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Piperidines; Prognosis; Protein Kinase Inhibitors; Survival Rate

If anaplastic lymphoma kinase (ALK) gene rearrangement in lung cancer is identified, ALK-tyrosine kinase inhibitors (ALK-TKIs) can be an effective treatment. However, the details of drug-induced lung injury (DILI) caused by ALK-TKI, which can be a serious side effect of ALK-TKIs, remains unclear. This study aimed to investigate the clinical features and the onset risk factors of DILI by ALK-TKIs in clinical practice.. The clinical features of 56 consecutive patients who received crizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were retrospectively examined. Among these, patients diagnosed with DILI due to ALK-TKIs were evaluated in terms of clinical features and parameters. Each clinical parameter before the administration of ALK-TKIs was compared between the DILI onset group and the non-onset group.. A total of seven cases were diagnosed with DILI due to ALK-TKIs; no DILI-related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance <80 mL/minute.. Extra caution for DILI due to ALK-TKIs may be needed when recommending ALK-TKIs for patients over 64 years of age, or with decreased renal function. CT images of the majority of patients with DILI by ALK-TKIs show an OP pattern.. Significant findings of the study: Extra caution is needed when recommending ALK-TKIs for patients over 64 years of age or those with decreased renal function. Computed tomography images of the majority of patients with DILI by ALK-TKIs show an OP pattern.. The same or a different ALK-TKI may be considered as a treatment option after the onset of DILI, based on careful judgment.

Topics: Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Squamous Cell; Crizotinib; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Lung Injury; Lung Neoplasms; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Risk Factors; Sulfones; Survival Rate

Anaplastic lymphoma kinase (ALK) inhibition is expected to be a promising therapeutic strategy for ALK-positive malignancies. We aimed to examine the efficacy and safety of alectinib, a second-generation ALK inhibitor, in patients with relapsed or refractory ALK-positive anaplastic large cell lymphoma (ALCL). This open-label, phase II trial included patients (aged 6 years or older) with relapsed or refractory ALK-positive ALCL. Alectinib 300 mg was given orally twice a day (600 mg/d) for 16 cycles, and the duration of each cycle was 21 days. Patients who weighed less than 35 kg were given a reduced dose of alectinib of 150 mg twice a day (300 mg/d). Ten patients were enrolled, and the median age was 19.5 years (range, 6-70 years). Objective responses were documented in eight of 10 patients (80%; 90% confidence interval, 56.2-95.9), with six complete responses. The 1-year progression-free survival, event-free survival, and overall survival rates were 58.3%, 70.0%, and 70.0%, respectively. The median duration of therapy was 340 days. No unexpected adverse events occurred. The most common grade 3 and higher adverse event was a decrease in neutrophil count in two patients. Alectinib showed favorable clinical activity and was well tolerated in patients with ALK-positive ALCL who had progressed on standard chemotherapy. Based on the results of the current study, the Ministry of Health, Labour and Welfare of Japan approved alectinib for the treatment of recurrent or refractory ALK-positive ALCL in February 2020.

Topics: Administration, Oral; Adult; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Child; Confidence Intervals; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Japan; Lymphoma, Large-Cell, Anaplastic; Male; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Recurrence; Survival Rate; Treatment Outcome; Young Adult

Alectinib demonstrated superior efficacy and a safety profile that compared favorably with crizotinib in treatment-naïve ALK+ non-small-cell lung cancer (NSCLC) in the phase III ALEX study. We present patient-reported outcomes (PROs) from ALEX to assess disease burden, treatment-related symptom tolerability, and health-related quality of life (HRQoL) with alectinib versus crizotinib.. Patients were randomized to receive alectinib 600 mg or crizotinib 250 mg twice daily until disease progression, death, or withdrawal. Pre-specified PRO endpoints were: mean change from baseline in symptoms, HRQoL, and functioning; and time to deterioration (TTD) in cough, dyspnea, chest pain, arm/shoulder pain, fatigue, and a composite of three symptoms (cough, dyspnea, chest pain). PRO data were collected using EORTC QLQ-C30 and LC13 questionnaires. Raw scores were standardized to a 0-100-point range, with a ≥10-point score change defined as clinically meaningful. TTD was defined as the time from randomization until confirmed clinically meaningful deterioration (i.e., a ≥10-point score change from baseline).. Baseline completion rates and characteristics were balanced in the PRO-evaluable population (alectinib n = 100, 66%; crizotinib n = 97, 64%). On average, alectinib-treated patients reported clinically meaningful improvements in lung cancer symptoms for longer than crizotinib-treated patients. Between-treatment differences in lung cancer symptoms tended to favor alectinib from 11.1 months (45 weeks) onwards, around the time of median PFS with crizotinib (11.1 months). TTD in lung cancer symptoms was similar between treatment arms, despite longer duration of symptom improvement with alectinib; composite symptom endpoint (hazard ratio 1.10 [95% confidence interval: 0.72-1.68]). Duration of clinically meaningful improvement in HRQoL was longer with alectinib versus crizotinib (Week 88 vs. Week 68, respectively). Better patient-reported tolerability was observed with alectinib versus crizotinib on common treatment-related symptoms.. PRO data support the superior efficacy and tolerability of alectinib relative to crizotinib demonstrated in the ALEX study.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Patient Reported Outcome Measures; Piperidines; Prognosis; Quality of Life; Survival Rate

At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34-0.65, p < 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months' follow-up (cutoff December 1, 2017).. Patients were randomized to receive twice-daily alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant.. Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32-0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of crizotinib), the safety of alectinib compared favorably with that of crizotinib.. Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant.

Topics: Adolescent; Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Crizotinib; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Prognosis; Survival Rate; Young Adult

Anaplastic lymphoma kinase-positive (ALK-positive) disease occurs in approximately 5% of all patients with non-small-cell lung cancer, with a similar incidence reported in Asian patients. This study is the first phase 3 randomised trial recruiting only Asian patients to compare alectinib with crizotinib as a first-line treatment for ALK-positive non-small-cell lung cancer with 600 mg of alectinib twice per day. This study assessed consistency of the progression-free survival benefit with the global phase 3 ALEX study.. In this randomised, open-label, phase 3 study done at 21 investigational sites in China, South Korea, and Thailand, Asian patients, aged 18 years or older, with ALK-positive non-small-cell lung cancer were randomly assigned (2:1) to twice-daily oral alectinib (600 mg) or crizotinib (250 mg). Patients were randomly assigned via a block-stratified (block size three) randomisation procedure, done centrally via an interactive voice or web response system, with stratification by Eastern Cooperative Oncology Group performance status and baseline CNS metastases. Clinical staff and the funder's drug safety and medical monitoring staff had access to treatment assignments. The independent review committee was masked to treatment assignment, and funder personnel did not have access to efficacy and safety summaries by treatment group, before the formal reporting of study results. Patients with asymptomatic CNS metastases were permitted. The primary endpoint was investigator-assessed progression-free survival. The primary analysis population for efficacy was the intention-to-treat population, defined as all randomly assigned patients. The primary analysis population for safety was defined as all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02838420.. Between Aug 3, 2016, and May 16, 2017, 187 patients were randomly assigned to treatment: 125 to alectinib and 62 to crizotinib. Median follow-up was 16·2 months (IQR 13·7-17·6) in the alectinib group, and 15·0 months (12·5-17·3) in the crizotinib group. Investigator-assessed progression-free survival was significantly prolonged with alectinib versus crizotinib (hazard ratio [HR] 0·22, 95% CI 0·13-0·38; p<0·0001; median progression-free survival not estimable vs 11·1 months). Independent review committee-assessed progression-free survival was also significantly longer in the alectinib group compared with the crizotinib group (HR 0·37, 0·22-0·61; p<0·0001). The proportion of patients who achieved an objective response was 114 (91%) of 125 with alectinib, and 48 (77%) of 62 with crizotinib, with a longer duration of response for alectinib than crizotinib (HR 0·22, 95% CI 0·12-0·40; p<0·0001). Time to CNS progression (cause-specific HR 0·14) and the percentage of patients who achieved a CNS objective response with measurable or non-measurable baseline CNS lesions were improved (32 [73%] of 44 patients treated with alectinib vs five [22%] of 23 patients treated with crizotinib). Despite longer treatment duration with alectinib than crizotinib (14·7 months vs 12·6 months, respectively), fewer patients had grade 3-5 adverse events (36 [29%] of 125 vs 30 [48%] of 62, respectively) or serious adverse events (19 [15%] of 125 vs 16 [26%] of 62, respectively).. Our results align with ALEX, confirming the clinical benefit of 600 mg of alectinib twice per day as a first-line treatment for ALK-positive non-small-cell lung cancer.. F Hoffmann-La Roche.

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; China; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Republic of Korea; Thailand; Treatment Outcome

The second-generation ALK tyrosine kinase inhibitor brigatinib has recently been approved in the European Union for use after crizotinib treatment in patients with EML4-ALK-rearranged lung cancer. In the current study, brigatinib was investigated as second-line or later-line treatment in 35 patients who had developed resistance to crizotinib, ceritinib, or alectinib. Most patients (68.6%) received brigatinib as second or third line (range: second to 12th line). In the total cohort, complete and partial responses were obtained for 9.1 and 75.8%, respectively. Overall median progression-free survival was 9.9 months, whereas the largest treatment cohort (brigatinib after crizotinib failure) showed a median progression-free survival of 8.4 months. Fifty-four percent of patients with baseline brain metastases responded to brigatinib treatment. Brigatinib was highly effective after crizotinib and ceritinib failure. Six patients had received alectinib as monotherapy, second-line, or third line before brigatinib; of these, four experienced partial responses and two progressed responses. Brigatinib treatment was well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Organophosphorus Compounds; Piperidines; Prognosis; Pyrimidines; Salvage Therapy; Sulfones; Survival Rate

We evaluated the cumulative incidence rate (CIR) of central nervous system (CNS) and non-CNS progression in alectinib-treated patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) to determine the extent to which alectinib may treat or control CNS disease.. Patients with crizotinib-pretreated locally advanced or metastatic disease received alectinib 600 mg orally twice daily in two phase II trials. All patients underwent baseline imaging and regular centrally reviewed scans.. At 24 months, the CIR for CNS progression was lower in patients without vs with baseline CNS metastases (8.0 vs 43.9%). Patients with baseline CNS disease and prior radiotherapy had a higher CIR of CNS progression than radiotherapy-naive patients (50.5 vs 27.4%) and a lower CIR of non-CNS progression (25.8 vs 42.5%). Adverse events leading to withdrawal occurred in 5.9% and 6.7% of patients with and without baseline CNS metastases, respectively.. This analysis indicates a potential role for alectinib in controlling and preventing CNS metastases.

Topics: Administration, Oral; Adult; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Disease Progression; Female; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Treatment Outcome; Young Adult

Despite improved progression-free survival, most patients treated with the first generation ALK inhibitor crizotinib ultimately experience central nervous system (CNS) progression. Brain metastases (BM) are associated with high clinical burden in patients with advanced anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). In this study we estimate the real-world economic burden of BM in newly diagnosed ALK+ NSCLC patients and investigate whether alectinib, a second generation ALK inhibitor that delays CNS progression, may help reduce healthcare costs in patients with ALK+ NSCLC.. Cost of BM was measured in ALK+ NSCLC patients identified from a stacked PharMetrics Plus and MarketScan claims database from January 2008 to March 2016 and December 2015, respectively. Per patient per month (PPPM) cost of BM was calculated as the difference in baseline-adjusted total costs in patients with and without BM over a variable follow-up period of up to 24 months. Cumulative incidence of new BM was derived from 88 alectinib-treated and 93 crizotinib-treated patients without baseline BM in a randomized phase III clinical trial, ALEX (NCT02075840). Costs of BM per patient were then calculated by applying the PPPM BM cost to the number of incident BM patients in each treatment cohort.. 207 patients with no BM and 198 with BM were selected from the claims database. Total cost of BM was estimated at $6,029 PPPM. 24-month cumulative incidence rates of BM from the clinical trial were 7.2% and 45.3% for alectinib and crizotinib, respectively. Over follow-up, alectinib was estimated to reduce BM-related costs by $41,434 per patient compared to crizotinib.. BM is associated with substantial economic burden. Alectinib was estimated to reduce BM-related costs by preventing or delaying the occurrence of BM compared to crizotinib.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cost of Illness; Crizotinib; Follow-Up Studies; Humans; Incidence; Lung Neoplasms; Neoplasm Metastasis; Piperidines; United States

This is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib.. ALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic ALK-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib. Patients were randomized 2 : 1 to receive alectinib 600 mg twice daily or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, both every 3 weeks) until disease progression, death, or withdrawal. Primary end point was investigator-assessed progression-free survival (PFS).. Altogether, 107 patients were randomized (alectinib, n = 72; chemotherapy, n = 35) in 13 countries across Europe and Asia. Median investigator-assessed PFS was 9.6 months [95% confidence interval (CI): 6.9-12.2] with alectinib and 1.4 months (95% CI: 1.3-1.6) with chemotherapy [hazard ratio (HR) 0.15 (95% CI: 0.08-0.29); P < 0.001]. Independent Review Committee-assessed PFS was also significantly longer with alectinib [HR 0.32 (95% CI: 0.17-0.59); median PFS was 7.1 months (95% CI: 6.3-10.8) with alectinib and 1.6 months (95% CI: 1.3-4.1) with chemotherapy]. In patients with measurable baseline central nervous system (CNS) disease (alectinib, n = 24; chemotherapy, n = 16), CNS objective response rate was significantly higher with alectinib (54.2%) versus chemotherapy (0%; P < 0.001). Grade ≥3 adverse events were more common with chemotherapy (41.2%) than alectinib (27.1%). Incidence of AEs leading to study-drug discontinuation was lower with alectinib (5.7%) than chemotherapy (8.8%), despite alectinib treatment duration being longer (20.1 weeks versus 6.0 weeks).. Alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile.. ClinicalTrials.gov NCT02604342; Roche study MO29750.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Pemetrexed; Piperidines; Prognosis; Salvage Therapy; Survival Rate

Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations.. Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly.. LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein -/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved.. These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

Topics: Adult; Brain Neoplasms; Carbazoles; Carcinoma, Neuroendocrine; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mutation; Oncogene Proteins, Fusion; Piperidines; Proof of Concept Study; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyridines; Thyroid Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays

To compare the overall survival of anaplastic lymphoma kinase-positive non-small-cell lung cancer patients who received alectinib with those who received ceritinib.. Two treatment arms (alectinib [n = 183] and ceritinib [n = 67]) were extracted from clinical trials and an electronic health record database, respectively. Propensity scores were applied to balance baseline characteristics. Kaplan-Meier and multivariate Cox regression were conducted.. After propensity score adjustment, baseline characteristics were balanced. Alectinib had a prolonged median overall survival (alectinib = 24.3 months and ceritinib = 15.6 months) and lower risk of death (hazard ratio: 0.65; 95% CI: 0.48-0.88).. Alectinib was associated with prolonged overall survival versus ceritinib, which is consistent with efficacy evidence from clinical trials.

Topics: Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Comparative Effectiveness Research; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Propensity Score; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Clinical experience of ceritinib in patients who progressed on alectinib is limited. In this prospective phase II study, we evaluated the activity of ceritinib in alectinib-pretreated patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic (stage IIIB/IV) non-small-cell lung cancer (NSCLC) in Japan. All patients were required to have ≥1 measurable lesion per RECIST, 1.1, and a World Health Organization Performance Status (WHO PS) of 0-1. Prior crizotinib and/or up to 1 chemotherapy regimen was allowed. Primary endpoint was investigator-assessed overall response rate (ORR) per RECIST 1.1. Ceritinib was given at a dose of 750 mg/day fasted. A total of 20 patients were enrolled from August 2015 to March 2017. All patients received prior alectinib (100%), 13 (65.0%) patients received prior platinum-based chemotherapy, and 4 (20%) patients received prior crizotinib. Median duration of exposure and the follow-up time with ceritinib were 3.7 months (range: 0.4-15.1) and 11.6 months (range: 4.8-23.0), respectively. Investigator-assessed ORR was 25% (95% CI: 8.7-49.1). Key secondary endpoints, all investigator assessed, included disease control rate (70.0%; 95% CI: 45.7-88.1), time to response (median, 1.8 months; range: 1.8-2.0), and duration of response (median, 6.3 months; 95% CI: 3.5-9.2). Median progression-free survival was 3.7 months (95% CI: 1.9-5.3). The most common adverse events reported were diarrhea (85.0%), nausea (80.0%), and vomiting (65.0%). Based on our findings, ceritinib could be considered as one of the treatment options for patients with ALK-positive NSCLC who progressed on alectinib. (Trial registration no. NCT02450903).

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX.. Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression.. In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n = 64; crizotinib, n = 58), 43 had measurable lesions (alectinib, n = 21; crizotinib, n = 22), and 46 had received prior radiotherapy (alectinib, n = 25; crizotinib, n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25-0.64] and those without (HR 0.51, 95% CI: 0.33-0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not.. Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy.. ClinicalTrials.gov NCT02075840.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Brain; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Crizotinib; Disease Progression; Female; Humans; Lung; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Treatment Outcome; Tumor Burden; Young Adult

Introduction Anaplastic lymphoma kinase (ALK) targeting drugs provide an important option for advanced non-small cell lung cancer patients with this distinct tumor type; however, there is considerable uncertainty as to which drug provides the optimal value after crizotinib treatment. This study estimated the cost-utility of alectinib vs ceritinib from a US payer perspective. Methods A cost-utility model was developed using partition survival methods and three health states: progression-free (PF), post-progression (PP), and death. Survival data were derived from the key clinical trials (alectinib: NP28761 & NP28673, ceritinib: ASCEND I and II). Costs included drugs, adverse events, and supportive care. Utilities were based on trial data and the literature. One-way and probabilistic sensitivity analyses (PSA) were performed to assess parameter uncertainty. Results Treatment with alectinib vs ceritinib resulted in increases of 2.55 months in the PF state, 0.44 quality adjusted life-years (QALYs), and $13,868, yielding a mean cost/QALY of $31,180. In the PSA, alectinib had a 96% probability of being cost-effective at a willingness-to-pay of $100,000/QALY. Drivers of model results were drug costs and utilities in the PF health state. The ICER ranged from $10,600-$65,000 per QALY in scenario analyses, including a sub-group analysis limited to patients with prior chemotherapy and crizotinib treatment. Conclusions Treatment with alectinib in ALK + crizotinib-treated patients increased time progression-free and QALYs vs ceritinib. The marginal cost increase was driven by longer treatment durations with alectinib. This model demonstrates that alectinib may be considered a cost-effective treatment after progression on crizotinib.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cost-Benefit Analysis; Crizotinib; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Markov Chains; Middle Aged; Models, Economic; Piperidines; Pyrazoles; Pyridines; Pyrimidines; Quality-Adjusted Life Years; Receptor Protein-Tyrosine Kinases; Sulfones; Survival Analysis

Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib.. J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316).. Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17-0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3-not estimated) and was 10·2 months (8·2-12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group.. These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study.. Chugai Pharmaceutical Co, Ltd.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasm Grading; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Single-Blind Method

Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease.. In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival.. During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib).. As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840 .).

Topics: Adult; Aged, 80 and over; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Disease-Free Survival; Female; Follow-Up Studies; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Young Adult

Findings from the global phase III ALEX trial unequivocally show that alectinib is superior to crizotinib as first-line therapy for ALK+ non-small cell lung cancer. Alectinib more than doubled progression-free survival, significantly reduced the incidence of brain and CNS metastases, and should be considered the new standard of care.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Neoplasm Metastasis; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Central nervous system (CNS) progression is common in patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) receiving crizotinib. Next-generation ALK inhibitors have shown activity against CNS metastases, but accurate assessment of response and progression is vital. Data from two phase II studies in crizotinib-refractory ALK+ NSCLC were pooled to examine the CNS efficacy of alectinib, a CNS-active ALK inhibitor, using Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) and Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria.. Both studies enrolled patients aged ≥18 years who had previously received crizotinib. NP28761 was conducted in North America and NP28673 was a global study. All patients received 600 mg oral alectinib twice daily and had baseline CNS imaging. CNS response for those with baseline CNS metastases was determined by an independent review committee.. Baseline measurable CNS disease was identified in 50 patients by RECIST and 43 by RANO-HGG. CNS objective response rate was 64.0% by RECIST (95% confidence interval [CI]: 49.2-77.1; 11 CNS complete responses [CCRs]) and 53.5% by RANO-HGG (95% CI: 37.7-68.8; eight CCRs). CNS responses were durable, with consistent estimates of median duration of 10.8 months with RECIST and 11.1 months with RANO-HGG. Of the 39 patients with measurable CNS disease by both RECIST and RANO-HGG, only three (8%) had CNS progression according to one criteria but not the other (92% concordance rate).. Alectinib demonstrated promising efficacy in the CNS for ALK+ NSCLC patients pretreated with crizotinib, regardless of the assessment criteria used.

Topics: Adult; Aged; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Young Adult

Alectinib demonstrated clinical efficacy and an acceptable safety profile in two phase II studies (NP28761 and NP28673). Here we report the pooled efficacy and safety data after 15 and 18 months more follow-up than in the respective primary analyses.. Enrolled patients had ALK receptor tyrosine kinase gene (ALK)-positive NSCLC and had progressed while taking, or could not tolerate, crizotinib. Patients received oral alectinib, 600 mg twice daily. The primary end point in both studies was objective response rate assessed by an independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included disease control rate, duration of response, progression-free survival, overall survival, and safety.. The pooled data set included 225 patients (n = 138 in NP28673 and n = 87 in NP28761). The response-evaluable population included 189 patients (84% [n = 122 in NP28673 and n = 67 in NP28761]). In the response-evaluable population, objective response rate as assessed by the IRC was 51.3% (95% confidence interval [CI]: 44.0-58.6 [all PRs]), the disease control rate was 78.8% (95% CI: 72.3-84.4), and the median duration of response was 14.9 months (95% CI: 11.1-20.4) after 58% of events. Median progression-free survival as assessed by the IRC was 8.3 months (95% CI: 7.0-11.3) and median overall survival was 26.0 months (95% CI: 21.4-not estimable). Grade 3 or higher adverse events (AEs) occurred in 40% of patients, 6% of patients had treatment withdrawn on account of AEs, and 33% had AEs leading to dose interruptions/modification.. This pooled data analysis confirmed the robust systemic efficacy of alectinib in ALK-positive NSCLC with a durable response rate. Alectinib also had an acceptable safety profile with a longer duration of follow-up.

Topics: Adult; Aged; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Treatment Outcome

Currently, a standard therapy has not been established for recurrent or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. While there are many treatment options, such as hematopoietic stem cell transplantation, patients with resistant disease to conventional chemotherapies have particularly poor prognosis. There is urgent need to develop new drugs because of the lack of a standard therapy and poor prognoses. This phase II trial is designed for evaluating the efficacy and safety of alectinib hydrochloride for patients with recurrent or refractory anaplastic lymphoma kinase -positive anaplastic large cell lymphoma. The primary endpoint is the response rate according to the Revised Response Criteria for Malignant Lymphoma. The secondary endpoints are pharmacokinetics, safety in children, complete response rate, response duration, progression-free survival, event-free survival, overall survival, and adverse events. The results of this trial will be the pivotal data for the drug approval of alectinib hydrochloride for recurrent or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma.

Topics: Carbazoles; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Lymphoma, Large-Cell, Anaplastic; Male; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib is an approved anaplastic lymphoma kinase (ALK) inhibitor that may also be effective for RET fusion-positive NSCLC.. RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy are being recruited. In step 1, alectinib (600 or 450 mg, twice daily) will be administered following a 3+3 design. The primary endpoint is safety. In step 2, alectinib will be administered at the recommended dose (RD) defined by step 1. The primary endpoint is the response rate of RET inhibitor treatment-naïve patients.. This is the first study to investigate the safety and preliminary efficacy of alectinib in RET fusion-positive NSCLC patients. If successful, alectinib treatment may lead to substantial and important changes in the management of NSCLC with RET fusion genes. J. Med. Invest. 64: 317-320, August, 2017.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Protocols; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Receptor Protein-Tyrosine Kinases

Alectinib, an anaplastic lymphoma kinase (ALK) inhibitor, is approved for treatment of patients with ALK+ non-small cell lung cancer who have progressed, on or are intolerant to, crizotinib. This study assessed the effect of a high-fat meal and the proton pump inhibitor, esomeprazole, on the pharmacokinetics (PK) of alectinib. This was an open-label, 2-group study in healthy subjects. In group 1 (n = 18), subjects were randomly assigned to a 2-treatment (A, fasted conditions; B, following a high-fat meal), 2-sequence (AB or BA) crossover assessment, separated by a 10-day washout. In group 2 (n = 24), subjects were enrolled in a 2-period, fixed-sequence crossover assessment to evaluate the effect of esomeprazole. PK parameters were evaluated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Administration of alectinib following a high-fat meal substantially increased the combined exposure of alectinib and M4 to 331% (90%CI, 279%-393%) and 311% (90%CI, 273%-355%) for C

Topics: Adult; Area Under Curve; Carbazoles; Cross-Over Studies; Diet, High-Fat; Drug Interactions; Esomeprazole; Female; Healthy Volunteers; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Random Allocation; Young Adult

The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluating drug-drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates.

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Midazolam; Middle Aged; Piperidines; Receptor Protein-Tyrosine Kinases; Rifampin; Treatment Outcome; Triazoles; Young Adult

The anaplastic lymphoma kinase (ALK) inhibitor alectinib is an effective treatment for ALK-positive non-small-cell lung cancer. This bioequivalence study evaluated the in vivo performance of test 3 formulations with the reduced wetting agent sodium lauryl sulfate (SLS) content. This randomized, 4-period, 4-sequence, crossover study compared alectinib (600 mg) as 25%, 12.5%, and 3% SLS hard capsule formulations with the reference 50% SLS clinical formulation in healthy subjects under fasted conditions (n = 49), and following a high-fat meal (n = 48). Geometric mean ratios and 90% confidence intervals (CIs) for C

Topics: Adult; Capsules; Carbazoles; Cross-Over Studies; Diet, High-Fat; Fasting; Female; Healthy Volunteers; Humans; Male; Middle Aged; Piperidines; Sodium Dodecyl Sulfate; Surface-Active Agents; Therapeutic Equivalency; Young Adult

Alectinib has shown marked efficacy and safety in patients with anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement-positive NSCLC and a good performance status (PS). It has remained unclear whether alectinib might also be beneficial for such patients with a poor PS.. Eligible patients with advanced ALK rearrangement-positive NSCLC and a PS of 2 to 4 received alectinib orally at 300 mg twice daily. The primary end point of the study was objective response rate (ORR), and the most informative secondary end point was rate of PS improvement.. Between September 2014 and December 2015, 18 patients were enrolled in this phase II study. Of those patients, 12, five, and one had a PS of 2, 3, or 4, respectively, whereas four patients had received prior crizotinib treatment. The ORR was 72.2% (90% confidence interval: 52.9-85.8%). The ORR did not differ significantly between patients with a PS of 2 and those with a PS of 3 or higher (58.3% and 100%, respectively [p = 0.114]). The PS improvement rate was 83.3% (90% confidence interval: 64.8-93.1%, p < 0.0001), with the frequency of improvement to a PS of 0 or 1 being 72.2%. The median progression-free survival was 10.1 months. Toxicity was mild, with the frequency of adverse events of grade 3 or higher being low. Neither dose reduction nor withdrawal of alectinib because of toxicity was necessary.. Alectinib is a treatment option for patients with ALK rearrangement-positive NSCLC and a poor PS.

Topics: Adult; Aged; Aged, 80 and over; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

Alectinib, a central nervous system (CNS)-active ALK inhibitor, has demonstrated efficacy and safety in ALK+ non-small-cell lung cancer that has progressed following crizotinib treatment. Other ALK inhibitors have shown concentration-dependent QTc prolongation and treatment-related bradycardia. Therefore, this analysis evaluated alectinib safety in terms of electrophysiologic parameters.. Intensive triplicate centrally read electrocardiogram (ECG) and matched pharmacokinetic data were collected across two alectinib single-arm trials. Analysis of QTcF included central tendency analysis [mean changes from baseline with one-sided upper 95% confidence intervals (CIs)], categorical analyses, and relationship between change in QTcF and alectinib plasma concentrations. Alectinib effects on other ECG parameters (heart rate, PR interval and QRS duration) were also evaluated.. Alectinib did not cause a clinically relevant change in QTcF. The maximum mean QTcF change from baseline was 5.3 ms observed pre-dose at week 2. The upper one-sided 95% CI was <10 ms at all time points. There was no relevant relationship between change in QTcF and alectinib plasma concentrations. Alectinib treatment resulted in a generally asymptomatic exposure-dependent decrease in mean heart rate of ~11 to 13 beats per minute at week 2. No clinically relevant effects were seen on other ECG parameters. Approximately 5% of patients reported cardiac adverse events of bradycardia or sinus bradycardia; however, these were all grade 1-2.. Alectinib does not prolong the QTc interval or cause changes in cardiac function to a clinically relevant extent, with the exception of a decrease in heart rate which was generally asymptomatic.

Topics: Algorithms; Anaplastic Lymphoma Kinase; Bradycardia; Carbazoles; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Electrocardiography; Heart Function Tests; Heart Rate; Humans; Long QT Syndrome; Lung Neoplasms; Monitoring, Physiologic; Piperidines; Receptor Protein-Tyrosine Kinases

Purpose Alectinib is an anaplastic lymphoma kinase (ALK) -specific kinase inhibitor that seems to be effective against non-small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor-naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Disease Progression; Disease-Free Survival; Female; Follow-Up Studies; Humans; Hyperbilirubinemia; Lung Neoplasms; Male; Middle Aged; Piperidines; Receptor Protein-Tyrosine Kinases; Retreatment; Survival Rate; Symptom Assessment; Time Factors

Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated.. In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore.. ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity.. Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection.. JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Disease-Free Survival; Female; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Piperidines; Prospective Studies; Receptor Protein-Tyrosine Kinases; Treatment Outcome; Young Adult

Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC.. Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC).. Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2.. Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.

Topics: Administration, Oral; Adult; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Alectinib--a highly selective, CNS-active, ALK inhibitor-showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib.. We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB-IV, ALK-positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov, number NCT01871805. The study is ongoing and patients are still receiving treatment.. Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months [IQR 3·3-7·1]), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36-60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 [36%]), fatigue (29 [33%]), myalgia 21 [24%]), and peripheral oedema 20 [23%]). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven [8%]), increased alanine aminotransferase (five [6%]), and increased aspartate aminotransferase (four [5%]). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment).. Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.. F Hoffmann-La Roche.

Topics: Adult; Aged; Alanine Transaminase; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Aspartate Aminotransferases; Carbazoles; Carcinoma, Non-Small-Cell Lung; Constipation; Creatine Kinase; Crizotinib; Drug Resistance, Neoplasm; Edema; Fatigue; Female; Humans; Lung Neoplasms; Male; Middle Aged; Myalgia; Piperidines; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Response Evaluation Criteria in Solid Tumors; Retreatment

Based on our preclinical study results, which showed that the activation of the hepatocyte growth factor/MET pathway is a potential mechanism of acquired resistance to alectinib, we launched the ALRIGHT (OLCSG1405 [alectinib-refractory non-small-cell lung cancer patients harboring the EML4-ALK fusion gene]), a phase II trial of the anaplastic lymphoma kinase (ALK)/MET inhibitor crizotinib in patients with non-small-cell lung cancer refractory to alectinib and harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. Patients with ALK-rearranged tumors who have developed disease progression during alectinib treatment will receive crizotinib monotherapy until disease progression or the occurrence of unacceptable toxicity. The primary endpoint is set as the objective response rate, assuming that a response in 50% of eligible patients will indicate potential usefulness and that 15% would be the lower limit of interest (1-sided α of 0.05, β of 0.20). The estimated accrual number of patients is 9. The secondary endpoints include progression-free survival, overall survival, adverse events, and patient-reported outcomes. We will also take tissue samples before crizotinib monotherapy to conduct an exploratory analysis of ALK and hepatocyte growth factor/MET expression levels and gene alterations (eg, mutations, amplifications, and translocations). We will obtain information regarding whether crizotinib, which targets not only ALK, but also MET, can truly produce efficacy with acceptable safety profiles in ALK

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Staging; Oncogene Proteins, Fusion; Piperidines; Prognosis; Prospective Studies; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Survival Rate; Young Adult

Alectinib, a lipophilic, basic, anaplastic lymphoma kinase (ALK) inhibitor with very low aqueous solubility, has received Food and Drug Administration-accelerated approval for the treatment of patients with ALK+ non-small-cell lung cancer. This paper describes the application of physiologically based absorption modeling during clinical development to predict and understand the impact of food and gastric pH changes on alectinib absorption. The GastroPlus

Topics: Adolescent; Adult; Aged; Animals; Carbazoles; Delayed-Action Preparations; Double-Blind Method; Female; Food; Gastric Acid; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Models, Theoretical; Piperidines; Placebos; Protein Kinase Inhibitors; Rats; Young Adult

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Fasting; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Therapeutic Equivalency; Treatment Failure; Young Adult

Purpose Alectinib has shown activity in the CNS in phase I and II studies. To further evaluate this activity, we pooled efficacy and safety data from two single-arm phase II studies (NP28761 and NP28673; ClinicalTrials.gov identifiers: NCT01871805 and NCT01801111, respectively) in patients with ALK-positive non-small-cell lung cancer (NSCLC). Patients and Methods Both studies included patients with ALK-positive NSCLC who had previously received crizotinib; all patients received alectinib 600 mg twice per day. The primary end point in both studies was independent review committee (IRC)-assessed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Additional end points (all by IRC) included CNS ORR (CORR), CNS disease control rate (CDCR), and CNS duration of response (CDOR). Results One hundred thirty-six patients had baseline CNS metastases (60% of the overall study populations); 50 patients (37%) had measurable CNS disease at baseline. Ninety-five patients (70%) had prior CNS radiotherapy; 55 patients completed the CNS radiotherapy more than 6 months before starting alectinib. Median follow-up time was 12.4 months (range, 0.9 to 19.7 months). For patients with baseline measurable CNS disease, IRC CORR was 64.0% (95% CI, 49.2% to 77.1%), CDCR was 90.0% (95% CI, 78.2% to 96.7%), and median CDOR was 10.8 months (95% CI, 7.6 to 14.1 months). For patients with measurable and/or nonmeasurable baseline CNS disease, IRC CORR was 42.6% (95% CI, 34.2% to 51.4%), CDCR was 85.3% (95% CI, 78.2% to 90.8%), and median CDOR was 11.1 months (95% CI, 10.3 months to not evaluable). CORR was 35.8% (95% CI, 26.2% to 46.3%) for patients with prior radiotherapy (n = 95) and 58.5% (95% CI, 42.1% to 73.7%) for patients without prior radiotherapy (n = 41). As previously reported, alectinib was well tolerated, regardless of baseline CNS disease. Conclusion Alectinib showed good efficacy against CNS metastases, in addition to systemic activity, in crizotinib-refractory ALK-positive NSCLC.

Topics: Adult; Aged; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Endpoint Determination; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Treatment Outcome

Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progression-free survival of 8-11 months while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib.. We enrolled patients with ALK-rearranged NSCLC who progressed on or were intolerant to crizotinib. We administered various oral doses of alectinib (300-900 mg twice a day) during the dose-escalation portion of the study (phase 1), to ascertain the recommended dose for phase 2. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.1) to investigate the activity of alectinib in all patients with a baseline scan and at least one post-treatment scan (CT or MRI), with central radiological review of individuals with brain metastases. We assessed safety in all patients who received at least one dose of alectinib. Here, we present data for the phase 1 portion of the study, the primary objective of which was to establish the recommended phase 2 dose; phase 2 is ongoing. This trial is registered at ClinicalTrials.gov, number NCT01588028.. 47 patients were enrolled. Alectinib was well tolerated, with the most common adverse events being fatigue (14 [30%]; all grade 1-2), myalgia (eight [17%]; all grade 1-2), and peripheral oedema (seven [15%] grade 1-2, one [2%] grade 3). Dose-limiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day; one individual had grade 3 headache and the other had grade 3 neutropenia. The most common grade 3-4 adverse events were increased levels of γ-glutamyl transpeptidase (two [4%]), a reduction in the number of neutrophils (two [4%]), and hypophosphataemia (two [4%]). Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib: acute renal failure; pleural effusion and pericardial effusion; and brain metastasis. At data cut-off (median follow-up 126 days [IQR 84-217]), 44 patients could be assessed for activity. Investigator-assessed objective responses were noted in 24 (55%) patients, with a confirmed complete response in one (2%), a confirmed partial response in 14 (32%), and an unconfirmed partial response in nine (20%). 16 (36%) patients had stable disease; the remaining four (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had an objective response; six (29%) had a complete response (three unconfirmed) and five (24%) had a partial response (one unconfirmed); eight (38%) patients had stable disease and the remaining two (10%) had progressive disease. Pharmacokinetic data indicated that mean exposure (AUC0-10) after multiple doses of alectinib (300-600 mg twice a day) was dose-dependent.. Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2.. Chugai Pharmaceuticals, F Hoffmann La-Roche.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Patient Selection; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Risk Assessment; Survival Analysis; Treatment Outcome

Currently, crizotinib is the only drug that has been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor.. In this multicentre, single-arm, open-label, phase 1-2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264.. Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20-300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93.5%, 95% CI 82.1-98.6) including two complete responses (4.3%, 0.5-14.8) and 41 partial responses (89.1%, 76.4-96.4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment.. CH5424802 is well tolerated and highly active in patients with advanced ALK-rearranged NSCLC.. Chugai Pharmaceutical Co, Ltd.

Topics: Adenocarcinoma; Adult; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Follow-Up Studies; Gene Rearrangement; Humans; Immunoenzyme Techniques; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Piperidines; Prognosis; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Alectinib and its metabolite, M4, have demonstrated a satisfactory clinical therapeutic effect in the treatment of anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer. Due to individual differences among patients, therapeutic drug monitoring (TDM) is critical for guaranteeing appropriate clinical drug use. To realize TDM for alectinib and its metabolite, M4, a honeycomb phenol-formaldehyde resin (PFR) with excellent hydrophilic properties, abundant adsorption force, and a stable porous structure was synthesized by modifying the porogens F127 and P123. The prepared PFR was employed as an adsorbent in a simple and efficient spin-column solid-phase extraction (SPE) process. A rapid method for detecting alectinib and its metabolite M4 in urine was thereby established. The established method showed a linear range of 0.0200 μg mL

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines; Solid Phase Extraction

The treatment landscape of metastatic non-small-cell lung cancer (NSCLC) has changed dramatically in the last decade. Anaplastic lymphoma kinase (ALK) rearrangement has been a focus of interest since ALK inhibitors produced outstanding clinical results compared with chemotherapy with cytotoxic agents in patients with ALK-positive NSCLC.. We present the case of a 56-year-old woman with metastatic ALK-positive NSCLC and an inability to swallow capsules or tablets. Unfortunately, all ALK inhibitors are capsule or tablet formulations.. We, therefore, decided to administer alectinib orally by opening the capsules and suspending the contents in water. Clinical imaging performed 12 months after initiating alectinib therapy indicated a complete response (CR). After 54 months of follow-up, CR has been maintained, and oral alectinib therapy has continued with no recurrence of the swallowing disturbance.. There are no current guidelines for oral targeted therapy in patients with swallowing disturbance, but alectinib administered orally by opening the capsules and suspending the contents in water can be a treatment option in patients with ALK-positive NSCLC and swallowing difficulty.

Topics: Capsules; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Middle Aged; Piperidines; Protein Kinase Inhibitors

Inflammatory myofibroblastic tumor (IMT) is an ultra-rare soft tissue neoplasm associated with fusion proteins encompassing the anaplastic lymphoma kinase (ALK) protein fused to a variety of partner proteins. Data regarding response to ALK-targeting agents based on fusion partner is limited.. A 30-year-old female sought emergency care after onset of abdominal and lower back pain in 2019. Computed tomography (CT) demonstrated a cystic, mesenteric mass within the pelvis measuring up to 8.9 cm. Complete laparoscopic excision of the mass from the mesentery of the right colon and terminal ileum was performed. Pathologic assessment revealed IMT with a fusion between sequestosome 1 and ALK (SQSTM1::ALK), described in only two other cases of IMT. Four months after surgery, CT revealed multi-focal, unresectable disease recurrence. She was referred to the University of Washington/Fred Hutchinson Cancer Center and placed on therapy with alectinib, after which she experienced a partial response. Three years after IMT recurrence, disease remains under control.. This is the third reported case of IMT associated with the novel SQSTM1::ALK fusion protein, and the second treated with alectinib. Treatment with the ALK inhibitor alectinib appears to be active in this setting.

Topics: Adult; Anaplastic Lymphoma Kinase; Female; Humans; Neoplasm Recurrence, Local; Piperidines; Sequestosome-1 Protein

Anaplastic lymphoma kinase (ALK) rearrangement, which is mostly showed as fused with echinoderm microtubule-associated protein-like 4 gene (EML4), accounts 3-7% of all common mutations in non-small lung cancer (NSCLC). An intergenic region (chr2: 30,193,816), which located on upstream of the adjacent ALK gene, was never been reported as a ALK patterner before.. A 56-year-old female patient who had symptoms of persistent cough and shortness of breath visited our facility on April 24, 2022. The chest computerized tomography (CT) examination revealed a massive right hydrothorax. After draining pleural effusion, a hilar mass accompanied multiple nodules in both lungs could been seen in image. Tracheoscopy revealed neoplasm in the medial segment of the middle lobe of the right lung, and the patient was diagnosed as lung adenocarcinoma pathologically. It tested positive for cytokeratin (CK) 7, NapsinA, ALK, and thyroid transcription factor-1 (TTF-1). Next generation sequence testing confirmed the presence of the intergenic region (chr2: 30,193,816)-ALK fusion in the tumor tissue. The patient was subsequently treated with Alectinib, and her symptoms are obviously relieved, the right hilar mass and metastatic nodule were reduced in the reexamination after three months.. The intergenic region (chr2: 30,193,816)-ALK fusion, which is firstly reported in lung adenocarcinoma, is a mutation with expression significance. It shows sensitivity to Alectinib.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Female; Humans; Lung Neoplasms; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

Topics: Carbazoles; Child; Glioma; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Topics: Carbazoles; Hemorrhage; Humans; Lung Diseases; Piperidines; Pulmonary Alveoli

The incidence of lung cancer in pregnancy is increasing because of an increase in cigarette smoking among young women, air pollution, and advanced maternal age. This is the third case report of a woman with metastatic anaplastic lymphoma kinase (ALK)-positive lung adenocarcinoma treated with alectinib during pregnancy. The patient was diagnosed with lung cancer at 26 weeks' gestation. Her condition rapidly progressed to disseminated intravascular coagulation accompanied by hypoxemia. After 5 days of treatment with alectinib 600 mg twice daily and best supportive care, the patient's symptoms quickly resolved. She delivered a healthy male newborn at 39 weeks' gestation. At birth, the alectinib concentration was 4.3 times higher in maternal plasma than that in newborn plasma (299.0 vs 69.2 ng/mL). The concentrations of alectinib in the amniotic fluid and the placenta were 27.3 ng/mL and 1136.25 ng/g, respectively. The alectinib concentration in the maternal milk (152 ng/mL) indicated that this drug could be excreted through the breast milk. At 12 months after the diagnosis, the mother had recovered well, and no developmental anomalies were observed in the infant.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Infant, Newborn; Lung Neoplasms; Male; Piperidines; Pregnancy; Protein Kinase Inhibitors

Topics: Carbazoles; Dietary Fats; Food; Humans; Piperidines; Randomized Controlled Trials as Topic

Tyrosine kinase inhibitors of anaplastic lymphoma kinase (ALK-TKIs) including alectinib have been the standard therapy against ALK fusion gene-positive non-small cell lung cancers (NSCLCs). Many ALK fusion variants have been identified in NSCLCs, and the predominant variants are echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) variant 1 (V1), V2 and V3a/b. However, there have been conflicting reports on the clinical responses of these variants to ALK-TKIs, and there are few reports on other less common ALK variants. To examine the influence of ALK variants on the efficacy of ALK-TKIs, we analyzed the sensitivity to alectinib of eight types of ALK variant: three major variants (V1, V2 and V3a) and five less common variants (V4; kinesin family member 5-ALK; kinesin light chain 1-ALK; striatin, calmodulin-binding protein-ALK; and tropomyosin-receptor kinase fused gene-ALK). Analysis was done by cell-free kinase assays using the recombinant proteins and by cell, growth assays using murine Ba/F3 cells expressing ALK variants. The kinase activity of each recombinant protein was significantly inhibited by alectinib. Intracellular ALK phosphorylation levels and its downstream signaling mediators, STAT3 and ERK, were suppressed by alectinib in each ALK variant-expressing Ba/F3 cell. Each cellular proliferation was markedly inhibited by alectinib treatment. There was no significant difference in the IC50 values between cells, with a <3.6-fold difference in responsiveness. In conclusion, these eight ALK variants had similar sensitivity to alectinib in vitro, indicating that it may not be possible to predict the response to alectinib just by determination of the ALK variant type in ALK fusion-positive NSCLCs.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Cell Proliferation; DNA, Circular; Extracellular Signal-Regulated MAP Kinases; Humans; Mice; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Signal Transduction; STAT3 Transcription Factor

Topics: Adenocarcinoma of Lung; alpha-Thalassemia; Carbazoles; Erythrocytes, Abnormal; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines

There is limited data on the clinical outcome, long-term survival and tolerability of sequential therapy of first-line crizotinib followed by alectinib in a real-world setting for Chinese patients with advanced ALK+ NSCLC.. The medical records of patients who received sequential therapy with first-line crizotinib followed by alectinib (no intermittent systemic therapy was allowed between the two ALK-TKIs) were collected from six centers in China. Combined time treatment to failure (C-TTF) was defined as the period from the start of crizotinib to the complete discontinuation of alectinib due to any cause.. A total of 61 patients were included in our study. Fifty-two patients were switched to alectinib due to disease progression, seven as a result of toxicity, and two due to patient preference. At the time of data cutoff, alectinib treatment was discontinued in 31 patients on account of disease progression while severe adverse events resulted in cessation of alectinib in another two patients. Rebiopsy was conducted in 21 patients following disease progression on alectinib in whom ALK secondary mutation was found in 13 patients. Patients with ALK secondary mutation demonstrated better PFS during treatment with subsequent ALK-TKIs compared with those without (10.4 vs. 3.1 m, p = 0.0018, HR = 0.08). With a median follow-up of 34.3 months, C-TTF was 39.2 months and estimated 5-year OS was 68.6% in the overall population.. Sequential therapy with first-line crizotinib followed by alectinib demonstrated long-term benefits. Different efficacy in subsequent ALK-TKI between patients with or without ALK secondary mutation further emphasized the importance of rebiopsy to guide targeted therapy more precisely.

Topics: Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; China; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Retrospective Studies

The echinoderm microtubule associated protein-like 4 gene (EML4) encodes the predominant anaplastic lymphoma kinase (ALK) fusion partner in non-small-cell lung cancer (NSCLC); however, the dynactin subunit 1 (DCTN1)-ALK rearrangement is extremely rare. The co-occurrence of primary epidermal growth factor receptor (EGFR) T790M mutation with EGFR exon 19 deletion (del) in patients with NSCLC is uncommon. Here we report a female lung adenocarcinoma patient with brain metastases and possible coexistence of primary EGFR T790M mutation/EGFR exon 19 del/DCTN1-ALK translocation. The patient received multiline treatment including chemotherapy, antivascular, and targeted therapies. To overcome developed resistance to chemotherapy or targeted therapy to prolong overall survival, the patient's circulating tumor DNA (ctDNA) was dynamically monitored. The patient responded to successive osimertinib and alectinib treatment, and alectinib achieved a nearly complete response for lung and brain lesions after she acquired osimertinib resistance. Furthermore, we summarize 22 published cases of patients with lung adenocarcinoma with concurrent EGFR mutation and ALK rearrangement, including details of clinical characteristics, natural history, and pertinent therapy of this uncommon tumor subtype. This literature review shows that EGFR inhibition was an indispensable aspect of the treatment of patients with EGFR/ALK co-alterations in the pre-alectinib era and that ALK inhibition with crizotinib did not show more eye-catching therapeutic results. Considering the effectiveness achieved by alectinib, this case study provides a new perspective for the treatment of lung cancer brain metastasis patients with concurrent EGFR/ALK mutations.

Topics: Acrylamides; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Aniline Compounds; Brain; Carbazoles; Carcinoma, Non-Small-Cell Lung; Dynactin Complex; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors

Topics: Adverse Drug Reaction Reporting Systems; Anemia, Hemolytic; Carbazoles; Humans; Piperidines; United States; United States Food and Drug Administration

Topics: Anaplastic Lymphoma Kinase; Ankyrin Repeat; Carbazoles; Carcinoma, Acinar Cell; Gene Fusion; Humans; Male; Middle Aged; Pancreatic Neoplasms; Piperidines; Treatment Outcome

Central nervous system (CNS) metastases in patients with ALK-positive non-small cell lung cancer (NSCLC) are a cause of substantial morbidity and mortality. Although alectinib had demonstrated promising intracranial efficacy in several clinical trials, data were limited on its CNS activity in real-world settings.. In this retrospective study, ALK-positive NSCLC patients with brain metastases (BM) or leptomeningeal metastases (LM) from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib. ALK-TKI-naive patients were enrolled in cohort 1, cohort 2 included patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib, and cohort 3 included patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs. The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1.. Sixty-five patients were eligible and included in our study (cohort 1: 20, cohort 2: 32, cohort 3: 13). For the overall population and patients with uncontrolled CNS metastases, similar intracranial response in CNS target lesions was observed: cohort 1: 81.8% and 80%; cohort 2: 76.5% and 86.7%; cohort 3: 42.8% and 33.3%. For patients in these three cohorts, 75% (6/8), 78.6% (11/14), and 83.3% (5/6) were reported to have significant improvement in CNS-related symptoms respectively. The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib (p < 0.001), and there was also a steep fall-over in the number of patients with ECOG ≥2 points before and after the administration of alectinib (p = 0.003). All patients (8/8) diagnosed with LM ± BM experienced substantial alleviation in CNS-related symptoms. In cohort 1 and cohort 2, no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone.. Our study substantiated the potent CNS activity of alectinib in real-world settings. Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively, which indicated that alectinib alone might defer the timing of local treatment. However, our results should be treated cautiously owing to limited sample size.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Retrospective Studies

Topics: Abetalipoproteinemia; Carbazoles; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Topics: Adenocarcinoma of Lung; Carbazoles; Humans; Lung Neoplasms; Neoplasm Metastasis; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases

We report a rare case of stage IV pulmonary combined large-cell neuroendocrine carcinoma (LCNEC) and adenocarcinoma (ACA), both demonstrating anaplastic lymphoma kinase (

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Neuroendocrine; Female; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

(1) Background: Just little is known about the interaction of ALK/ROS1-targeting kinase inhibitors with ionizing radiation (IR), particularly regarding side effects. We investigated the toxicity in two different lung cell lines both ALK/ROS1 wildtype (healthy and tumor origin) as representatives for normal lung tissue; (2) Methods: Human lung cell line BEAS-2B and malignant A549 lung cancer cells (ALK/ROS1 wt) were treated with alectinib or crizotinib, 2 Gy irradiation or a combination of KI and IR. Cell toxicity was analyzed by cell death (Annexin, 7AAD), colony forming, migration assay and live-cell imaging (TMRM, DRAQ7, Caspase3/7). Cell cycle (Hoechst) were analyzed by flow cytometry; (3) Results: Crizotinib led to higher cell death rates than alectinib, when cells were treated with 10 µM KI. Alectinib induced a more intense growth inhibition of colonies. Both inhibitors showed additive effects in combination with irradiation. Combination treatment (IR + KI) does not lead to synergistic effect on neither cell death nor colony forming; (4) Conclusions: The influence of simultaneous KI and IR was studied in non-mutated ALK/ROS1 cell lines. Both KIs seems to be well tolerated in combination with thoracic radiotherapy and lacked synergistic reinforcement in cellular toxicity. This supports the feasibility of ALK/ROS1 inhibition in combination with thoracic irradiation in future clinical trials.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Radiation, Ionizing

There are no evidence-based data in the literature to demonstrate that alectinib shows a clinically relevant advantage over chemotherapy in anaplastic lymphoma kinase-positive non-small cell lung cancer pretreated with crizotinib. Therefore, we designed this systematic review and meta-analysis protocol to reveal whether the safety and efficacy of alectinib are indeed superior to chemotherapy alone in this special group of patients.. This protocol will be written following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols statement guidelines. We will search databases from Web of Science, Embase, PubMed, Wanfang Data, Scopus, Science Direct, Cochrane Library from their inception to June 2022, restricting them to human subjects and clinical trials. Outcomes include progression-free survival, central nervous system progression, and incidence of adverse events. Pooled analyses will be calculated using fixed-effect models, whereas random-effect models will be applied in case of significant heterogeneity across studies. Any disagreements will be discussed and resolved in discussions with the third reviewer.. We hypothesized that alectinib would be superior to chemotherapy in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer pretreated with crizotinib.. The review will add to the existing literature by showing compelling evidence and improved guidance in clinic settings.. 10.17605/OSF.IO/PQF53.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Meta-Analysis as Topic; Piperidines; Protein Kinase Inhibitors; Systematic Reviews as Topic

Genomic fusions of anaplastic lymphoma kinase (ALK) are a well-established therapeutic target in non-small-cell lung cancer (NSCLC). Although various ALK fusion variants have been identified in NSCLC, their responses to ALK tyrosine-kinase inhibitors (TKIs) are heterogeneous. We report the case of a 71-year-old female patient diagnosed with lung adenocarcinoma with liver metastases. A novel CTNND1 (exon 14)-ALK (exon 20) fusion was identified from the biopsy sample by next-generation sequencing (NGS) and validated by immunohistochemistry (IHC) staining. Alectinib was administered, and the patient soon achieved partial response (PR). The progression-free survival (PFS) exceeded 15 months as of January 25, 2022. Our findings expand the spectrum of ALK rearrangements and provide a potential treatment option for lung adenocarcinoma patients with CTNND1-ALK fusions.

Topics: Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Patients with advanced non-small-cell lung cancer (NSCLC) who have a genetic marker called rearrangement in the anaplastic lymphoma kinase, or

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Crizotinib; Disease Progression; Humans; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrimidines

ALK (anaplastic lymphoma kinase) gene rearrangements have been reported in 3-5% of NSCLC patients. Different ALK fusion forms can mediate different downstream signaling pathways and may exhibit different sensitivities to ALK tyrosine kinase inhibitors (TKIs). To identify more fusion partners that are sensitive to ALK-TKIs, we present a case of 46-year-old woman with stage IV lung adenocarcinoma. NGS panel analysis suggested that a novel SSFA2-ALK fusion was identified in this patient. Moreover, this fusion was validated through IHC (VENTANA ALK (D5F3) antibody) and FISH (ZytoLight ALK Break Apart FISH Probe). Importantly, to the best of our knowledge, there is no report about SSFA2-ALK fusion in solid cancers. Moreover, the patient achieved an admirable response to alectinib, with a clinical evaluation of complete response (CR). In summary, our findings expand the spectrum of ALK fusion patterns and provide robust evidence for the precise administration of alectinib in the future.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

The anaplastic lymphoma kinase (ALK) inhibitor alectinib is recommended as a first-line treatment for ALK lung cancer. Interstitial lung disease is the most common adverse event leading to discontinuation of alectinib. The purpose of this study was to use the Japanese Adverse Drug Event Report database for the evaluation of incidence trends and timing of alectinib toxicity in the lungs.. Adverse drug reactions (ADRs) by alectinib were extracted between April 2004 and March 2021. Data related to lung toxicity ADRs were analyzed, and the relative risk was estimated using the reporting odds ratio (ROR) and 95% confidence interval (CI). The time of onset of the lung toxicity signs was noted.. We obtained 524 reports of ADRs associated with alectinib. Of these, 157 were lung toxicity, including interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema. The RORs for these signs were 10.28 (95%CI=8.38-12.60), 9.19 (5.58-15.13), 7.40 (3.67-14.88), and 7.01 (3.13-15.69), respectively. The median onset times (quartiles, 25-75%) of interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema associated with alectinib treatment were 92 (36-195), 57 (51-129), 228 (62-431), and 83 (22-96) days, respectively.. Among the lung toxicity signs, interstitial lung disease had the highest ROR, suggesting a strong causal relationship with alectinib treatment. Interstitial lung disease most frequently developed within 60 days after the start of treatment. These results will be useful for monitoring adverse events associated with the use of alectinib.

Topics: Adverse Drug Reaction Reporting Systems; Carbazoles; Humans; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Pharmacovigilance; Piperidines; Protein Kinase Inhibitors; Pulmonary Edema; Receptor Protein-Tyrosine Kinases

This retrospective observational study analyzed the clinical characteristics, treatment patterns and outcomes of 120 patients with advanced ALK-positive non-small-cell lung cancer (ALK+ NSCLC) according to data collected between November 2019 and October 2020 in 38 Spanish hospitals. Patients had progressed after 1-5 prior treatment lines (which included crizotinib in any prior line) and received subsequent therapy with alectinib in a local expanded access program. Median age was 58.7 years, 50% of patients were female, 64.1% had ECOG PS of 0-1, 85% presented stage IV, 95% had adenocarcinoma histology and 20.8% had brain metastases. After a median 9.6 months of alectinib treatment, objective response rate (ORR) was 54.5%, disease control rate (DCR) was 80%, median progression-free survival (PFS) was 9.4 months and median overall survival (OS) was 24.1 months. Patients with brain metastases achieved an intracranial DCR of 71.4%. Adverse events (AEs) were reported in 35.8% of patients (14.2% of AEs were grade ≥3). Over 40% of patients received some treatment after alectinib, most frequently lorlatinib (65.2%) and brigatinib (32.6%). This study provides information on real-world treatment patterns and confirms the tolerability and prolonged PFS and OS observed with alectinib in clinical trials, in unselected pretreated patients with advanced ALK+ NSCLC.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

The advancements in cancer treatment, particularly in the last two decades, have been promising. Non-small-cell lung cancer (NSCLC) is one of the most important diseases experiencing these promising developments. ALK positivity, which is caused by the rearrangement of different gene fragments between two chromosomes, affects about 5% of NSCLC patients. This provides a target for next-generation therapies. One of these targeted therapy drugs is alectinib. The authors examined the outcomes of 271 patients with body-disseminated NSCLC who received alectinib as initial targeted therapy. These patients were not chosen to participate in a clinical phase study. They were treated with an approved drug; the study also included 97 patients who had previously received chemotherapy. The median duration of survival without disease worsening was 26 months for all patients receiving alectinib treatment. This value was 28.8 months in 177 patients who had not received any treatment before alectinib. Regardless of disease status, 77% of all patients were found to be alive at the end of the first year. Alectinib treatment resulted in a significant improvement of the disease in approximately four out of five patients. The treatment's side effects were generally tolerable or manageable. Only four patients were reported to have discontinued their medication due to treatment-related side effects. These real-world findings are compatible with previous clinical research. Alectinib is an important first-line treatment option for patients with advanced, ALK-positive NSCLC.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Retrospective Studies

Topics: Carbazoles; Carcinoma; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Second-generation anaplastic lymphoma kinase (. To estimate the relative overall survival (OS) for brigatinib vs alectinib with indirect treatment comparisons (ITCs) using ALEX and ALTA-1L clinical trial data.. The latest aggregate data from the ALEX trial and final patient-level data from ALTA-1L were used. ITCs were conducted with/without treatment crossover adjustments to estimate relative OS. Bucher methods, anchored matching-adjusted indirect comparisons (MAICs) and unanchored MAICs were employed in ITCs without treatment crossover adjustments. An inverse probability of censoring weight Cox model, a marginal structure model and rank-preserving structural failure time models (with/without re-censoring) within an anchored MAIC were used in ITCs with treatment crossover adjustments. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported.. HRs for brigatinib vs alectinib for relative OS generated from ITCs without treatment crossover adjustments ranged from 0.90 (95% CI: 0.59-1.38) in the unanchored MAIC to 1.20 (95% CI: 0.69-2.11) using the Bucher method. Methods employing treatment switching adjustments estimated HRs for relative OS ranging from 0.74 (95% CI: 0.38-1.45) to 1.11 (95% CI: 0.63-1.94). Results from all ITCs did not indicate statistically different survival profiles.. Regardless of ITC methodology, OS is comparable for brigatinib vs alectinib in patients with

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrimidines

Alectinib is one of the targeted therapies commonly given to patients with advanced non-small cell lung cancer (NSCLC) with mutations in the ALK gene. The most common adverse effects of alectinib are fatigue, constipation, edema, myalgia and anemia. Meanwhile, bradycardia was reported as a very common adverse effect, but generally asymptomatic, unlike the reported patient in this case report. This case report's purpose is to increase awareness of the possibility of adverse effects due to alectinib administration that require immediate intervention in order to improve the quality of life and patient survival, especially in patients with advanced NSCLC.

Topics: Anaplastic Lymphoma Kinase; Bradycardia; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Quality of Life; Receptor Protein-Tyrosine Kinases

We report an unplanned pregnancy in an HIV-positive woman in her 20s who was undergoing treatment for 6 months with alectinib (Alecensa) for stage IV non-small-cell lung carcinoma. Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor alectinib, a molecule that inhibits proteins involved in tumour cell growth, is the recommended first-line treatment option in case of ALK mutation. Although the patient was informed of the need for definitive contraception, she became pregnant during the treatment with alectinib. A complete tumour response was observed at the time the pregnancy was discovered. Treatment discontinuation was proposed as the patient wanted to keep the pregnancy. Alectinib was temporarily stopped throughout the remaining pregnancy period inline with the patient's wishes. The pregnancy was uncomplicated. She delivered a healthy female baby vaginally, with treatment being resumed after delivery. After 34 follow-up months, the patient remained in oncological remission and the child's physical development is normal.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Child; Female; HIV Infections; Humans; Lung Neoplasms; Piperidines; Pregnancy; Pregnancy, Unplanned; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Anaplastic lymphoma kinase ( ALK ) rearrangement defines a unique nonsmall cell lung cancer (NSCLC) molecular subtype, of which the patients could potentially benefit from anti- ALK therapies. So far, the outcomes of the canonical echinoderm microtubule-associated protein-like ( EML-ALK ) patients subjected to ALK inhibitors are well established. However, given the increasing complexity of ALK fusion partners, as detected by high-throughput sequencing, the responses of those with rare ALK fusion events remain to be explored. Here, we report a lung adenocarcinoma patient with brain metastasis harboring an ARHGAP5 downstream intergenic region ALK fusion, as detected by using DNA-based next-generation sequencing, who experienced a partial response to alectinib treatment. While whole- transcriptome RNA sequencing (RNA-seq) failed to identify potential ALK fusion transcripts, subsequent targeted deep RNA-seq revealed the expression of EML4-ALK transcripts in the tumor tissue. Given the increasing application of the ALK-tyrosine kinase inhibitors (TKIs), it is extremely crucial to define the patients who could be suitable for this treatment in clinic. The present case has provided supporting evidence that noncanonical ALK rearrangements on the genomic level are often functionally relevant and targetable by ALK-TKI, particularly in cases with sub-optimal quantity and quality for RNA validation.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; DNA, Intergenic; Humans; Lung Neoplasms; Microtubule-Associated Proteins; Piperidines; Protein Kinase Inhibitors; RNA

Anaplastic lymphoma kinase tyrosine kinase inhibitors are standard therapeutic agents prescribed for anaplastic lymphoma kinase-positive non-small cell lung cancer, and treatment with these agents has been shown to contribute to long-term survival in patients. However, there is no consensus regarding the course of treatment after the onset of anaplastic lymphoma kinase tyrosine kinase inhibitors related drug-induced interstitial lung disease. Here, we present a case of successful lorlatinib treatment after the onset of drug-induced interstitial lung disease caused by alectinib.. A 57-year-old Japanese man was diagnosed with stage IVB non-small cell lung cancer by bronchoscopy, but gene mutation testing could not be performed because of the small amount of specimen. After diagnosis, first-line therapy with cisplatin/pemetrexed was initiated, but the patient developed renal dysfunction. Bronchoscopy was performed again to guide further treatment, and the non-small cell lung cancer was found to be anaplastic lymphoma kinase positive. Alectinib was started after the onset of progressive disease, but it resulted in drug-induced interstitial lung disease, necessitating alternative treatments. He subsequently received nanoparticle albumin bound paclitaxel, which was halted in view of the renal dysfunction. Thereafter, lorlatinib was administered, which was continued without drug-induced interstitial lung disease relapse.. Since alectinib can occasionally cause drug-induced interstitial lung disease, as in the present case, lorlatinib may be an option to continue treatment in patients without other treatment alternatives.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Kidney Diseases; Lactams; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles

A 28-year-old male patient presented with multiple lymphadenopathies and extranodal masses. He was diagnosed with stage IVB ALK-positive anaplastic large cell lymphoma after the right axillary lymph node biopsy. A partial metabolic response with fluorodeoxyglucose accumulation was observed in the residual disease of the upper left hilar lymph node after eight courses of brentuximab vedotin, cyclophosphamide, adriamycin, and prednisolone. We started alectinib at 600 mg daily, which achieved a complete metabolic response (CMR) after three months. The CMR was maintained and alectinib was continuously administered without adverse events at the last follow up. Alectinib showed high efficacy and tolerability, though the optimal period and long-term adverse effects of administration remain unclear. Therefore, further studies are necessary.

Topics: Adult; Anaplastic Lymphoma Kinase; Brentuximab Vedotin; Carbazoles; Humans; Lymphoma, Large-Cell, Anaplastic; Male; Neoplasm, Residual; Piperidines

Neoadjuvant therapy prior to surgical resection for locally advanced lung cancer has evolved to incorporate systemic cytotoxic chemotherapy +/- immunotherapy +/- radiotherapy. The role of neoadjuvant precision therapies remains understudied.. We report cases with major and complete pathologic responses to off-label neoadjuvant alectinib.. A case with stage IIIA (cT1b cN2 cM0) EML4-ALK variant 3a/b lung adenocarcinoma received 6 weeks of alectinib followed by R0 left upper lobectomy with complete pathological response (ypT0 ypN0). Another case with stage IIIA (cT3 cN2 cM0) EML4-ALK variant 2 received 12 weeks of alectinib followed by R0 right middle lobectomy with a major pathologic response (ypT1a ypN0) but systemic recurrence 12 months post-operatively.. Ongoing clinical trials are evaluating the role of both neoadjuvant and adjuvant ALK-directed therapy. Our cases support the completion of ongoing trials (ALINA: NCT03456076 and ALNEO: NCT05015010), and highlight the ability of second generation ALK inhibitors to induce major and complete pathologic responses in the neoadjuvant setting plus the likely role of long-term adjuvant kinase inhibitor therapy to prevent radiographic/clinical recurrence.

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Lung Neoplasms; Neoadjuvant Therapy; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

A 55-year-old Chinese man with a right lung mass and lymph node metastasis (T4N3M0 IIIB) was diagnosed with lung adenocarcinoma after a CT-guided biopsy. With the wide application of next-generation sequencing (NGS) in tumour detection, we found a rare CCDC85A-ALK fusion. The patient received alectinib, which had marked efficacy. This is the first report of a lung adenocarcinoma patient harbouring a new uncommon anaplastic lymphocyte kinase fusion that showed a remarkable response to alectinib. NGS aids in selecting treatment in non-small cell lung cancer patients.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

A remarkable concurrence of an EGFR mutation and an EML4-ALK fusion (double positive) occasionally occurs within a narrow number of patients. Previous studies using targeted therapy on EGFR/ALK co-mutated patients have commonly focused on single tyrosine kinase inhibitors (TKIs) or on the sequential use of EGFR-TKIs and ALK-TKIs. At present, no consensus exists regarding the treatment of patients with double positive mutations. The effectiveness of precision therapy also remains unknown.. A 53-year-old female non-smoker who described recurrent coughing and blood in her sputum over a month-long interval was examined at a local hospital.. Using computed tomography (CT) and positron emission tomography CT (PET-CT), the patient was diagnosed with Stage IVb lung adenocarcinoma (T4N3M1).. The patient had a novel ALK-RAB10 rearrangement identified using DNA sequencing, which, at the transcript level, was actually a canonical ALK fusion that caused a response to alectinib therapy.. The patient has achieved partial remission (PR), with a progression free survival (PFS) of 16 months, and continues to benefit.. Our results may indicate differential sensitivities to TKIs in patients harboring an EGFR mutation and an ALK rearrangement. Our patient's response to alectinib, instead of to EGFR-TKIs, may lead to an expanded list of alectinib beneficiaries who have rare gene co-alterations in lung adenocarcinoma.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Piperidines; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors

Targeted therapy with anaplastic lymphoma kinase inhibitor alectinib has become standard therapy for selected patients with non-small cell lung carcinoma. Few data are available on the renal effects of alectinib. We report on a case of acute kidney injury in a patient using alectinib for less than 2 weeks and on serum sodium and creatinine during long-term use of alectinib.. A 70-year-old Asian woman was diagnosed with metastasized non-small cell lung carcinoma (cT4N3M1c, stage IV) with echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase gene rearrangement and received alectinib, in two daily doses of 600 mg. Eleven days after the initiation of therapy, she was seen at the emergency department with acute kidney injury. Renal biopsy showed lesions in the proximal tubular epithelial cells. Nine days after alectinib cessation, renal function recovered quickly and reintroduction of alectinib in a reduced dose was tolerated, while withholding metformin, enalapril, and naproxen. In seven other patients, data on estimated glomerular filtration rate showed decreased kidney function at 3 months with stabilization at 6 months. Serum sodium at 3 months increased during alectinib treatment and increased further at 6 months.. Our data suggest direct or indirect toxic (proximal) tubulopathy due to alectinib with a good prognosis after cessation. Adverse acute renal effects of alectinib may be prevented by avoiding other medication influencing renal hemodynamics, in particular nonsteroidal anti-inflammatory drugs. Without these co-medications, alectinib could be reintroduced in our patient.

Topics: Acute Kidney Injury; Aged; Anaplastic Lymphoma Kinase; Anti-Inflammatory Agents; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Creatinine; Enalapril; Female; Humans; Kidney; Lung Neoplasms; Metformin; Microtubule-Associated Proteins; Naproxen; Piperidines; Protein Kinase Inhibitors; Sodium

Six anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), including one domestic (ensartinib) and five imported ALK-TKIs (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib), have been recommended as first-line treatments for advanced ALK-positive NSCLC in China. This study sought to examine the cost-effectiveness of these six novel therapies in Chinese patients.. We constructed a Markov model to compare the cost-effectiveness of the six ALK-TKIs as a first-line treatment for patients with advanced ALK-positive NSCLC from the perspective of the Chinese healthcare system. Transition probabilities were estimated by synthesizing data from the PROFILE 1,029 trial and a network meta-analysis. Health state utilities and costs were sourced from published literature, publicly available national databases, and local general hospitals. The robustness of model was assessed. Compared with crizotinib, ensartinib achieved additional 0.12 quality-adjusted life-year (QALY) with marginal costs of $3,249, resulting in an incremental cost-effectiveness ratio (ICER) of $27,553/ QALY. When compared with ceritinib and brigatinib, ensartinib achieved additional 0.06 and 0.03 QALYs with substantially reduced costs. When compared with lorlatinib and alectinib, ensartinib was associated with a lower QALY and decreased total costs; the ICERs for lorlatinib and alectinib were $934,101/ QALY and $164,888/ QALY, respectively.. For Chinese patients with advanced ALK-positive NSCLC, ensartinib was a cost-effective option compared with crizotinib, and was a dominant alternative to ceritinib and brigatinib. Although lorlatinib and alectinib were associated with prolonged survival compared with ensartinib, they were less cost-effective than ensartinib due to the overwhelming total costs.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Cost-Benefit Analysis; Crizotinib; Humans; Lactams; Lung Neoplasms; Network Meta-Analysis; Organophosphorus Compounds; Piperazines; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridazines; Pyrimidines; Sulfones

The echinoderm microtubule-associated protein-like 4 gene and anaplastic lymphoma kinase gene (EML4-ALK) is the most frequent fusion variant of ALK rearrangements in non-small cell lung cancer (NSCLC). With the widespread application of next-generation sequencing (NGS), more fusions and co-mutations of EML4-ALK have been discovered. Complex co-mutation of EML4-ALK fusions together with BRAF V600E, though rarely occurred, also deserves attention to determine the standard of caring these patients. Herein, we report a case of lung adenocarcinoma harboring a complex ALK fusion that coexisted with a BRAF mutation, as tested by DNA-NGS prior to treatment.. A 51-year-old non-smoking man, without any symptoms, was admitted to hospital due to small pulmonary nodules and enlarged supraclavicu larlymph nodes found in health checkup.. He was diagnosed with stage IVB (T4N3M1c) lung adenocarcinoma. BRAF V600E (abundance 3.75%) mutation and a novel thus little-understood EML4-ALK (E13, A5; abundance 2.16%) fusion were identified by DNA-NGS analysis of lymph node biopsy tissue in December 2019.. Darafenib plus trametinib targeted therapy and chemotherapy were given firstly, but tumor progression was not inhibited. The ALK inhibitor alectinib was prescribed then.. The patient exhibited a rapid disease response to ALK tyrosine kinase inhibitors alectinib with a complete remission of widespread metastatic disease and progression-free survival of more than 26 months, but not to darafenib plus trametinib targeted BRAF V600E therapy. Re-analyzed the patient's DNA-NGS original data, showed it is a rare and complex EML4-ALK (E13, A5, A20) fusion in fact. Additional RNA-NGS analysis showed it verified to be a canonical EML4-ALK (E13, A20) fusion transcript and coexisting with a BRAF V600E mutation.. This case suggests that for patients with rare or complex EML4-ALK fusions at DNA level, additional RNA-NGS is necessary to verify its functionality as early as possible. Targeting EML4-ALK firstly may be more preferable despite the coexisting of BRAF V600E.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Microtubule-Associated Proteins; Middle Aged; Mutation; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; RNA

Relapsed and refractory ALK-positive anaplastic large cell lymphoma (ALCL) has a poor prognosis. In this report, we present 3 relapsed/refractory pediatric ALCL patients, 1 of these with central nervous system involvement. All 3 patients were treated with ALK inhibitor and achieved complete response. Both crizotinib and alectinib have shown significant activity in pediatric patients with refractory ALK-positive ALCL.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Child; Crizotinib; Female; Humans; Infant; Lymphoma, Large-Cell, Anaplastic; Neoplasm Proteins; Piperidines; Recurrence

Lung cancer complicated with Trousseau syndrome (TS) or disseminated intravascular coagulation (DIC) has a severe prognosis. We herein report an elderly lung cancer patient who presented with a critically ill condition due to concomitant TS and DIC and responded dramatically to alectinib. There are no rules regarding treatment indications based on the age or severity of critically ill patients. If the patient's cancer cells are positive for anaplastic lymphoma kinase rearrangement, alectinib is worthwhile to administer, even in a critically ill condition. In our patient, anticoagulation failed to suppress the TS complications. We also report how to prevent the recurrence of TS.

Topics: Adenocarcinoma of Lung; Aged; Carbazoles; Critical Illness; Disseminated Intravascular Coagulation; Humans; Lung Neoplasms; Piperidines

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Follow-Up Studies; Humans; Lung Neoplasms; Maximum Tolerated Dose; Piperidines; Protein Kinase Inhibitors; Survival Analysis; Trastuzumab

Photodynamic therapy with a photosensitizer such as protoporphyrin-IX, a light sensitive metabolite of heme synthesis, is a highly selective treatment for various carcinomas. In previous studies, we found a significant down regulation of the relevant enzyme ferrochelatase in gastrointestinal carcinomas leading to an accumulation of protoporphyrin-IX within the tumor cells. Recent studies showed that a novel anti-cancer drug, Alectinib, an orally available, highly selective, potent second-generation inhibitor of anaplastic lymphoma tyrosinkinase binds to ferrochelatase. Therefore, we were interested to see whether Alectinib treatment might lead to an accumulation of protoporphyrin IX.. Tumor cells of different origin were cultured, treated with LED-light and Alectinib. Results were gained by flow cytometry, immunohistochemistry and western blotting. Apoptosis was determined by flow cytometric analysis of Annexin V-FITC stained cells. In addition, cells were counterstained with propidium iodide to distinguish early apoptotic cells and late apoptotic/necrotic cells.. Here, we report that photodynamic treatment of tumor cell lines of different origin in combination with Alectinib increased protoporphyrin-IX specific fluorescence and concomitantly cell death.. The usage of Alectinib could be another step for enhancing the effectiveness of photodynamic therapy. Further experiments will show whether photodynamic therapy in combination with Alectinib could be a new strategy for the treatment of e.g. peritoneal disseminated carcinomas.

Topics: Aminolevulinic Acid; Carbazoles; Fluorescence; Humans; Light; Neoplasms; Photochemotherapy; Photosensitizing Agents; Piperidines; Protoporphyrins; Tumor Cells, Cultured

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC) harboring ALK- rearrangements. However, a small population of tumor cells survives due to adaptive resistance under drug pressure and ultimately acquires drug resistance. Thus, it is necessary to elucidate the mechanisms underlying the prevention of drug resistance to improve the prognosis of patients with ALK-rearranged NSCLC. We identified novel adaptive resistance, generated through c-Jun N-terminal kinase (JNK)/c-Jun signaling, to initial ALK-TKIs-alectinib and brigatinib-in ALK-rearranged NSCLC. Inhibition of JNK/c-Jun axis showed suppression of growth and promotion of apoptosis induced by ALK-TKIs in drug-tolerant cells. JNK inhibition, in combination with the use of ALK-TKIs, increased cell apoptosis through repression of the Bcl-xL proteins, compared with ALK-TKI monotherapy. Importantly, combination therapy targeting JNK and ALK significantly delayed the regrowth following cessation of these treatments. Together, our results demonstrated that JNK pathway activation plays a pivotal role in the intrinsic resistance to ALK-TKIs and the emergence of ALK-TKI-tolerant cells in ALK-rearranged NSCLC, thus indicating that optimal inhibition of tolerant signals combined with ALK-TKIs may potentially improve the outcome of ALK-rearranged NSCLC.

Topics: Anaplastic Lymphoma Kinase; Animals; Apoptosis; bcl-X Protein; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Rearrangement; Heterografts; Humans; JNK Mitogen-Activated Protein Kinases; Mice; Microarray Analysis; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Proteome; Pyrimidines; Signal Transduction

Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small cell lung cancer. Population pharmacokinetic (PK) models were developed for alectinib and its major active metabolite M4 using phase I/II PK data in crizotinib-failed patients (N = 138). The PK profiles were best described by two separate models with similar structure for both entities: open one-compartment models with sequential zero/first-order input and first-order elimination rate. Body weight with fixed allometric scaling factor on clearance and volume of both entities was the only significant covariate. Bayesian feedback analyses of the PK data collected from Japanese and global treatment-naïve patients in phase III studies (N = 334) confirmed the body weight effect. Landmark Cox proportional hazards analyses of progression-free survival in treatment-naïve patients identified the average molar concentrations of both entities alectinib and M4 during the first 6 weeks of treatment as a significant covariate, with an optimal response achieved for concentrations above 1040 nmol/L. With 600 mg twice daily (b.i.d.), 92% of global patients are above this threshold concentration, compared with only 43% of patients with 300 mg b.i.d. In Japan, where the body weight distribution is lower, the approved 300 mg b.i.d. dose brings about 70% of Japanese patients above this threshold. Logistic regression analyses found no significant relationship between the combined alectinib-M4 molar concentration and first occurrence of adverse events. These pharmacometric results were used to expedite and facilitate regulatory approvals of 600 mg b.i.d. for first-line ALK-positive NSCLC in the United States and European Union in 2017 and in China in 2018.

Topics: Anaplastic Lymphoma Kinase; Bayes Theorem; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines

Lung cancer is the most common cancer type and the leading cause of cancer-related mortality worldwide. The positivity rate of the anaplastic lymphoma kinase (ALK) mutation in non-small cell lung cancer (NSCLC) patients has been reported as 3-7%. This study aimed to investigate the pathological, clinical and demographic characteristics of ALK-mutant NSCLC patients who received first-line alectinib as a tyrosine kinase inhibitor in two different centers.. The study was performed at the Medical Oncology Departments of Ankara City Hospital and Atatürk Chest Diseases and Thoracic Surgery Training and Research Hospital. Patients diagnosed with ALK-mutant NSCLC and received alectinib treatment as a first-line tyrosine kinase inhibitor were enrolled to study and retrospectively analyzed.. A total of 38 patients (15 males, 23 females) were included in the study. Median age was 56.5. 55.3% of the patients were non-smokers. All of the patients had adenocarcinoma histology. Thirty-four patients (89.5%) were metastatic. Brain metastasis was detected in 44.7% of the patients. Thirty-three patients (86.8%) were using alectinib in first-line treatment. The remaining five patients were seen to have received at least one course of chemotherapy before. The objective response rate was 78.9% with alectinib treatment. The percentage of the patients who experienced at least one side effect was 34.2% and serious side effects were 7.9%. After median 9.5 months follow-up, median progression-free survival (PFS) was not achieved. 24-month PFS was 67% and 24-month overall survival was 84%.. Our results were compatible with previous studies in terms of the clinical, pathological and demographic features of the patients with ALK mutation. We observed that the majority of patients were non-smokers, relatively young, and female patients. The objective response rate and survival results were similar with phase 3 studies.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Retrospective Studies

Although anaplastic lymphoma kinase (ALK) inhibitors are effective treatment options for ALK-positive non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis, achieving long-term survival in patients with NSCLC with meningeal carcinomatosis resistant to ALK inhibitors is difficult. Lorlatinib, a third-generation ALK inhibitor, was designed for selective CNS penetration, and exerts potent antitumor activity against tumors resistant to first- and/or second-generation ALK inhibitors. However, there is limited information about the activity of lorlatinib in ALK inhibitor-resistant meningeal carcinomatosis. Here, we report a case of ALK-positive lung adenocarcinoma with meningeal carcinomatosis in which lorlatinib was used after resistance to alectinib and brigatinib.. A 55-year-old woman with no history of smoking presented to our hospital with a swelling on the left neck. Clinical imaging and histopathological examination revealed a tumor of adenocarcinoma histology in the left upper lung with no CNS metastasis.. The patient was diagnosed with ALK-positive lung adenocarcinoma (cT3N3M1b: stage IVA).. She received the second-generation ALK inhibitors, alectinib and brigatinib, in the first and second-line settings, respectively. However, she developed meningeal carcinomatosis. Hence, treatment with lorlatinib was initiated in the third-line setting.. The symptoms associated with meningeal carcinomatosis, such as disturbance of consciousness and diplopia, improved dramatically. At 8 months from the initiation of lorlatinib, the patient remained well without disease progression.. Lorlatinib is an effective treatment option for patient with ALK-positive NSCLC who develop meningeal carcinomatosis resistant to second-generation ALK inhibitors. Therefore, lorlatinib should be considered in such cases, even when patients exhibit serious symptoms associated with meningeal carcinomatosis.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Humans; Lactams; Lung Neoplasms; Meningeal Carcinomatosis; Middle Aged; Organophosphorus Compounds; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyrimidines

Quantitative assessment of bias from unmeasured confounding and missing data can help evaluate uncertainty in findings from indirect comparisons using real-world data (RWD).. To compare the effectiveness of alectinib vs ceritinib in terms of overall survival (OS) in patients with ALK-positive, crizotinib-refractory, non-small cell lung cancer (NSCLC) and to assess the sensitivity of these findings to unmeasured confounding and missing data assumptions.. This comparative effectiveness research study compared patients from 2 phase 2 alectinib trials and real-world patients. Patients were monitored from June 2013 to March 2020. Comparisons of interest were between alectinib trial data vs ceritinib RWD and alectinib RWD vs ceritinib RWD. RWD treatment groups were selected from nationally representative cancer data from US cancer clinics, the majority from community centers. Participants were ALK-positive patients aged 18 years or older with advanced NSCLC, prior exposure to crizotinib, and Eastern Cooperative Oncology Group Performance Status (PS) of 0 to 2. Data analysis was performed from October 2020 to March 2021.. Initiation of alectinib or ceritinib therapy.. The main outcome was OS.. In total, there were 355 patients: 183 (85 men [46.4%]) in the alectinib trial, 91 (43 men [47.3%]) in the ceritinib RWD group, and 81 (38 men [46.9%]) in the alectinib RWD group. Patients in the alectinib trial were younger (mean [SD] age, 52.53 [11.18] vs 57.97 [11.71] years), more heavily pretreated (mean [SD] number of prior therapy lines, 1.95 [0.72] vs 1.47 [0.81]), and had more favorable baseline ECOG PS (ECOG PS of 0 or 1, 165 patients [90.2%] vs 37 patients [77.1%]) than those in the ceritinib RWD group. The alectinib RWD group (mean [SD] age, 58.69 [11.26] years) had more patients with favorable ECOG PS (ECOG PS of 0 or 1, 49 patients [92.4%] vs 37 patients [77.1%]) and more White patients (56 patients [72.7%] vs 53 patients [62.4%]) compared with the ceritinib group. Compared with ceritinib RWD, alectinib-exposed patients had significantly longer OS in alectinib trials (adjusted hazard ratio [HR], 0.59; 95% CI, 0.44-0.75; P < .001) and alectinib RWD (HR, 0.46; 95% CI, 0.29-0.63; P < .001) after adjustment for baseline confounders. For the worst-case HR estimate of 0.59, residual confounding by a hypothetical confounder associated with mortality and treatment by a risk ratio greater than 2.24 was required to reverse the findings. Conclusions were robust to plausible deviations from random missingness for missing ECOG PS and underrecorded comorbidities and central nervous system metastases in RWD.. Alectinib exposure was associated with longer OS compared with ceritinib in patients with ALK-positive NSCLC, and only substantial levels of bias examined reversed the findings. These findings suggest that quantitative bias analysis can be a useful tool to address uncertainty of findings for decision-makers considering RWD.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Piperidines; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Sulfones; Survival Analysis

ALK-positive histiocytosis is a rare malignancy which was first described in 2008 and recognized as a systemic histiocytic disorder that can affect multiple organs. Less than 20 cases were reported to date, and much fewer cases were presented as disseminated disease, especially with lung and central nervous system (CNS) involvement. The clinical presentation, cytologic and histologic features were diverse in prior reported cases. Diagnosis relied on clinical, pathological findings and might be determined by molecular identification of anaplastic lymphoma kinase (ALK) gene translocation. Exclusion of other tumors such as Erdheim-Chester disease, Langerhans cell histiocytosis (LCH) and histiocytic sarcoma are required. Because of their rarity and diverse features, no standard treatment was applied so far. Here we reported a 51-year-old Asian female patient documented as ALK-positive histiocytosis with lung, intracranial and lymph nodes involvement. Surgery for left frontal tumor resection was performed. Of note was the presence of foam-like histiocytes, epithelioid cells and Touten-like histiocytes scattered in the lesion, emperipolesis also could be observed. Histiocytes were positive immunostaining for CD68/PGM-1, CD163 and ALK1 in cytoplasmic pattern. Fluorescence in situ hybridization (FISH) analysis confirmed ALK gene translocation and next generation sequencing (NGS) revealed KIF5B-ALK fusion. The patient received treatment of second-generation ALK inhibitor-alectinib after diagnosed and showed durable remission. Therefore, our case highlights a new treatment option for this rare entity.

Topics: Carbazoles; Female; Histiocytosis, Langerhans-Cell; Humans; In Situ Hybridization, Fluorescence; Middle Aged; Piperidines; Receptor Protein-Tyrosine Kinases

Alectinib is a tyrosine kinase inhibitor (TKI) approved for use as first-line metastatic therapy for patients with anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Certain medical conditions related to the tumor lesions may not allow oral administration of TKIs.. We hereby report the case of a 90-year-old patient with anaplasic lymphoma kinase-rearranged lung cancer with severely impaired general condition and swallowing disorders.. A thoracic computerized tomography (CT)-scan confirmed the presence of a mediastinal tumor lesion explaining the swallowing disorders secondary to recurrent paralysis.. As no oral administration was feasible, alectinib was administered by percutaneous gastrostomy.. The patient had few side-effects. He presented a major clinical and radiological response. After 2 months of treatment with alectinib, his mini-mental state examination had increased from 8/30 to 23/30. He had a 60% reduction in targeted pulmonary, bone and node lesions according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). After 6 months of treatment, the patient's performance status had evolved from 3 to 1. This improvement in general condition made it possible to remove the feeding tube.. In cases of lung cancer with oncogenic addiction, enteral administration of TKIs should be considered for elderly patients with an impaired general condition.

Topics: Aged, 80 and over; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Drug Administration Routes; Gastrostomy; Humans; Lung Neoplasms; Male; Piperidines; Protein Kinase Inhibitors

More than 20 types of ALK fusion variant subtypes have been identified, including different fusion partner genes or EML4-ALK fusions with different breakpoints. However, different ALK fusions show different sensitivities to ALK-tyrosine kinase inhibitors (ALK-TKIs) and the emergence of rare fusions brings great challenges to the target therapy in clinic. We report a rare EML4-ALK (E6;A18) fusion in a patient with lung adenocarcinoma that responded well to alectinib. This is the second case of this rare variant reported but the first report of response to an ALK-TKI. This evidence is the first to show that alectinib may be effective for this rare fusion type of non-small cell lung cancer, and these findings have important implications for drug selection in patients with this subtype. Further studies are needed to understand the function of this variant.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Exons; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

Anaplastic lymphoma kinase (ALK) rearrangement is the second most common targetable oncogene-dirven gene in nonsmall cell lung cancer. Owing to the advanced sequencing technologies, new partner genes of ALK have been constantly detected.. A 42-year-old Chinese woman went to our hospital with the chief complaint of cough and expectoration for 1 month. The patient had no fever, chest pain, and hemoptysis.. She was diagnosed with advanced lung adenocarcinoma. The patient underwent lung biopsy guided by computed tomography and pathology showed poorly differentiated adenocarcinoma. To explore possibility of targeted therapy, the tumor samples were subjected to next-generation sequencing, and a rare 3 ALK fusion variant ALK-LRRN2, LTBP1-ALK, and HIP1-ALK was identified.. The patient subsequently received alectinib treatment, and achieved partial response. No significant drug related adverse reactions were found during alectinib treatment. The progression-free survival achieved 25 months.. Together, we identified a rare triple ALK fusion variant, ALK-LRRN2, LTBP1-ALK and HIP1-ALK, in a patient with lung adenocarcinoma. The patient benefited from alectinib treatment, which could provide a certain reference for the patients with such gene alteration.

Topics: Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Adhesion Molecules, Neuronal; DNA-Binding Proteins; Drug Resistance, Neoplasm; Female; Gene Fusion; Humans; Latent TGF-beta Binding Proteins; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Humans; Lung Neoplasms; Male; Piperidines; Treatment Outcome

In the following report, we describe a case of alkaline phosphatase (ALP) elevation occurring during treatment with alectinib (Alecensa™), which was administered for anaplastic lymphoma kinase (ALK) mutated metastatic non-small cell lung cancer (mNSCLC). A 51 year-old female with widespread metastatic disease exhibited a rapid and significant response within a very short period to alectinib therapy, accompanied by a rapid increase of ALP to more than six times the upper limit of normal (grade 3) ALP, decreasing to within normal limits within 3 weeks after initiation of therapy without any dose modification.

Topics: Alkaline Phosphatase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Middle Aged; Piperidines

Topics: Adult; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Radiosurgery; Treatment Outcome

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Gene Rearrangement; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Patient Acuity; Piperidines

Anaplastic lymphoma kinase (ALK)-translocations are present in up to 5% of non-small cell lung cancer (NSCLC), most of them being adenocarcinomas. Even though the availability of five potent ALK-inhibitors for the treatment of ALK-positive NSCLC patients, there is no consensus about the ideal therapy sequence. Alectinib has been so far successfully and routinely used as first-line therapy, especially in patients presenting central nervous system lesions; however, with the very recent European approval of brigatinib in the first line, a new treatment option is now available for ALK+ patient collective. In this case series, efficient systemic and intracranial responses to alectinib late-line treatment following brigatinib therapy are reported. This therapeutic sequence is going to gain therefore more importance in a near future.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Middle Aged; Organophosphorus Compounds; Piperidines; Prognosis; Pyrimidines

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Biomarkers, Tumor; Carbazoles; Cytoskeletal Proteins; Female; Humans; Lung Neoplasms; Middle Aged; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Piperidines; Prognosis; Sequence Analysis, RNA

Drug-induced immune hemolytic anemia (DIIHA) is a rare condition with an increasing incidence associated with the frequent use of certain drugs. An 85-year-old woman with lung adenocarcinoma prescribed alectinib complained of dyspnea on exertion at our hospital. Based on her laboratory tests results on admission, we focused on the clinical course of anemia and hemolysis progression after alectinib administration. The patient's anemia and hemolysis gradually improved after discontinuation of alectinib, leading to a diagnosis of alectinib-induced IHA, presented here as the first case encountered in a patient with lung adenocarcinoma. Furthermore, we discuss the importance of correlating clinical laboratory findings in DIIHA.

Topics: Adenocarcinoma of Lung; Aged, 80 and over; Anemia, Hemolytic; Carbazoles; Female; Humans; Lung Neoplasms; Piperidines

Topics: Carbazoles; Cryptogenic Organizing Pneumonia; Humans; Piperidines

Even though alectinib is a potent second-generation ALK inhibitor with a favorable safety profile, alectinib-induced interstitial lung disease (ILD) could be fatal. There are case reports described successful alectinib rechallenge in mild ILD. However, the feasibility and safety of rechallenge in severe cases remains to be elucidated.. A 76-year-old female was a case of stage IV lung adenocarcinoma harboring ALK rearrangement. Respiratory failure following severe ILD developed one month after alectinib administration. She received mechanical ventilation in intensive care uint. ILD subsided gradually after methylprednisolone pulse therapy and discontinuation of alectinib.. Given that the ALK inhibitors are the treatment of choice for advanced lung cancer patients with ALK rearrangement. Our report demonstrated the potential feasibility of alectinib re-use in cases of severe druginduced ILD.

Topics: Adenocarcinoma of Lung; Aged; Carbazoles; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Most advanced non-small cell lung cancer (NSCLC) patients are accompanied by brain metastasis which is the major cause of increased mortality. The fusion rearrangement of anaplastic lymphoma kinase (ALK) gene is an important feature of brain metastasis in lung cancer. The novel ALK inhibitors alectinib and lorlatinib are shown to be effective against NSCLC brain metastasis, while their underlying mechanism of action is unclear. Epithelial-mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs) play important roles in brain metastasis by regulating the blood-brain barrier (BBB). To reveal the molecular function of alectinib and lorlatinib, we explored their effects on the cellular levels of EMT markers: VIM and FN1 and the matrix metalloproteinases MMP-9 and MMP-7. The mRNA and protein levels of VIM, FN1, MMP-9, and MMP-7 were elevated in H3122 cells. However, upon alectinib and lorlatinib treatment, the levels were significantly reduced. Similar results were obtained when these experiments were performed either in a dose-dependent or time-dependent manner. Furthermore, alectinib and lorlatinib also inhibited the cell viability and migration of H3122 cells. Interestingly, in comparison to individual drugs, the combination of alectinib and lorlatinib was found to be substantially more effective. Overall, these results suggest that alectinib and lorlatinib possibly function through the downregulation of MMPs and EMT in NSCLC metastasis.

Topics: Aminopyridines; Biomarkers, Tumor; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Movement; Cell Survival; Down-Regulation; Epithelial-Mesenchymal Transition; Humans; Lactams; Lung Neoplasms; Matrix Metalloproteinases; Piperidines; Pyrazoles; Tumor Cells, Cultured

Anaplastic lymphoma kinase (ALK) rearranged lung cancers represent 4% to 6% of all pulmonary adenocarcinomas, and echinoderm microtubule associated protein like 4 (EML4)-ALK fusions are the most common subgroup. Herein, we report a case of two successive drug reactions due to ALK inhibitors. A 69-year-old female with stage IVB EML4-ALK fused lung adenocarcinoma developed a generalized morbilliform eruption 10 days after starting alectinib. Skin biopsy findings were consistent with a drug reaction. Her findings resolved after alectinib was discontinued. Another ALK inhibitor, lorlatinib was started and she developed multiple asymptomatic cutaneous and oral nodules 4 months later. Biopsies from these nodules showed sarcoidal granulomas without evidence of metastases or infection. ALK inhibitors are associated with numerous adverse events, including various cutaneous eruptions. However, a sarcoidal drug reaction involving the skin has not been reported. Identification of drug reactions to targeted therapy can avoid long-term sequelae and misinterpretation of the clinical findings as disease progression or infection.

Topics: Adenocarcinoma of Lung; Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Biopsy; Carbazoles; Cell Cycle Proteins; Drug-Related Side Effects and Adverse Reactions; Female; Granuloma; Humans; Lactams; Microtubule-Associated Proteins; Neoplasm Staging; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Sarcoidosis; Serine Endopeptidases; Skin; Withholding Treatment

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.

Topics: A549 Cells; Acrylamides; Anaplastic Lymphoma Kinase; Angiogenesis Inhibitors; Aniline Compounds; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Combined Modality Therapy; Crizotinib; Drug Synergism; Erlotinib Hydrochloride; Female; Genes, erbB-1; Heterografts; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Mutation; Neovascularization, Pathologic; Oncogenes; Piperidines; Platelet Endothelial Cell Adhesion Molecule-1; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Ramucirumab; Random Allocation; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2

Liquid biopsy analyzes the current status of primary tumors and their metastatic regions. We aimed to develop an optimized protocol for single-cell sequencing of floating tumor cells (FTCs) in pleural effusion as a laboratory test. FTCs were enriched using a negative selection of white blood cells by a magnetic-activated cell sorting system, and CD45-negative and cytokeratin-positive selection using a microfluidic cell separation system with a dielectrophoretic array. The enriched tumor cells were subjected to whole-genome amplification (WGA) followed by genome sequencing. The FTC analysis detected an EGFR exon 19 deletion in Case 1 (12/19 cells, 63.2%), and EML4-ALK fusion (17/20 cells, 85%) with an alectinib-resistant mutation of ALK (p.G1202R) in Case 2. To eliminate WGA-associated errors and increase the uniformity of the WGA product, the protocol was revised to sequence multiple single FTCs individually. An analytical pipeline, accurate single-cell mutation detector (ASMD), was developed to identify somatic mutations of FTCs. The large numbers of WGA-associated errors were cleaned up, and the somatic mutations detected in FTCs by ASMD were concordant with those found in tissue specimens. This protocol is applicable to circulating tumor cells analysis of peripheral blood and expands the possibility of utilizing molecular profiling of cancers.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Cell Separation; Crizotinib; DNA; Drug Resistance, Neoplasm; Exons; Female; Gene Amplification; Gene Deletion; Gene Expression Profiling; Genes, erbB-1; High-Throughput Nucleotide Sequencing; Humans; Immunomagnetic Separation; Keratins; Leukocyte Common Antigens; Liquid Biopsy; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplastic Cells, Circulating; Oncogene Proteins, Fusion; Piperidines; Pleural Effusion, Malignant; Protein Kinase Inhibitors

The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited.. We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group.. Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001).. The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Gene Rearrangement; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Retrospective Studies; Time Factors

Besides the clinical benefit of crizotinib in ALK-rearranged metastatic non-small cell lung cancer (NSCLC), concerns about its hepatotoxicity have arisen. It is not clear whether this is a drug class side effect or if the use of other selective ALKs inhibitors is safe after this serious adverse event. While evidence from clinical trials is scarce, reports of treatment after crizotinib-induces hepatitis may add to clinical decision.. Herein, we report a case of acute hepatitis induced by crizotinib in a 32-years-old female diagnosed with metastatic NSCLC, harboring the ALK-rearrangement. After 60 days of crizotinib therapy, the patient presented with acute hepatitis, diagnosed after investigation of non-specific symptoms, such as nausea and fatigue. Serum aspartate aminotransferase and alanine aminotransferase levels had increased from baseline to 3010 IU/L and 9145 IU/L, respectively. Total bilirubin increased up to 7.91 mg/dL, but she did not develop liver failure. After crizotinib discontinuation, a gradual hepatic function recovery occurred. Unfortunately, during the period without specific oncology treatment, her disease showed an unequivocal progression. Therefore, she started on alectinib with great response, and no liver function alteration recurred.. This case suggests that alectinib, even belonging to the same drug class, could be used as an alternative agent when crizotinib is the etiology of liver damage, but more robust evidence has awaited.

Topics: Adult; Bilirubin; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Hepatitis; Humans; Liver; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Treatment Outcome

We present here a case of ALK-positive lung adenocarcinoma that has been started on Alectinib. Treatment has been initiated at the recommended initial dose, but it subsequently required a dose adjustment following adverse drug events. Alectinib is a second-generation, CNS-active, tyrosine kinase inhibitor used in the treatment of ALK-positive non-small cell lung cancer. Its efficacy as a first-line treatment and as a second-line agent after Crizotinib has been proven across several trials both in terms of overall response rate and progression-free survival. The use of Alectinib is associated with side effects that occasionally lead to treatment discontinuation, interruption, or dose adjustment. Several studies have used two starting doses - 300 mg and 600 mg twice daily - across different populations and have consistently shown efficacy of Alectinib for both treatment doses. Results of these studies have also revealed that body weight, rather than race, affect the pharmacokinetics of Alectinib. Randomized trials have shown that the 600 mg dose is associated with more grade ≥3 adverse events and more changes in treatment in contrast to the 300 mg dose. A lower dose of Alectinib may limit treatment disruptions and dose reductions particularly for specific patient populations-particularly those with a lower body weight.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Lung Neoplasms; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic

We reviewed haematological investigations for 43 patients treated at a single centre with alectinib, an inhibitor of anaplastic lymphoma kinase (ALK) which is considered standard first-line treatment for patients with ALK-rearranged advanced non-small cell lung cancer. Ninety-five percent of patients developed marked acanthocytosis, echinocytosis and/or spheroacanthocytosis, not observable with prior treatment with other ALK-inhibitors. Anaemia developed in 73% of patients (38% <100 g/L, 8% <80 g/L), though definite new haemolysis was present in only 11%. Eosin-5-maleimide binding was reduced in all assessed patients, and increased membrane cholesterol was identified in one patient assessed with lattice light sheet microscopy. We have identified a previously undescribed phenomenon whereby alectinib induces red cell membrane abnormalities in nearly all patients through an unclear, but likely ALK-independent, mechanism, resulting in mild anaemia without universal haemolysis.

Topics: Abetalipoproteinemia; Anaplastic Lymphoma Kinase; Anemia; Carbazoles; Carcinoma, Non-Small-Cell Lung; Hemolysis; Humans; Lung Neoplasms; Maleimides; Piperidines; Protein Kinase Inhibitors; Retrospective Studies

ALK gene rearrangement was observed in 3%-5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI-resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

Topics: Aminopyridines; Aniline Compounds; Animals; Apoptosis; Benzamides; Carbazoles; Cell Line; Cell Survival; Crizotinib; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Immunoblotting; Indazoles; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mice; Mice, Inbred BALB C; Molecular Dynamics Simulation; Neoplasm Recurrence, Local; Piperidines; Proto-Oncogene Proteins; Pyrazines; Pyrazoles; Receptor Protein-Tyrosine Kinases

Topics: Carbazoles; Crizotinib; Humans; Japan; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Deglutition Disorders; Diet; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Glioblastoma (GBM) is the most common, but extremely malignant, brain tumor; thus, the development of novel therapeutic strategies for GBMs is imperative. Many tyrosine kinase inhibitors (TKIs) have been approved for various cancers, yet none has demonstrated clinical benefit against GBM. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is confirmed only during the embryonic development period in humans. In addition, various ALK gene alterations are known to act as powerful oncogenes and therapeutic targets in various tumors. The antitumor activity of various TKIs was tested against three human GBM cell lines (U87MG, LN229, and GSC23), which expressed substantially low ALK levels; second-generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death. In addition, treatment with either alectinib or ceritinib modulated the activation of various molecules downstream of RTK signaling and induced caspase-dependent/-independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in human GBM cells. In addition, alectinib and ceritinib also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral GBM xenografts compared with controls. These results suggested that treatment with the second-generation ALK inhibitors, alectinib and ceritinib, might serve as a potent therapeutic strategy against GBM.

Topics: Administration, Oral; Anaplastic Lymphoma Kinase; Animals; Brain Neoplasms; Carbazoles; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Mice; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Signal Transduction; STAT3 Transcription Factor; Sulfones; Temozolomide; Treatment Outcome; Xenograft Model Antitumor Assays

Fusion proteins of the anaplastic lymphoma kinase (ALK) are promising therapeutic targets for cancer and other human diseases, especially for non-small cell lung cancer (NSCLC) and anaplastic large-cell lymphomas (ALCLs). We described herein a structure-based design, synthesis, and evaluation of ALK PROTACs (proteolysis-targeting chimeras) based on Alectinib as the warhead. We firstly screened CRBN ligands as the E3 ligase moiety, then obtained a series of potent ALK degraders based on different CRBN ligands, exemplified by SIAIS091 and SIAIS001 with lenalidomide/thalidomide-based linkers. Both of them induced effective ALK degradation at low nanomolar concentrations in cells, and showed much better growth inhibition effects than Alectinib. SIAIS091 or SIAIS001 also promoted cell cycle arrest in G1/S phase. Finally, SIAIS001 exhibited good oral bioavailability in Pharmacokinetics study.

Topics: Administration, Oral; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biological Availability; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Humans; Lung Neoplasms; Molecular Structure; Piperidines; Protein Kinase Inhibitors; Structure-Activity Relationship

Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking.. Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy.. Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31-1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0-1 vs. 2-3 HR 0.09 [95% CI, 0.02-0.33]; p < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26-5.99]; p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01-0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08-1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib.. Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

Topics: Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Taiwan

This is the first case report of a patient with ALK-rearranged metastatic lung adenocarcinoma who became pregnant during treatment with alectinib. A multidisciplinary team of gynecologists, neonatologists, oncologists, psychologists, and pharmacologists was set up to handle the case. According to patient's preference, the study drug was continued throughout pregnancy and the woman delivered a healthy baby girl at 35 weeks and 5 days of gestation. Fetal parameters remained normal during pregnancy. At birth, alectinib levels were 14 times higher in maternal plasma than in the fetus (259 versus 18 ng/mL). The average concentration of alectinib in the placenta was 562 ng/g. The baby was followed during her first 20 months, and no developmental anomalies were observed. After 32 months from diagnosis, the mother is well and in partial remission.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Female; Humans; Infant, Newborn; Lung Neoplasms; Piperidines; Pregnancy; Protein Kinase Inhibitors

Anaplastic lymphoma kinase (ALK) + anaplastic large cell lymphoma (ALCL) is considered as a good prognosis lymphoma. However, in an extremely rare subset of patients, ALK+ ALCL with leukemic presentations is known to be chemotherapy-resistant. Although several novel therapies have been tested, the standard therapy for relapsed/refractory ALK+ ALCL has not been established yet.. An 18-year-old female patient who had conventional chemotherapy- and Brentuximab Vedotin (BV)-resistant ALK+ ALCL with leukemic presentation. She was successfully treated with an ALK inhibitor, crizotinib. Crizotinib induced complete remission (CR) and bridged to allogeneic bone marrow transplantation (BMT).. However, her ALCL relapsed on day 60 after BMT and she developed high grade fever and lymphadenopathy.. Although crizotinib was given to the patient immediately after relapse, she developed grade 3 nausea and could not continue to take it. Then, we gave alectinib to the patient, which promptly induced sustained CR without any further chemotherapy. The patient received second stem cell transplantation using umbilical cord blood with myeloablative regimen in 2nd CR.. The patient has been in CR under maintenance therapy of alectinib for more than 16 months.. Both ALK inhibitors demonstrated drastic efficacy for our patient who had chemotherapy- and BV-resistant ALK+ ALCL with leukemic presentation. Alectinib showed less gastro-intestinal toxicity than crizotinib and the patient was able to take it even at the relatively early phase of stem cell transplantation.

Topics: Adolescent; Anaplastic Lymphoma Kinase; Carbazoles; Cord Blood Stem Cell Transplantation; Crizotinib; Female; Humans; Lymphoma, Large-Cell, Anaplastic; Medical Illustration; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Transplantation, Homologous

Routine therapeutic drug monitoring is a promising approach for the rational use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase (ALK) inhibitors. The purpose of this study was to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of 5 EGFR-TKIs (afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib) and 3 ALK inhibitors (alectinib, ceritinib, and crizotinib).. A 100-mL aliquot of serum was diluted with 100 μL of 1% aqueous ammonia containing internal standards and then purified using the supported liquid extraction method. LC-MS/MS was conducted in positive ionization mode, and the method was validated according to published guidelines.. Calibration curves were linear across concentration ranges examined. The intra- and interassay accuracies were 90.7%-110.7% and 94.7%-107.6%, respectively. All intra- and interassay imprecision values were ≤10.1%. The EGFR-TKIs and ALK inhibitors examined in this study, except osimertinib, which could be stored on ice for at least 5 hours, were stable at room temperature for 3 hours. For the internal standard-normalized matrix factors, the mean recovery and percent coefficient of variation values ranged between 54%-112% and 1.7%-11.7%, respectively. This method successfully determined serum concentrations of afatinib, alectinib, erlotinib, gefitinib, and osimertinib in clinical samples. Serum levels of kinase inhibitors consistently reflected those reported in previous studies.. An LC-MS/MS method suitable for the simultaneous determination of 5 EGFR-TKIs and 3 ALK inhibitors in serum was developed and validated. The newly developed method enabled the determination of 5 of 8 target drugs examined in clinical samples. However, a large number of clinical samples need to be analyzed to verify the usefulness of the method.

Topics: Acrylamides; Afatinib; Aniline Compounds; Carbazoles; Chromatography, Liquid; Crizotinib; Erlotinib Hydrochloride; Gefitinib; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Quinazolinones; Sulfones; Tandem Mass Spectrometry

Renal (RIP) and hepatic (HIP) impairments are prevalent conditions in cancer patients. They can cause changes in gastric emptying time, albumin levels, hematocrit, glomerular filtration rate, hepatic functional volume, blood flow rates, and metabolic activity that can modify drug pharmacokinetics. Performing clinical studies in such populations has ethical and practical issues. Using predictive physiologically-based pharmacokinetic (PBPK) models in the evaluation of the PK of alectinib, ruxolitinib, and panobinostat exposures in the presence of cancer, RIP, and HIP can help in using optimal doses with lower toxicity in these populations. Verified PBPK models were customized under scrutiny to account for the pathophysiological changes induced in these diseases. The PBPK model-predicted plasma exposures in patients with different health conditions within average 2-fold error. The PBPK model predicted an area under the curve ratio (AUCR) of 1, and 1.8, for ruxolitinib and panobinostat, respectively, in the presence of severe RIP. On the other hand, the severe HIP was associated with AUCR of 1.4, 2.9, and 1.8 for alectinib, ruxolitinib, and panobinostat, respectively, in agreement with the observed AUCR. Moreover, the PBPK model predicted that alectinib therapeutic cerebrospinal fluid levels are achieved in patients with non-small cell lung cancer, moderate HIP, and severe HIP at 1-, 1.5-, and 1.8-fold that of healthy subjects. The customized PBPK models showed promising ethical alternatives for simulating clinical studies in patients with cancer, RIP, and HIP. More work is needed to quantify other pathophysiological changes induced by simultaneous affliction by cancer and RIP or HIP.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Carbazoles; Fasting; Female; Humans; Liver Diseases; Male; Middle Aged; Models, Biological; Neoplasms; Nitriles; Panobinostat; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Renal Insufficiency

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.

Topics: Adenocarcinoma of Lung; Aged; Aminopyridines; Carbazoles; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Muscle, Skeletal; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Pyrazoles

Anaplastic lymphoma kinase (ALK) rearrangements are drivers of a subset of non-small cell lung cancer (NSCLC). The rapid progression of ALK inhibitors has significantly prolonged the progression-free survival of patients with ALK gene-sensitive mutations. However, the response of patients with rare ALK rearrangements to tyrosine kinase inhibitors remains unknown. Here, we report a rare case of striatin (STRN)-ALK-positive NSCLC showing primary resistance to first-line therapy alectinib and limited clinical activity of crizotinib in the alectinib-resistant setting.

Topics: Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Piperidines; Protein Kinase Inhibitors

Most patients treated with anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors for ALK-positive non-small cell lung cancer (NSCLC) develop resistance, leading to metastasis, with progression to the central nervous system (CNS) being a primary concern. Although alectinib has better CNS penetration than crizotinib, patients treated with alectinib also develop CNS progression. CNS metastases more likely occurs during crizotinib treatment due to less blood-brain barrier (BBB) penetration capability than alectinib. CNS progression pattern may be different during crizotinib and alecitinib treatment. Understanding the characteristics of CNS progression is important for developing treatment strategies.. We compared the clinical-radiographic characteristics of CNS metastases among patients undergoing crizotinib and alectinib treatment for ALK-positive NSCLCs.. We retrospectively analyzed the radiographic and clinical characteristics of CNS progression in ALK-positive NSCLC patients treated with crizotinib or alectinib at our hospital between July 2011 and May 2020. CNS and systemic tumor progression were evaluated using computed tomography or magnetic resonance imaging. Fifty-three and 65 patients were treated with crizotinib and alectinib, respectively. Baseline CNS metastasis was observed in 18 and 27 patients in the crizotinib and alectinib groups, respectively. Among the patients in the crizotinib and alectinib groups who developed disease progression, 15/49 (30.6%) and 9/44 (20.5%) had CNS progression, respectively (P = .344). Intra-CNS progression-free survival was significantly longer in the alectinib group than in the crizotinib group (median: 14.0 vs 5.6 months, P = .042). The number of CNS metastases sized ≥3 cm, rate of peritumoral brain edema, and the second progression pattern after treatment continuation was not significantly different between the groups.. We observed no significant difference in the clinical-radiographic characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Local therapy, including stereotactic radiosurgery, for CNS progression may be suitable and important following alectinib and crizotinib treatment.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Crizotinib; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Prognosis; Retrospective Studies; Survival Rate; Young Adult

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Ganglioglioma; Gene Fusion; Humans; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Vinculin

A 64-year-old man presented with reduced vision in the right eye (visual acuity of 6/24 Snellen). The patient reported having a chronic cough and recent weight loss with difficulty in swallowing and abnormal liver function test 8 months prior to his presentation. He was a chronic smoker for 45 years, having quit a year earlier. Fundus examination showed a unifocal large yellow-brown subretinal mass involving the posterior segment of the eye and associated with subretinal fluid. The patient was diagnosed with a choroidal metastasis and was referred urgently to the oncology team who confirmed the presence of non-small cell lung cancer with distant metastases. He started treatment with alectinib (second-generation tyrosine kinase inhibitor). A few weeks later, his vision improved and, on examination, there was complete resolution of the choroidal mass and the associated subretinal fluid. Alectinib led to rapid resolution of his choroidal secondary and has excellent ocular safety profile.

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Choroid Neoplasms; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines

Anaplastic lymphoma kinase (. We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare. This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with

Topics: Adolescent; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Crizotinib; Female; Gene Rearrangement; Humans; Male; Middle Aged; Neoplasms; Piperidines; Retrospective Studies; Treatment Outcome; Young Adult

Topics: Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Colorectal Neoplasms; Crizotinib; Female; Gene Rearrangement; Humans; Lactams; Neoplasm Metastasis; Piperidines; Pyrazoles; Treatment Outcome

Serious Acute Respiratory Syndrome Coronavirus 2 (SARSCoV2) has led to COVID 19 pandemic a year ago and it has not been globally taken under control yet. COVID 19 tends to have poorer prognosis in cancer patients. Additionally, we have no well-established guidelines for management of these patients during pandemic, in terms of treatment of 'cancer' and treatment of 'COVID 19'. Tyrosine kinase inhibitors (TKIs) are given without any break in cancer patients to have better survival outcomes in daily routine. However, there is no well-established data to continue or delay ALK inhibitors in lung cancer patients infected with SARS-CoV2. Concomittant use of ALK inhibitors and COVID 19 antiviral treatment is a dilemma because of the lack of data in this area.. A 47-year old female metastatic ALK positive nonsquamous cell lung cancer patient on alectinib, a second generation ALK inhibitor was diagnosed with symptomatic COVID 19. She was given favipiravir for COVID 19 while continuing alectinib.. To best of our knowledge, this is the first case who continued alectinib without dose adjustment during antiviral COVID-19 medication without clinically worsening. There is limited data about 'concomittant' use of TKIs and antiviral COVID 19 medication in the literature. There are some case reports, but they generally tended to delay or suspend TKIs during COVID 19 antiviral medication. Our case differs from them in terms of continuation of alectinib without any break or additional side effects during favipiravir for symptomatic COVID 19. We consider that our case might contribute to the literature in terms of management of cancer patients on targeted therapy during COVID 19 antiviral treatment. However, clinical trials are needed in this area.

Topics: Anaplastic Lymphoma Kinase; Antiviral Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; COVID-19 Drug Treatment; Female; Humans; Lung Neoplasms; Middle Aged; Piperidines; Protein Kinase Inhibitors

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cost-Benefit Analysis; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors

Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements are found in ~ 5% of patients with non-small cell lung cancer (NSCLC). Several tyrosine kinase inhibitors (TKIs) have been developed for treatment of so-called ALK-positive NSCLC. In cases of tumor progression during treatment with second-generation ALK-TKIs, such as alectinib, brigatinib, or ceritinib, National Comprehensive Cancer Network guidelines propose a switch to lorlatinib, a third-generation ALK-TKI, or to cytotoxic chemotherapy. However, they do not mention switching to other second-generation ALK-TKIs. Here, we present a rare case of a 53-year-old Japanese woman, who had never smoked, with ALK-positive lung adenocarcinoma who survived alectinib-resistant postoperative recurrence for 4 years by switching to ceritinib. She underwent curative resection for lung adenocarcinoma, but the cancer recurred at the bronchial stump and mediastinal lymph nodes. After platinum-doublet chemotherapy, the patient still had a single growing liver metastasis, but the tumor was found to harbor EML4-ALK rearrangement. Therefore, the patient started to take ALK-TKIs. Alectinib was the second ALK-TKI used to treat this patient. Alectinib shrank the liver metastasis, which was surgically resected. The tumor relapsed again during continued treatment with alectinib, which was switched to ceritinib. Ceritinib was effective for the relapsed tumor and treatment continued well for 4 years. This case report suggests that, in case of tumor progression during treatment with a second-generation ALK-TKI, switching to another second-generation ALK-TKI may be one of the treatment options. Further analyses are warranted to find robust markers to determine which ALK-TKI is best for each patient.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carbazoles; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Development; Drug Screening Assays, Antitumor; Humans; Mice; Molecular Structure; Neoplasms, Experimental; Piperidines; Protein Kinase Inhibitors; Proteolysis; Rats; Structure-Activity Relationship

We describe a case of an anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer with development of uterine metastasis after crizotinib and alectinib treatment. Gene analysis from the tissue of uterine metastasis revealed the presence of 1151Tins, which was considered to be a crizotinib and alectinib resistance mutation. Subsequent therapy with the third-generation ALK inhibitor lorlatinib, but not ceritinib, showed antitumor activity for 1 year. The uterus is an uncommon site for metastasis from lung cancer, and our case indicated that serial gene analysis could provide new information about ALK inhibitor resistance.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Gene Rearrangement; Humans; Lactams; Lung Neoplasms; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Uterine Neoplasms

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

We report an anaplastic lymphoma kinase (ALK)-positive patient shows a poor response to the ALK inhibitor alectinib due to the high expression of programmed death-ligand 1 (PD-L1). After treatment with alectinib, the pathological form changed from adenocarcinoma into squamous cell carcinoma without novel genetic changes. This case may reveal a direct relationship between ALK mutation and a high level of PD-L1 expression.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; B7-H1 Antigen; Carbazoles; Carcinoma, Squamous Cell; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors

ALK, ROS1, and RET kinase fusions are important predictive biomarkers of tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Analysis of cell-free DNA (cfDNA) provides a noninvasive method to identify gene changes in tumor cells. The present study sought to use cfRNA and cfDNA for identifying fusion genes. A reliable protocol was established to detect fusion genes using cfRNA and assessed the analytical validity and clinical usefulness in 30 samples from 20 cases of fusion-positive NSCLC. The results of cfRNA-based assays were compared with tissue biopsy and cfDNA-based liquid biopsy (Guardant360 plasma next-generation sequencing [NGS] assay). The overall sensitivity of the cfRNA-based assay was 26.7% (8/30) and that of cfDNA-based assay was 16.7% (3/18). When analysis was limited to the samples collected at chemo-naïve or progressive disease status and available for both assays, the sensitivity of the cfRNA-based assay was 77.8% (7/9) and that of cfDNA-based assay was 33.3% (3/9). Fusion gene identification in cfRNA was correlated with treatment response. These results suggest that the proposed cfRNA assay is a useful diagnostic test for patients with insufficient tissues to facilitate effective administration of first-line treatment and is a useful tool to monitor the progression of NSCLC for consideration of second-line treatments.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Biomarkers, Tumor; Biopsy; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell-Free Nucleic Acids; Crizotinib; Cytoskeletal Proteins; Disease Progression; Drug Resistance, Neoplasm; Female; Gene Fusion; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); High-Throughput Nucleotide Sequencing; Humans; Liquid Biopsy; Lung; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; RNA, Messenger; Sensitivity and Specificity

Lung cancers with anaplastic lymphoma kinase (ALK) rearrangements are highly sensitive to treatment with ALK tyrosine kinase inhibitors (TKIs). Due to the very low rate of patients with squamous cell carcinoma enrolled in clinical trials, the efficacy of ALK inhibitors in patients with ALK-rearranged squamous cell carcinoma in the lung remains unclear. Herein, we present the case of a 70-year-old female patient with squamous cell lung cancer harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. The patient was treated with the ALK-TKI alectinib as first-line regimen and achieved a dramatic response without severe adverse events, demonstrating alectinib as a therapeutic option for patients with ALK-positive squamous cell carcinoma.

Topics: Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Squamous Cell; Female; Gene Rearrangement; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Bromelain, the aqueous extract of pineapple, has been used as a food supplement with reported nutritional and therapeutic benefits. Bromelain has anti-cancer, anti-inflammatory, antithrombotic, and fibrinolytic effects. Anaplastic lymphoma kinase (ALK) inhibitors, including alectinib (ALC), ceritinib (CER), and crizotinib (CRZ), have been efficiently used in the management of non-small cell lung cancer (NSCLC). The solubility of ALC, CER, and CRZ is much higher at low acidic pH (pH 1) and it decreases as the pH increases affecting their absorption with a subsequent decrease in their bioavailability. It was thought that the intake of bromelain could result in a decrease in the bioavailability of ALC, CER, and CRZ due to bromelain-induced alkalizing effect following digestion. On the contrary, bromelain could possibly increase plasma exposure of the cited drugs due to its known muco-permeation enhancing effect. The therapeutic-anticancer effect of bromelain can be possibly increased/enhanced with concomitant intake of other anticancer medications or it can add to the value of food supplements for its known nutritional benefits. Thus, this work aims at studying the possibility of any PK interaction when bromelain was taken while on ALC/CER/CRZ therapy. In this work, a new UPLC-MS/MS method was developed and validated for the simultaneous determination of ALC, CER, and CRZ in rat plasma. Further application of the proposed method was performed to test the possibility of the PK interaction between bromelain and the selected ALK inhibitors in Wistar rats. Simple protein precipitation with acetonitrile was used for sample preparation. Chromatographic analysis was performed on Waters BEH™ C18 column with a mixture of acetonitrile/water containing 0.1 % formic acid (70: 30, v/v) as the mobile phase. The method permitted the analysis of ALC, CER, and CRZ in concentration ranges of 2-200, 0.4-200, and 4.0-200 ng/mL, respectively. Bromelain administration caused a significant decrease in plasma levels of CER and CRZ with lowered C

Topics: Anaplastic Lymphoma Kinase; Animals; Bromelains; Carbazoles; Carcinoma, Non-Small-Cell Lung; Chromatography, High Pressure Liquid; Chromatography, Liquid; Crizotinib; Lung Neoplasms; Pharmaceutical Preparations; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Rats; Rats, Wistar; Sulfones; Tandem Mass Spectrometry

Neurofibromatosis type 1 (NF1), a genetically determined neurodevelopmental disorder and tumor syndrome, is associated with cognitive impairments, including in executive function and sleep-related problems. Consistent with the human data, NF1 heterozygous (Het) mice show impaired spatial learning and memory in the water maze and extinction of contextual fear memory. It is not clear whether neurological phenotypes might depend on the parental carrier. In this study, we compared the behavioral and cognitive performance of NF1 Het and wild-type litter mates with either the father (PC) or the mother (MC) as the NF1 carrier on a F1 C57BL/66/129SvJ background. The behavioral and cognitive phenotypes and responsiveness to Alk inhibition in heterozygous NF1 offspring depended on whether the parental carrier was maternal or paternal. Alk inhibition (20 mg/kg) increased activity levels during the dark period in NF1 Het PC, but not MC, mice. In the water maze, NF1 Het PC, but not MC, mice showed reduced cognitive flexibility and impaired ability to locate the third hidden platform location, which was improved by Alk inhibition (3.6 mg/kg). Consistent with reduced cognitive flexibility, WT, but not NF1, mice showed better performance in the third than second water maze probe trial. Finally, Alk inhibition (10 mg/kg) increased baseline activity of NF1 MC, but not PC, mice during the fear conditioning test. Thus, the effective dose depends on the behavioral test and genotype but indicates that in NF1 patients cognitive flexibility might be particularly sensitive to Alk inhibition.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Behavior, Animal; Carbazoles; Cognition; Cognitive Dysfunction; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fear; Female; Genotype; Heterozygote; Male; Maze Learning; Mice; Mice, Inbred C57BL; Neurofibromatosis 1; Neurofibromin 1; Parents; Piperidines

ALK targeting with tyrosine kinase inhibitors (TKIs) is a highly potent treatment option for the therapy of ALK positive non-small cell lung cancer (NSCLC). However, pharmacokinetics of TKIs leads to clinically significant drug interactions, and the interfering co-medication may hamper the anti-cancer therapeutic management. Here, we present for the first time a drug interaction profile of ALK-TKIs, crizotinib and alectinib, and immunosuppressive agent cyclosporine A in kidney transplant recipients diagnosed with ALK+ lung cancer. Based on therapeutic drug monitoring of cyclosporin A plasma level, the dose of cyclosporine A has been adjusted to achieve a safe and effective therapeutic level in terms of both cancer treatment and kidney transplant condition. Particularly, 15 years upon the kidney transplantation, the stage IV lung cancer patient was treated with the 1st-line chemotherapy, the 2nd-line ALK-TKI crizotinib followed by ALK-TKI alectinib. The successful therapy with ALK-TKIs has been continuing for more than 36 months, including the period when the patient was treated for COVID-19 bilateral pneumonia. Hence, the therapy of ALK+ NSCLC with ALK-TKIs in organ transplant recipients treated with cyclosporine A may be feasible and effective.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Interactions; Humans; Kidney Transplantation; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines; Receptor Protein-Tyrosine Kinases

Topics: Carbazoles; Humans; Lung Neoplasms; Piperidines; Receptor Protein-Tyrosine Kinases

Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown a high response rate and long progression-free survival in primary treatment of ALK-positive non-small-cell lung cancer (NSCLC). De novo resistance or refractory subtype is rare event. Herein, we identify the first case with serial next-generation sequencing (NGS) results that harboured a rare echinoderm microtubule associated protein like 4 gene (EML4) -ALK (breaking site at exon 19) fusion in a lung adenocarcinoma (LUAD) patient who acquired alectinib resistance rapidly (less than 3 months), followed by multi-drug resistance and short survival time.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Exons; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear.. This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed.. Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%.. The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; Crizotinib; DNA Mutational Analysis; Drug Resistance, Neoplasm; Female; High-Throughput Nucleotide Sequencing; Humans; Lactams; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Mutation; Piperidines; Predictive Value of Tests; Prospective Studies; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Factors; Sulfones; Taiwan; Treatment Outcome

An 89-year-old female who had been clinically diagnosed with primary lung cancer underwent right upper lobectomy and lymph node dissection(ND2a-2). Postoperative pathological staging revealed a stage ⅡA(pT1bN1M0)adenocarcinoma that was negative for an EGFR mutation. Nineteen months after surgery, the patient developed a mediastinal lymph node metastasis, and radiotherapy was prescribed. Thirty-eight months later, she developed new mediastinal/hilar lymph node metastases and was prescribed pemetrexed(500 mg on day 1 of each of 3 weeks)as the first-line therapy. A complete response was evident after 10 courses. However, she developed grade 3 nausea, and pemetrexed was discontinued. During 10 months of follow-up, no new lesion appeared; therefore, follow-up was discontinued. Ninety-three months after surgery, she was referred to our hospital because an abnormal shadow was apparent on chest roentgenography. A thorough examination revealed pleural dissemination, pulmonary metastases, mediastinal/hilar lymph node metastases, an adrenal metastasis, and bone metastases. Although her performance status(PS)was poor(grade 4), as the diagnosis was ALK fusion gene-positive adenocarcinoma, alectinib(600 mg once daily)was commenced as the second-line therapy. Complete response was achieved 14 months later(ie, 108 months after surgery and 89 months after postoperative recurrence). Thus, an octogenarian patient with poor PS and ALK fusion gene-positive adenocarcinoma exhibited a complete response after treatment with alectinib.

Topics: Aged, 80 and over; Carbazoles; Female; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Piperidines; Receptor Protein-Tyrosine Kinases

Topics: Anaplastic Lymphoma Kinase; Breast Neoplasms; Calmodulin-Binding Proteins; Carbazoles; Female; Humans; Membrane Proteins; Middle Aged; Nerve Tissue Proteins; Piperidines; Protein Kinase Inhibitors

Topics: Amides; Carbazoles; COVID-19; Humans; Piperidines; Pyrazines; SARS-CoV-2

Topics: Antineoplastic Agents; Carbazoles; Defibrillators, Implantable; Humans; Male; Middle Aged; Piperidines; Ventricular Fibrillation

to report outcomes of four cases of chemo-refractory RET-rearranged non-small cell lung carcinomas (NSCLCs) treated with alectinib in a single center.. we retrospectively assessed and reported the activity and tolerability of alectinib 600 mg twice daily in advanced and chemo-refractory RET-rearranged NSCLC patients treated in a Brazilian institution. Identification of RET rearrangements was performed using the FoundationOne® next-generation sequencing (NGS) platform.. The four patients herein reported were white, female and non-smokers, ranging between 59-66 years of age. All patients had been previously treated with chemotherapy and were TKI naïve; three of them presented disease progression to nivolumab as well. Molecular tumor profiling showed a KIF5B-RET fusion in three patients and a CCDC6-RET in the fourth. One patient exhibited disease progression and clinical deterioration two months after treatment initiation. Disease control was documented in two patients with PFS ranging from 4 to 5 months (one partial metabolic response and one stable disease). In one of the cases, which developed oligoprogression on alectinib, radiation therapy plus post-progression alectinib were able to provide additional disease control for 9 more months. No grade 3/4 adverse events, dose reductions or discontinuation due to toxicity were documented.. Although this is a small single center evaluation, alectinib was well tolerated and demonstrated clinical activity against advanced RET-rearranged NSCLCs, suggesting its potential role in this specific subset of malignancies. Clinical trials addressing its efficacy and the optimal dosing schedule in the present context are underway, and results are eagerly awaited.

Topics: Aged; Carbazoles; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Retrospective Studies

The effectiveness of ALK receptor tyrosine kinase (ALK) inhibitors can be limited by the development of ALK resistance mutations. This exploratory analysis assessed the efficacy of alectinib in patients with NSCLC and ALK point mutations using pooled data from two single-arm phase II studies.. Studies NP28673 and NP28761 enrolled adults with locally advanced/metastatic ALK-positive NSCLC who had progressed on crizotinib. ALK mutation analysis was conducted on cell-free DNA from 187 patients post-crizotinib/pre-alectinib, and from 49 of these patients who subsequently progressed on alectinib.. Baseline characteristics were generally balanced across patient subgroups. At baseline, 34 distinct ALK mutations were identified in 48 of 187 patients (25.7%). Median investigator-assessed progression-free survival was longer in patients without ALK single-nucleotide variants (n = 138) versus those with (n = 48): 10.2 months (95% confidence interval [CI]: 8.1-14.3) versus 5.6 months (95% CI: 4.5-10.9), respectively. Sixteen of 32 patients (50%) with ALK resistance mutations to crizotinib achieved an investigator-assessed response to alectinib (all partial responses); most of these ALK mutations were known to be sensitive to alectinib. Analysis of plasma samples obtained post-progression on alectinib revealed that 26 of 49 (53%) samples harbored 16 distinct ALK mutations, with known alectinib-resistance mutations, I1171 T/N/S, G1202R, and V1180L, observed in 15 of 49 (31%) tumors.. Alectinib appears clinically active against ALK rearrangements and mutations, as well as several ALK variants that can cause resistance to crizotinib. The use of cell-free DNA in plasma samples may be an alternative noninvasive method for monitoring resistance mutations during therapy.

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mutation; Piperidines; Prospective Studies; Protein Kinase Inhibitors

The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) expressed in regions of the brain that control motor function, cognition, and motivation. As a result, D2R is involved in the pathophysiology of disorders such as schizophrenia and drug addiction. Understanding the signaling pathways activated by D2R is crucial to finding new therapeutic targets for these disorders. D2R stimulation by its agonist, dopamine, causes desensitization and internalization of the receptor. A previous study found that inhibitors of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) blocked D2R desensitization in neurons in the ventral tegmental area of the brain. In the present study, using a cell-based system, we investigated whether ALK regulates D2R internalization. The ALK inhibitor alectinib completely inhibited dopamine-induced D2R internalization. Since GPCRs can transactivate receptor tyrosine kinases, we also examined if D2R stimulation activated ALK signaling. ALK phosphorylation increased by almost 2-fold after dopamine treatment and ALK coimmunoprecipitated with D2R. To identify the signaling pathways downstream of ALK that might regulate D2R internalization, we used pharmacological inhibitors of proteins activated by ALK signaling. Protein kinase C

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Dopamine; HEK293 Cells; Humans; Phosphorylation; Piperidines; Protein Kinase C; Protein Kinase Inhibitors; Receptors, Dopamine D1; Receptors, Dopamine D2; Recombinant Proteins; RNA, Small Interfering; Signal Transduction

A 47-year-old female with ALK-rearranged lung adenocarcinoma developed leptomeningeal metastasis (LM) after progression on first-line crizotinib. Alectinib 300 mg was commenced and the patient achieved clinical and radiographic improvements. After nine months of alectinib 300 mg, she started to experience symptomatic LM. Two concurrent non-EML4-ALK rearrangements, LOC388942-ALK and LINC00211-ALK, were identified from the CSF but not from the plasma samples. With the primary lung lesions remaining stable, the alectinib dose was increased to 600 mg twice daily which alleviated the clinical symptoms of symptomatic LM. After 7.6 months of alectinib 600 mg, the patient again experienced CNS progression. With both CSF and plasma samples revealing no druggable mutations, the alectinib dose was re-escalated to 900 mg twice daily, resulting in clinical benefits lasting for two months. Her therapy was then switched to lorlatinib which controlled the disease for 8.7 months until her demise. The LINC00211-ALK fusion, which retains the ALK kinase domain, detected from the CSF was the mechanism of treatment efficacy in this patient. The central nervous system (CNS) has been increasingly recognized as a site of treatment failure in multiple cancers, including non-small cell lung cancer (NSCLC). Our case demonstrated that alectinib dose-escalation and lorlatinib overcame ALK inhibitor resistance in the CNS in an ALK-positive LM patient. Furthermore, we provide the first clinical evidence of the efficacy of sequential ALK inhibitors in targeting LINC00211-ALK in a patient with LM.

Topics: Anaplastic Lymphoma Kinase; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Female; Gene Rearrangement; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Microtubule-Associated Proteins; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Serine Endopeptidases

Anaplastic lymphoma kinase (ALK) is expressed in ~ 60% of glioblastomas and conveys tumorigenic functions. Therefore, ALK inhibitory strategies with alectinib are conceivable for patients with glioblastoma. The aims of this preclinical study were to investigate efficacy as well as to understand and potentially overcome primary and acquired resistance mechanisms of alectinib in glioblastoma.. Efficacy of alectinib was analyzed dependent on ALK expression in different glioblastoma initiating cells and after lentiviral knockdown of ALK. Alectinib resistant cells were generated by continuous treatment with increasing alectinib doses over 3 months. M-RNA, phospho-protein and protein regulation were analyzed to decipher relevant pathways associated to treatment or resistance and specifically inhibited to evaluate rational salvage therapies.. Alectinib reduced clonogenicity and proliferation and induced apoptosis in ALK expressing glioblastoma initiating cells, whereas cells without ALK expression or after ALK depletion via knockdown showed primary resistance against alectinib. High expression of cMyc and activation of the ERK1/2 pathway conferred resistance against alectinib in ALK expressing glioblastoma cells. Pharmacological inhibition of these pathways by cMyc inhibitor or MEK inhibitor, trametinib, overcame alectinib resistance and re-sensitized resistant cells to continued alectinib treatment. The combination of alectinib with radiotherapy demonstrated synergistic effects in inhibition of clonogenicity in non-resistant and alectinib resistant glioblastoma cells.. The data offer rationales for alectinib treatment in ALK expressing glioblastoma and for the use of ALK expression status as potential biomarker for alectinib treatment. In addition, the results propose MEK inhibition or radiotherapy as reasonable salvage treatments after acquired alectinib resistance.

Topics: Anaplastic Lymphoma Kinase; Apoptosis; Biomarkers, Tumor; Carbazoles; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Tumor Cells, Cultured

The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17-0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018).. Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018.. Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26-0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35-1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib).. At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Crizotinib; Disease Progression; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Prognosis; Survival Rate

Crizotinib, ceritinib, and alectinib improved survival in patients with anaplastic lymphoma kinase (ALK) arrangement non-small-cell lung cancer (NSCLC); however, the long-term economic outcomes of using ceritinib and alectinib versus crizotinib are still unclear.. This analysis aimed to evaluate the cost effectiveness of ceritinib and alectinib versus crizotinib in the Chinese healthcare setting.. A Markov model was developed to project the economic and health outcomes for the treatment of advanced NSCLC with ceritinib, alectinib or crizotinib. A network meta-analysis was performed to calculate the hazard ratios of ceritinib and alectinib versus crizotinib by pooling published trials. Cost and utility values were obtained from the literature, and one-way and probabilistic sensitivity analyses were carried out to determine the robustness of the model outcomes. The primary outputs included total cost, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER).. Treatment with alectinib and ceritinib yielded an additional 1.00 and 1.09 QALYs and incremental costs of $62,232 and $15,165, resulting in an ICER of $62,231 and $13,905 per QALY compared with crizotinib, respectively. Parameters related to drug costs and progression-free survival were the main drivers of the model outcomes. From the probabilistic sensitivity analysis, ceritinib and alectinib had a 99.9% and 0% probability of being cost effective, respectively, at a willingness-to-pay threshold of US$28,410/QALY.. Our results indicate that compared with crizotinib and alectinib, ceritinib is a cost-effective option for treatment-naïve patients with ALK-positive advanced NSCLC.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cost-Benefit Analysis; Crizotinib; Drug Costs; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Quality-Adjusted Life Years; Sulfones

ALK FISH assay guides clinical decision to initiate therapy with ALK inhibitors in patients with stage IV non-small cells lung cancer (NSCLC). In this single institution retrospective study, we investigated the association between the strength of ALK positivity and progression-free survival (PFS) We screened 4,829 patients tested for ALK rearrangement by FISH from 01/06/2012 to 06/30/2018 and included 66 stage IV NSCLC ALK positive patients, who were ALK inhibitor naïve, received an ALK inhibitor, and been followed at least 10 months to the study. The median PFS for cases high positive cases [≥=50% positive nuclei; n = 49] and low positive cases [16-49% positive nuclei; n = 17] is 16 months and 4 months respectively, and the hazard ratio is 2.89 [95 CI 1.34-6.2] (p = 0.0068). When cases are stratified according to cut-off ≥=30% positive nuclei, the median PFS for cases above (n = 55) and below the cut-off (n = 11) is 12 and 3 months, respectively and the hazard ratio is 9.60 [95 CI 2.63-35.04] (p < 0.0001) Patients with low FISH positive results have shorter PFS. Although a biological reason is plausible, false positivity may be a contributing factor. For low positive results, confirmation of the FISH result with an orthogonal technology is warranted.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Decision-Making; Crizotinib; False Positive Reactions; Female; Follow-Up Studies; Gene Rearrangement; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Male; Middle Aged; Piperidines; Progression-Free Survival; Proportional Hazards Models; Protein Kinase Inhibitors; Retrospective Studies

Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer.

Topics: Adaptor Proteins, Signal Transducing; Anaplastic Lymphoma Kinase; Animals; Apoptosis; Carbazoles; Cell Line, Tumor; Cell Survival; Female; Gene Rearrangement; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Transcription Factors; YAP-Signaling Proteins

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; China; Cost-Benefit Analysis; Humans; Lung Neoplasms; Piperidines; Receptor Protein-Tyrosine Kinases

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; China; Cost-Benefit Analysis; Humans; Lung Neoplasms; Piperidines; Receptor Protein-Tyrosine Kinases

Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%-5% of non-small cell lung cancers (NSCLCs). ALK inhibitors show a very high response rate to ALK-positive NSCLCs. However, the emergence of acquired resistance is inevitable. In this study, we investigated the drugs for overcoming resistance especially compound mutations after sequential treatment with crizotinib, alectinib, and lorlatinib.. Next-generation sequencing (NGS) and Sanger sequencing were performed on a liver biopsy tissue obtained from a clinical case. Ba/F3 cells in which mutant EML4-ALK were overexpressed were prepared, and cell viability assay and immunoblotting were performed to check the sensitivity of five independent ALK inhibitors.. I1171S + G1269A double mutation was identified by NGS and Sanger sequencing on a liver biopsy tissue from a patient who relapsed on lorlatinib treatment. Ceritinib and brigatinib-but not other ALK inhibitors-were active against the compound mutations in the cell line model.. With the sequential ALK inhibitors treatment, cancer cells accumulate new mutations in addition to mutations acquired previously. The identified compound mutation (I1171S + G1269A) was found to be sensitive to ceritinib and brigatinib, and indeed the patient's tumor partially responded to ceritinib.. ALK compound mutation was found in a clinical sample that was resistant to lorlatinib after sequential ALK-tyrosine kinase inhibitor (TKI) treatment. Ceritinib and brigatinib are potential overcoming drugs against ALK I1171S + G1269A double mutation.

Topics: Aged; Anaplastic Lymphoma Kinase; Apoptosis; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Mutation; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Sulfones; Tumor Cells, Cultured

The aim of the study is to evaluate the cost-effectiveness of alectinib for first-line treatment of ALK+ advanced non-small-cell lung cancer compared to crizotinib in the French setting. This study used a partitioned survival model, with three discrete health states (progression-free survival, post-progression survival and death). Survival probabilities were derived from a randomised Phase III clinical trial comparing alectinib to crizotinib (ALEX). Beyond the length of the trial (18 months), the efficacy of both treatments was considered equivalent. Occurrence of adverse events or brain metastases were considered as inter-current events. Utilities (and disutilities for intercurrent adverse events) derived from the EQ-5D were applied. Costs were attributed using standard French national public health tariffs. Projected mean overall survival was 4.62 years for alectinib and 4.18 years for crizotinib. Projected mean progression-free survival was 30.30 months for alectinib and 16.13 months for crizotinib. The total number of quality-adjusted life years projected was 3.40 for alectinib and 2.84 for crizotinib. The projected total cost of treatment over the lifetime of the model was € 246,022 for alectinib and € 195,486 for crizotinib. This extra cost was principally attributable to treatment acquisition costs and management before progression. Alectinib was associated with lower costs related to brain metastases and to management post-progression. The incremental cost per life year gained was 115,334 €/year and the incremental cost-effectiveness ratio was 90,232 €/QALY. First-line treatment of ALK+ NSCLC with alectinib provides superior clinical outcomes to crizotinib and is cost-effective in the French context.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Crizotinib; Female; Follow-Up Studies; France; Humans; Lung Neoplasms; Male; Middle Aged; Models, Statistical; Piperidines; Prognosis; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Survival Rate

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.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Asian People; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Recombinant Proteins; Sulfones

Topics: Adolescent; Aminopyridines; Anaplastic Lymphoma Kinase; Bone Neoplasms; Carbazoles; Chemoradiotherapy; DNA-Binding Proteins; Female; Humans; Lactams; Lactams, Macrocyclic; Oncogene Proteins, Fusion; Piperidines; Pyrazoles; Rhabdomyosarcoma; RNA-Binding Protein FUS; Transcription Factors

Leptomeningeal 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.. We 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.. A925L/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).. These findings indicate the potential of novel therapies targeting both ALK and EGFR for the treatment of ALK TKI-resistant LMC in ALK-rearranged NSCLC.

Topics: Acrylamides; Amphiregulin; Anaplastic Lymphoma Kinase; Aniline Compounds; Animals; Carbazoles; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Mice; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has sufficient clinical efficacy and satisfactory safety in ALK-positive non-small cell lung cancer (NSCLC) patients with or without brain metastasis. Alectinib has now become an important drug in the first-line treatment of advanced ALK-positive NSCLC; however, resistance is almost inevitable. The increased expression of hepatocyte growth factor (HGF) and its physiological receptor tyrosine kinase MET have been shown to be linked to acquired resistance to various tyrosine kinase inhibitors (TKIs), and this phenomenon has been observed in some ALK-positive NSCLC tumour tissues. In this study, we found that HGF levels in the culture supernatant of an ALK-positive cell line tended to increase with time and could be further increased by alectinib in a time-dependent manner. Exogenous or endogenous HGF did not cause resistance to the ALK/MET double-targeted small molecule inhibitor crizotinib, but it was an important cause of alectinib resistance. Furthermore, Gab1 was a key effector in the HGF/MET signal transduction pathway that mediated alectinib resistance. The antidiabetic drug metformin combined with alectinib overcame alectinib resistance triggered by HGF/MET through disrupting the complex between MET and Gab1, thereby inhibiting Gab1 phosphorylation and the activation of downstream signal transduction pathways. These results suggest that metformin combined with alectinib may be useful for overcoming alectinib resistance induced by the activation of the HGF/MET signalling pathway and improving the efficacy of alectinib.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Hepatocyte Growth Factor; Humans; Lung Neoplasms; Metformin; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Carbazoles; Circulating Tumor DNA; Humans; Lung Neoplasms; Mutation; Piperidines; Prospective Studies; Protein Kinase Inhibitors

Topics: Anaplastic Lymphoma Kinase; Animals; Apoptosis; ATP-Binding Cassette Transporters; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Gene Rearrangement; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Piperidines; Protein Kinase Inhibitors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Anaplastic lymphoma kinase (ALK) rearranged metastatic non-small cell lung cancer (NSCLC) comprises 5%-7% of all lung cancer and carries a good prognosis with available ALK-inhibitors. Majority of registration trials in ALK-inhibitors did not include Indian patients. Hence, this study was planned to analyze the outcome of Indian patients treated with ALK-inhibitors and associated challenges.. This is a multi-center study in 5 major tertiary care cancer centers across India treating ALK-rearranged NSCLC patients from April 2013 to April 2019. ALK rearrangement was determined by Ventana immunohistochemistry with D5F3 clone and/or by break-apart FISH. Patients treated with ALK-inhibitors in any lines of treatment were included in this study. Patients were evaluated for clinicopathologic features, patterns of ALK-inhibitors use and outcome. Progression free-survival (PFS) and overall survival (OS) were calculated and data were censored on April 30, 2019.. A total of 274 patients were studied, out of which 250 patients received ALK inhibitor and were analyzed further for outcome. The median age was 50 years (range: 24-82) and male to female ratio of 1.17:1. ALK was evaluated by immunohistochemistry in majority of patients (97%), 3 patients by FISH and 3 more patients were evaluated by both methods. Sixty-five percent (n = 162) of the patients received ALK-inhibitor as first line therapy, 51 patients received ALK-inhibitor as switch maintenance therapy after initial chemotherapy. Crizotinib and Ceritinib were used in 88% and 12%, respectively. One patient received Alectinib. Forty-one percent of patients had CNS progression. After median follow up of 27 months (1-72 months), the median OS was 24.7 months with OS rate of 72%, 51%, and 18% at 1, 2, and 4-years respectively. Median OS was 21.2, 26, and 38 months in the first line ALK-inhibitors use (n = 162), switch maintenance group (n = 51) and second line ALK-inhibitors use (postchemotherapy progression) (n = 33), respectively. No baseline variable predicted PFS. Presence of brain metastasis (P = 0.039) and first line ALK-inhibitors use (P = 0.032) emerged as poor prognostic factor for OS on multivariate analysis. PFS rate was 70%, 47%, and 31% at 6, 12, and 18 months respectively.. This is one of the largest real-world data on outcome of ALK inhibitors in ALK-rearranged NSCLC from Asia. In absence of second line ALK inhibitor, initial chemotherapy followed by ALK-inhibitors (switch maintenance) had better outcome. This fact may be studied in individual patient data meta-analysis. Poor performance status and brain metastases at presentation are poor prognostic factors for overall survival. Second-line ALK inhibitor use crucial for better outcome and access to clinical trials are much needed in Indian patients.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Follow-Up Studies; Gene Rearrangement; Humans; India; Lung Neoplasms; Male; Middle Aged; Piperidines; Prognosis; Pyrimidines; Retrospective Studies; Sulfones; Survival Rate; Young Adult

Oiling-out is a unique phenomenon that the liquid phase is separated into two parts during crystallization. The emergence of new liquid phase changes the environment where crystals nucleate and grow, we call "mother phase," because target material and impurities become distributed to each phase according to their own particular distribution ratios. In our previous study on crystallization of an intermediate compound with impurities (denoted Imp-A, -B, and -C), we found that when oiling-out was formed, incorporation of Imp-C was inhibited, because Imp-C was distributed to the mother phase less than Imp-A and -B. In this study, we explored the effect of EtOH solution composition on impurity profile of the crystallized product in oiling-out crystallization, and found that the low content of Imp-B in the EtOH solution, the higher content of Imp-C in the crystallized product. Our finding revealed that not only oiling-out but also Imp-B played a key role in inhibiting the incorporation of Imp-C into the crystals.

Topics: Carbazoles; Crystallization; Ethanol; Molecular Structure; Particle Size; Piperidines; Solutions; Surface Properties

Alectinib confers a pronounced survival benefit in patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status. Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases.. We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement-positive non-small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long-term survival benefit in such patients.. Eighteen patients with ALK rearrangement-positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study.. The median follow-up time for all patients was 27.3 months. The median progression-free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1-30.8 months), and the median survival time (MST) and the 3-year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8-64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886).. Alectinib showed a pronounced survival benefit for patients with ALK rearrangement-positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Survival Analysis

Topics: Adult; Age Factors; Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Comorbidity; Cost of Illness; Crizotinib; Female; Health Expenditures; Health Resources; Health Services; Humans; Insurance Claim Review; Lung Neoplasms; Male; Middle Aged; Patient Acceptance of Health Care; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Regression Analysis; Residence Characteristics; Retrospective Studies; Sex Factors; Socioeconomic Factors; Sulfones

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Female; Humans; Lung Neoplasms; Middle Aged; Myositis; Piperidines; Protein Kinase Inhibitors

Topics: Adenocarcinoma of Lung; Carbazoles; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Oncogene Proteins, Fusion; Piperidines; Receptor Protein-Tyrosine Kinases

Topics: Acrylamides; Amphiregulin; Aniline Compounds; Carbazoles; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Piperidines; Receptor Protein-Tyrosine Kinases

Topics: Acrylamides; Amphiregulin; Aniline Compounds; Carbazoles; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Piperidines; Receptor Protein-Tyrosine Kinases

Topics: Carbazoles; Feasibility Studies; Humans; Lung Neoplasms; Neoadjuvant Therapy; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

The anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) alectinib was approved in Japan in 2014 for the treatment of ALK fusion gene-positive advanced non-small cell lung cancer (NSCLC). With the approvals of crizotinib in 2012 and ceritinib in 2017, Japan became the first country with multiple ALK TKIs available for first-line or later use in patients with ALK-positive advanced NSCLC. Here, we collected and evaluated real-world data on ALK TKI clinical usage patterns and sequencing in patients with ALK-positive NSCLC in Japan.. This retrospective observational study used the Japanese Medical Data Vision database to analyze data from patients with a confirmed diagnosis of lung cancer who visited a healthcare facility in the database between April 2010 and March 2017, underwent an ALK test, received a prescription for an ALK TKI, and were at least 18 years old as of the date of the first ALK TKI prescription. There were no exclusion criteria. Descriptive analyses of demographics, baseline characteristics, ALK TKI treatment patterns and sequences, non-ALK TKI treatments received before, during, and after ALK TKI treatment, and treatment durations were reported.. A total of 378 patients met the inclusion criteria and were evaluated in mutually exclusive groups of patients receiving one, two, or three ALK TKIs. The initial ALK TKI prescribed was crizotinib for 52.1% of patients and alectinib for 47.9% of patients; however, the proportion of patients receiving alectinib as the initial ALK TKI increased over time following the Japanese approval of alectinib in 2014. Of the 117 patients who received two or three ALK TKIs, 106 received crizotinib as the first ALK TKI and 11 received alectinib. Before the date of the patient's first ALK TKI prescription, 153 of 378 patients (40.5%) had received chemotherapy. Of 104 patients who discontinued ALK therapy, 46.2% received chemotherapy and 5.8% received immunotherapy as their next treatment.. At the time of this analysis, most patients who received more than one ALK TKI received crizotinib as the initial ALK TKI. Additional ALK TKIs have since been approved in Japan as first-line or later therapeutic options for patients with ALK-positive NSCLC, but the optimal sequence of ALK TKI usage remains undetermined. As new data continue to emerge, additional research will be warranted to evaluate ALK TKI sequences that do not include crizotinib as the first therapy in this patient population.

Topics: Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Sulfones

Alectinib is an oral tyrosine kinase inhibitor currently recommended by the National Comprehensive Cancer Network (NCCN) as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase (ALK) gene rearrangement-positive non-small cell lung cancer (NSCLC). Skin toxicity is a known adverse effect of this medication, yet current recommendations are unclear regarding how to best manage patients who develop severe skin toxicity while taking alectinib.. Here, we describe a case of successful rechallenge with alectinib by utilizing a desensitization procedure in a patient who had developed severe alectinib-induced skin toxicity about two weeks into treatment.. Alectinib is currently recommended as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase gene rearrangement-positive NSCLC due to improved progression-free survival when compared to crizotinib. The development of skin toxicity can lead to early discontinuation of alectinib treatment, forcing providers and patients to select alternative, potentially less effective options. This case report provides evidence that patients who have experienced severe skin toxicity due to alectinib may be able to continue this first-line treatment option by rechallenging them using a desensitization procedure.

Topics: Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Desensitization, Immunologic; Drug Hypersensitivity; Exanthema; Female; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. However, patients inevitably develop resistance to such therapies. To investigate novel mechanisms of resistance to second generation ALK inhibitors, we characterized and modeled ALK inhibitor resistance of ALK-positive patient-derived xenograft (PDX) models established from advanced-stage lung adenocarcinoma patients who have progressed on one or more ALK inhibitors.. Whole exome sequencing was performed to identify resistance mechanisms to ALK inhibitors in PDXs generated from biopsies at the time of relapse. ALK fusion status was confirmed using fluorescent in situ hybridization, immunohistochemistry, RNA-sequencing, RT-qPCR and western blot. Targeted therapies to overcome acquired resistance were then tested on the PDX models.. Three PDX models were successfully established from biopsies of two patients who had progressed on crizotinib and/or alectinib. The PDX models recapitulated the histology and ALK status of their patient tumors, as well as their matched patients' clinical treatment outcome to ALK inhibitors. Whole exome sequencing identified MET amplification and previously unreported BRAF V600E mutation as independent mechanisms of resistance to alectinib. Importantly, PDX treatment of inhibitors specific for these targets combined with ALK inhibitor overcame resistance.. Bypass signaling pathway through c-MET and BRAF are independent mechanisms of resistance to alectinib. Individualized intervention against these resistance pathways could be viable therapeutic options in alectinib-refractory lung adenocarcinoma.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Drug Resistance, Neoplasm; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Mutation; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf

Topics: Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Erythrocytes; Female; Hemolysis; Humans; Lung Neoplasms; Male; Piperidines; Protein Kinase Inhibitors

Choroidal metastasis is a rare metastatic location although the most common intraocular neoplasm. In general, choroidal metastases respond favorably to systemic therapy targeted toward the primary neoplasm. In patients with choroidal metastasis of ALK rearranged non small cell lung cancer (NSCLC), targeted therapy using Alk inhibitors gradually replaced radiotherapy as the best treatment. Alectinib is a second-generation ALK inhibitors. Here we describe 2 clinical cases of patients with choroidal metastasis of ALK rearranged NSCLC who received Alectinib as first-line therapy achieving disease control and quality of life improvement.. In case report 1, 62-year-old man presented with scintillated scotomas at the level of the right eye; in case report 2, 69-year-old man presented with respiratory distress, persistent cough resistant to medical therapy, pain, and blurred vision.. In case report 1, fundus and ultrasonographic examination showed circumscribed choroid thickening with dome-like appearance compatible with repetitive lesion. Computed tomographic/y (CT) showed multiple bilateral pulmonary nodular formations and adenocarcinoma of the lung was diagnosed by a transbronchial biopsy.In case report 2, CT showed a primary lesion of 36 × 27 mm in the middle lobe with bilateral lung metastases and lymphadenopathies. Multiple hepatic metastases and minor suspicious bone repetitions. A liver biopsy made a diagnosis of adenocarcinoma compatible with pulmonary primitiveness. An ocular fluoroangiography evidenced a left choroidal metastasis.. Case report 1, 2, medical treatment with Alectinib 1200 mg/day was initiated.. In case report 1, a few days after beginning the treatment, both systemic symptoms like respiratory distress and low vision were palliated. Reassessment by CT confirmed treatment response. In case report 2, clinically, visus disorders had already improved 2 weeks after beginning treatment. CT showed pulmonary, nodal, and hepatic response. Stability of bone metastases occurred after 2 months. In addition, ocular ultrasonography documented the regression of previously reported lesions confirmed treatment response.. Alectinib works very well in intracranial metastases and is assumed to be so on the ocular ones as well, with benefit for the patient in quality of life.

Topics: Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Choroid Neoplasms; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

Ovarian cancer is prone to recurrence and chemotherapy resistance. Ovarian tumours of some patients have been positive for anaplastic lymphoma kinase fusion gene expression (ALK+). Preclinical studies indicate that anaplastic lymphoma kinase inhibitor can suppress the growth of ovarian cancer cells and transplantation tumours. Here, we present a patient with metastatic ALK+ high-grade serous ovarian cancer that testing positive for EML4-ALK (microtubule-associated protein-like 4 gene, fused to the anaplastic lymphoma kinase gene), experienced dramatic benefit after administration of the anaplastic lymphoma kinase inhibitor alectinib. This is the first clinical evidence that treatment with alectinib may provide a personalized maximum benefit for patients with high-grade serous ovarian cancer who are positive for EML4-ALK.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Ovarian Epithelial; Female; Humans; Middle Aged; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Ovarian Neoplasms; Piperidines; Protein Kinase Inhibitors; Treatment Outcome

Topics: Carbazoles; Crizotinib; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Topics: Aged; Anaplastic Lymphoma Kinase; Anti-HIV Agents; Betacoronavirus; Carbazoles; Carcinoma, Non-Small-Cell Lung; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Combinations; Humans; Hydroxychloroquine; Lopinavir; Lung; Lung Neoplasms; Male; Masks; Noninvasive Ventilation; Pandemics; Piperidines; Pneumonia, Viral; Ritonavir; SARS-CoV-2; Tomography, X-Ray Computed; Treatment Outcome

Anaplastic lymphoma kinase (ALK) rearrangement is identified in approximately 3-7% of all metastatic non-small cell lung cancer (NSCLC) patients, and ALK tyrosine kinase inhibitors (TKIs) have revolutionized the management of this subset of lung cancer cases.. This study aims to show alectinib (TKI) effectiveness and safety with focus on alectinib intracranial efficacy for ALK+ NSCLC patients.. Patient 1 was a 46-year-old woman diagnosed with non-small cell lung cancer with an echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene (ALK+). She presented with intracranial and liver metastases and poor performance status of ECOG 3. Alectinib was initiated as a second line therapy, after whole brain irradiation and discontinuation of first line chemotherapy after two cycles, due to the central nervous system progression and liver metastases. Good response was consequently achieved, characterized with improved overall performance and without significant adverse events. Patient 2 was a 53-year old man with left sided lung adenocarcinoma surgically treated in 2017. Post-operative pTNM stage was IIB with a positive resection margin- R1. He received adjuvant chemotherapy and radiotherapy. In 2019, after two and half years of being disease free, he presented with severe cerebral symptoms leading to poor performance status. CT scan of the brain showed multiple brain metastases. He was treated with first line alectinib after completion of whole brain radiotherapy. In 5 months period he got significantly better and able for work again.. We recommend alectinib as a first and second line treatment approach for ALK+ NSCLC patients, in particular the ones with brain metastases at the time of diagnosis and poor PS.

Topics: Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

Alectinib is a highly efficacious inhibitor for the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in the clinic; however, serious adverse events (AEs) occurred in 44.0% of patients. Herein, we explored magnetic/TAT dual-targeted nanocarriers as delivery systems for alectinib. Magnetic targeting efficiently enhanced the extravasation of alectinib-loaded nanoparticles from vessels into the tumor tissue, while the TAT targeting reactivated in the tumor tissue significantly improved the tumor cellular uptake of the nanocarrier. As a result, this dual-targeted polymeric nanocarrier exhibited superior therapeutic effects and induced tumor shrinkage in vivo. Meanwhile, this dual-targeted nanocarrier also minimized alectinib-induced hepatotoxicity, providing an efficient strategy to extend the application of alectinib for NSCLC patients.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Topics: Acrylamides; Afatinib; Aminopyridines; Anaplastic Lymphoma Kinase; Aniline Compounds; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; B7-H1 Antigen; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; ErbB Receptors; Gefitinib; Hope; Humans; Lactams; Lung; Lung Neoplasms; Piperidines; Programmed Cell Death 1 Receptor; Pyrazoles; Quinazolinones; Survival Analysis

Guidelines recommend testing for multiple biomarkers in non-small cell lung cancer (NSCLC) tumors. Blood-based liquid biopsy analyzing cell-free DNA (cfDNA) could be used in addition to tumor biopsy genotyping, especially if tissue/time are limiting.. To investigate the clinical utility of early cfDNA analysis (Guardant360® CDx) in treatment-naïve NSCLC patients.. A prospective cohort of treatment-naïve patients with metastatic NSCLC who underwent tumor and cfDNA analysis between 12/2018 and 2/2019 were included.. Ten patients were included: 6 males, median age 70.5 years (range 48-87), 8 prior smokers. Liquid biopsy was sent when cancer cells were detected in the biopsy specimen. Median time from diagnosis to receiving the report on the last biomarker from the tumor biopsy was 20 days (range 9-34); median time from blood draw to receiving the cfDNA findings was 9 days (range 7-12). The median difference between the cfDNA and the tumor analysis reports was 20 days (range 9-28). Actionable biomarkers were identified in four patients by both the biopsy analysis and the cfDNA analysis (2cases with EGFR mutations, one with ROS1 fusion, and one with EML4-ALK fusion for whom the biopsy analysis also identified an EGFR mutation not detected in the cfDNA analysis). Overall, eight patients received treatment (2 died before treatment initiation). Three patients received biomarker-based treatment (1 osimertinib, 1 alectinib, and 1 crizotinib).. These findings suggest that cfDNA analysis should be ordered by the pulmonologists early in the evaluation of patients with NSCLC, which might complement the tumor biopsy.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; DNA, Neoplasm; Female; Genotyping Techniques; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Prospective Studies

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carbazoles; Cell Line, Tumor; Cell Proliferation; Crizotinib; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fluorine Radioisotopes; Humans; Mice; Molecular Structure; Piperidines; Positron-Emission Tomography; Protein Kinase Inhibitors; Pyrimidines; Radionuclide Imaging; Structure-Activity Relationship; Sulfones; Tissue Distribution

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines; Receptor Protein-Tyrosine Kinases

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Piperidines; Progression-Free Survival; Receptor Protein-Tyrosine Kinases

Few cases of lung mucoepidermoid carcinomas with anaplastic lymphoma kinase (ALK) fusion have been reported. A 35-year-old woman was found to have an abnormal chest X-ray. A tumor and obstructive pneumonitis in her left upper lobe was detected using computed tomography (CT). She was admitted to our hospital, and was diagnosed with mucoepidermoid carcinoma by transbronchial biopsy. Left pneumonectomy and lymphadenectomy were performed for lung mucoepidermoid carcinoma and a mediastinal lymph node metastasis (pT2aN2M0, stage ⅢA). Postoperative radiotherapy (50 Gy) to the mediastinum and chemotherapy were performed followed by several radiotherapies for cervical and mediastinal lymph node and right ischium metastases. Since then, further radiotherapy was impossible. However, we detected ALK fusion in the resected specimen and the cancer responded to alectinib hydrochloride.

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Mucoepidermoid; Female; Humans; Lung Neoplasms; Lymph Node Excision; Piperidines

The recent approval of anaplastic lymphoma kinase (ALK) inhibitors for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC) has dramatically transformed cancer therapy. However, leptomeningeal metastases (LM) are frequent and often devastating complications of ALK-rearranged NSCLC, and treatment against LM remains challenging. Herein we report a case of a 19-year-old male diagnosed with ALK-rearranged NSCLC with LM. He experienced heavy treatment before introduction of alectinib therapy, which continued for approximately 5.5 years with marked efficacy. However, he experienced recurrence of a bulbar metastasis after discontinuation of alectinib. Reintroduction of standard-dose alectinib therapy resolved the lesion again. Our findings suggest that ALK-tyrosine kinase inhibitor therapy should be continued in patients showing a long-term complete response, unless intolerable toxicities are present, and that rechallenge treatment with alectinib may represent a therapeutic option for central nervous system metastases.

Topics: Adult; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Neoplasm Recurrence, Local; Oncogene Proteins, Fusion; Piperidines; Prognosis

Topics: Carbazoles; Female; Humans; Lung Neoplasms; Middle Aged; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrimidines

The emergence of oral targeted therapy in the management of non-small cell lung cancer with targetable oncogenes has led to significant improvements in progression-free survival, toxicity profile, and quality of life compared to intravenous chemotherapy. However, patients unable to swallow or with exclusive enteral feeding are left without alternative formulations for these targeted therapies given their availability only in tablet or capsule formulations. We report a case of a woman with metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer who was unable to swallow and was successfully treated with an oil-based alectinib liquid suspension.

Topics: Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Piperidines; Quality of Life; Suspensions

Brigatinib, ceritinib, and alectinib are approved to treat crizotinib-refractory anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC), but no trial has compared them head-to-head. A matching-adjusted indirect comparison (MAIC) was conducted to estimate the relative efficacy of these agents in the crizotinib-refractory setting.. MAIC is a propensity score-type method that adjusts for differences in baseline characteristics between trials to estimate relative efficacy. Analyses were based on patient-level data from the ALTA trial for brigatinib and published summary-level trial data from ASCEND-1 and ASCEND-2 for ceritinib and NP28761 and NP28673 for alectinib. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared.. After matching, all key baseline characteristics were balanced between trials. Compared with ceritinib, brigatinib was associated with longer PFS (ASCEND-1: median 15.7 vs 6.9 months, hazard ratio (HR) [95% confidence interval] = 0.38 [0.26-0.57]; ASCEND-2: median = 18.3 vs 7.2 months, HR = 0.33 [0.20-0.56]) and OS (ASCEND-1: not available; ASCEND-2: median 27.6 vs 14.9 months, HR = 0.33 [0.17-0.63]). Versus alectinib, brigatinib was associated with longer PFS (NP28761: median = 17.6 vs 8.2 months, HR = 0.56 [0.36-0.86]; NP28673: median = 17.6 vs 8.9 months, HR = 0.61 [0.40-0.93]); results for OS were inconclusive (NP28761: median = 27.6 vs 22.7 months, HR = 0.70 [0.42-1.16]; NP28673: median = 27.6 vs 26.0 months, HR = 0.66 [0.39-1.09]). ORR was similar.. In crizotinib-refractory ALK + NSCLC patients, relative efficacy estimates suggest brigatinib may have prolonged PFS and OS vs ceritinib and prolonged PFS vs alectinib.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Organophosphorus Compounds; Piperidines; Proportional Hazards Models; Pyrimidines; Sulfones

Topics: Acute Disease; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug-Related Side Effects and Adverse Reactions; Female; Hepatitis; Humans; Liver; Lung Neoplasms; Piperidines

Rapid progression of metastatic non-small cell lung cancer (NSCLC) after discontinuation of tyrosine kinase inhibitors or anaplastic lymphoma kinase (ALK) inhibitors has been described and is associated with a poor prognosis. We describe the first reported case of accelerated NSCLC tumor extension throughout the entire spinal epidural space.. A 68-year-old woman with stage IV ALK-positive metastatic NSCLC presented with acute neck pain, urinary retention, and lower extremity weakness 15 days post discontinuation of alectinib. Magnetic resonance imaging (MRI) with contrast was significant for a new compressive lesion spanning the entire cervical, thoracic, and lumbar spine, which was new compared with MRI obtained 20 days before and was suspicious for infection. Cervical (C3-C7), thoracic (T9-T12), and lumbar (L3-L5) decompression were performed with collection of culture and pathology specimens. Repeat MRI obtained for acute neurologic deterioration on postoperative day 2 noted further progression of disease and continued thoracic cord compression. After urgent T1-9 laminectomy, specimens were again sent for pathology, cultures, and cytology. No evidence of infection was noted, and all pathologic specimens evaluated were consistent with metastatic adenocarcinoma. Despite operative intervention, the patient continued to decline, suffering from recurrent pleural effusions, and eventual cardiopulmonary arrest 11 days after admission.. The differential diagnosis when evaluating presumed spine epidural abscess should include tumor and metastatic disease, even in cases of rapid development. Recent termination of tyrosine kinase inhibitors or ALK inhibitors may result in severe disease flares, and a history of such should raise clinical suspicion for metastatic progression. In addition to cultures, biopsy for pathologic diagnosis should be collected during decompressive surgery.

Topics: Aged; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cervical Vertebrae; Diagnosis, Differential; Disease Progression; Epidural Space; Fatal Outcome; Female; Humans; Lumbar Vertebrae; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Spinal Neoplasms; Thoracic Vertebrae; Withholding Treatment

Central nervous system (CNS) metastases represent a significant source of morbidity and mortality for patients with ALK tyrosine kinase gene (ALK)-positive NSCLC. Alectinib has demonstrated robust CNS activity in both crizotinib-naive and crizotinib-resistant settings. However, the CNS efficacy of alectinib has not been established in patients with untreated symptomatic, large CNS metastases.. In this retrospective study, patients were eligible if they had advanced ALK-positive NSCLC with large (defined as ≥1 cm) or symptomatic CNS metastases and received alectinib. Medical records and radiographic imaging were reviewed to determine treatment outcomes. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1.. Of the 19 patients, 15 (79%) had measurable CNS disease at baseline and were evaluable for response. The CNS objective response rate in these patients was 73.3% (95% confidence interval [CI]: 44.9%-92.2%), the CNS disease control rate was 100.0% (95% CI: 78.2%-100.0%), and the median CNS duration of response was 19.3 months (95% CI: 14.3 months-not evaluable). In 18 evaluable patients with measurable and/or nonmeasurable baseline CNS disease, the CNS objective response rate was 72.2% (95% CI: 46.5%-90.3%), the CNS disease control rate was 100.0% (95% CI: 81.5%-100.0%), and the median CNS duration of response was 17.1 months (95% CI: 14.3 months-not evaluable). All eight patients with symptoms attributable to CNS metastases had clinical improvement upon starting alectinib therapy. Six patients (32%) eventually required salvage brain radiotherapy.. Alectinib demonstrated meaningful CNS efficacy in patients with ALK-positive NSCLC with untreated symptomatic or large brain metastases.

Topics: Adult; Aged; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Piperidines; Young Adult

Alectinib is a member of the family of anaplastic lymphoma kinase inhibitors. This agent is effective in the treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung cancer and has excellent blood-brain barrier penetrability. It is generally well tolerated; however, significant toxicities such as interstitial lung disease have been reported. We present herein an instance of interstitial lung disease four weeks into alectinib treatment. Alectinib was held, and the patient showed clinical and radiographic improvement of her interstitial lung disease. Alectinib was then resumed at half dosage without further complications. Prompt recognition of adverse reactions to this targeted agent is paramount. Cessation of therapy may be needed on a case-to-case basis. However, as our case highlights, safe re-introduction of alectinib can be accomplished in some cases.

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Middle Aged; Piperidines; Protein Kinase Inhibitors

Topics: Brain; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Treatment Outcome

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Drug Approval; Drug Development; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; United States; United States Food and Drug Administration

Mutations in the

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lung Neoplasms; MicroRNAs; Mutation; Piperidines; Protein Kinase Inhibitors

We conducted a large-scale surveillance study as a post-marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) in Japan. Patients receiving 300 mg twice-daily alectinib (September 2014 to June 2015) were monitored until termination of alectinib or completion of 18 months of treatment at 519 Japanese study sites. The primary endpoint was the incidence of adverse drug reactions (ADR), which are important identified risks for alectinib in Japanese patients. Overall survival (OS), a key secondary endpoint, was assessed according to information on outcome. Overall, 1251 patients were enrolled. The median patient age was 62.0 years; 12.9% of patients were aged ≥75 years. At baseline, 63.0% of patients had received crizotinib and 40.6% had brain metastases. Altogether, 1512 ADR occurred in 654 patients (53.6%), with 164 grade ≥3 ADR in 123 patients (10.1%). Commonly occurring ADR were hepatic disorders (all grades, 19.8%; grade ≥3, 2.0%), decreased neutrophil and/or white blood cell count (all grades, 7.6%; grade ≥3, 1.1%), and interstitial lung disease (all grades, 3.8%; grade ≥3, .7%). Median OS was not estimable. The 18-month cumulative OS rate was longer in patients with ECOG performance status ≤1 (vs 2 or ≥3; 83.7% vs 44.5% or 27.2%), without prior crizotinib (vs with; 81.1% vs 73.4%), receiving first-line alectinib (vs second and third or later line; 83.0% vs 79.2% or 71.9%), without brain metastases (vs with; 79.5% vs 71.5%). These data confirm the favorable safety and effectiveness of alectinib in patients with ALK-positive NSCLC in Japan.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Survival Analysis; Treatment Outcome; Young Adult

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Fibroblasts; Humans; Lung Neoplasms; Piperidines

Heterogeneity in strategies for survival and proliferation among the cells that constitute a tumour is a driving force behind the evolution of resistance to cancer therapy. The rules mapping the tumour's strategy distribution to the fitness of individual strategies can be represented as an evolutionary game. We develop a game assay to measure effective evolutionary games in co-cultures of non-small cell lung cancer cells that are sensitive and resistant to the anaplastic lymphoma kinase inhibitor alectinib. The games are not only quantitatively different between different environments, but targeted therapy and cancer-associated fibroblasts qualitatively switch the type of game being played by the in vitro population from Leader to Deadlock. This observation provides empirical confirmation of a central theoretical postulate of evolutionary game theory in oncology: we can treat not only the player, but also the game. Although we concentrate on measuring games played by cancer cells, the measurement methodology we develop can be used to advance the study of games in other microscopic systems by providing a quantitative description of non-cell-autonomous effects.

Topics: Biological Evolution; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cells, Cultured; Fibroblasts; Game Theory; Humans; Lung Neoplasms; Models, Biological; Piperidines; Protein Kinase Inhibitors

Topics: Adenocarcinoma of Lung; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Renal Dialysis; Safety

An inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm that typically develops in the lungs and seldom in the head and neck region. It is often related to the anaplastic lymphoma kinase (ALK) fusion gene. Crizotinib, a first-generation ALK inhibitor, has been shown to have a notable response in patients with ALK-positive IMT. Here, we report the first case of a 46-year-old man with IMT harboring a novel SQSTM1-ALK fusion gene who demonstrated marked response to alectinib. The patient presented a right neck mass (5-cm diameter) that progressively enlarged and expanded to the upper mediastinum. ALK-rearranged IMT was diagnosed after complete tumor resection. Spindle cells displayed diffuse cytoplasmic staining for ALK on immunohistochemistry. A fluorescence in situ hybridization analysis revealed the translocation of a part of the ALK gene locus at chromosome 2p23. FoundationOne CDx™ assay identified an SQSTM1-ALK gene fusion. After a year, right cervical, subclavian, and mediastinal lymph node metastases, considered unresectable, developed. Notably, the patient exhibited a marked response to alectinib treatment and has sustained for 17 months following systemic therapy initiation without significant adverse events. This report highlights the possibility of alectinib being a reasonable option for advanced IMT with the SQSTM1-ALK fusion.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Head and Neck Neoplasms; Humans; Male; Middle Aged; Myofibroblasts; Piperidines; Protein Kinase Inhibitors; Tomography, X-Ray Computed; Treatment Outcome

The development and full validation of a sensitive and selective ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method are described for the simultaneous analysis of afatinib, alectinib, crizotinib and osimertinib in human lithium heparinized plasma. Afatinib-d6, crizotinib-d5 and erlotinib-d6 were used as internal standards. Given osimertinib's instability in plasma and whole blood at ambient temperature, samples should be solely processed on ice (T = 0 °C). Chromatographic separation was obtained on an Acquity UPLC ® BEH C18; 2.1 × 50 mm, 1.7 μm column, which was eluted with 0.400 mL/minute flow on a linear gradient, consisting of 10 mM ammonium formate (pH 4.5) and acetonitrile. Calibration curves for all compounds were linear for concentration ranges of 1.00 to 100 ng/mL for afatinib and 10.0 to 1000 ng/mL for alectinib, crizotinib and osimertinib, herewith validating the lower limits of quantification at 1.00 ng/mL for afatinib and 10.0 ng/mL for alectinib, crizotinib and osimertinib. Within-run and between-run precision measurements fell within 10.2%, with accuracy ranging from 89.2 to 110%.

Topics: Acrylamides; Afatinib; Aniline Compounds; Carbazoles; Chromatography, High Pressure Liquid; Crizotinib; Drug Stability; Humans; Limit of Detection; Linear Models; Male; Middle Aged; Piperazines; Piperidines; Reproducibility of Results; Tandem Mass Spectrometry

To assess the cost-effectiveness of alectinib versus crizotinib as first-line treatments for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients from the perspective of China's healthcare system.. A Markov model was developed to assess the clinical outcomes and costs of alectinib and crizotinib, which included five health states: progression-free (PF) without central nervous system (CNS) progression, PF with CNS progression, post-progression (PP) without CNS progression, PP with CNS progression, and death. Clinical data for transition probabilities were obtained from the ALEX trial at the updated data cutoff. Healthcare resource utilization and costs were derived from clinical expert opinions and published literature. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to assess the uncertainty of the results. Scenario analyses were conducted including using clinical data from the ALESIA trial in Asian patients, using utilities from the ALEX trial, and choosing different parametric survival models.. In base case analysis, alectinib yielded an additional 1.04 quality-adjusted life years (QALYs) with incremental costs of $54,827, resulting in an incremental cost-effectiveness ratio (ICER) of $52,869/QALY. In scenario analysis, the ICER was $56,787/QALY using clinical data from the ALESIA trial. In probabilistic sensitivity analysis, the probabilities of alectinib being cost-effective were 0.4% and 43.7% when the willingness-to-pay (WTP) thresholds were $28,109/QALY and $50,000/QALY, respectively.. Alectinib could prolong the mean time of PF and delay the time to CNS progression. However, because of its high drug cost, alectinib was unlikely to be cost-effective for untreated ALK-positive NSCLC patients in China.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; China; Cost-Benefit Analysis; Crizotinib; Disease Progression; Drug Costs; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Quality-Adjusted Life Years

Transformation to small cell lung cancer is one phenomenon of acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Few case reports have focused on other types of histological transformation. We report a case of transformation of ALK rearrangement-positive adenocarcinoma to NSCLC with neuroendocrine differentiation during alectinib therapy. A 36-year-old woman presented with a tumor in the left lower lobe and bone metastases. She was diagnosed with ALK rearrangement-positive adenocarcinoma by histopathology of the primary tumor. Alectinib had been effective for 8 months before new lesions appeared. Histopathological re-examination of a recurrent tumor revealed poorly differentiated carcinoma with insulinoma-associated protein 1 (INSM1) expression, which remained ALK-positive. Expression of CD133, BCL-2, and SOX2 was positive in comparison to the initial tumor. Expression of SOX2 became more strongly positive than it was before treatment. The immunohistochemical findings of these markers associated with cancer stem-like cells and/or neuroendocrine differentiation suggest that cancer stem cells play a role in the mechanisms of histological transformation and acquired resistance of ALK rearrangement-positive cancer. To our knowledge, this is the first report to suggest an association between cancer stem-like cells and histological transformation in ALK rearrangement-positive lung cancer.

Topics: Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Antigens, CD; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Transformation, Neoplastic; Female; Gene Rearrangement; Humans; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Repressor Proteins; SOXB1 Transcription Factors

Little is known regarding the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) efficacy and safety in the elderly.. Consecutive patients (n = 53) with ALK-positive advanced non-small cell lung cancer treated with an ALK TKI were identified through internal databases of three cancer centers and divided into groups A (< 65 years old; n = 34) and B (≥65 years old; n = 19). Progression-free survival (PFS), ALK TKI safety and overall survival (OS) were assessed. Uni- and multivariate PFS and OS analyses were performed.. Crizotinib, ceritinib, and alectinib were administered in 94 and 100%, 35 and 31%, 38 and 52% of patients in groups A and B, respectively. The median PFS (months) was 5.4 (95% CI, 3.4-12.4) and 5.6 (95% CI, 2.5-14.7) with crizotinib (log-rank 0.0009, p = 0.9), 4.7 (95% CI, 1.0-11.5) and 23.0 (95% CI, 0.8-27.7) with ceritinib (log-rank 0.44, p = 0.5), and 21.2 (95% CI, 1.2 to not reached, NR) and 5.6 (95% CI, 0.5 to NR) with alectinib (log-rank 0.53, p = 0.5) in groups A and B, respectively. The median OS (months) comprised 29.8 (95% CI, 21.0 to NR) and 25.1 (95% CI, 10.8-53.6) in groups A and B, respectively (log-rank 0.57, p = 0.4). Age affected neither PFS nor OS. 19 and 37%, 50 and 40%, and 0 and 0% of patients in groups A and B, treated with crizotinib, ceritinib, and alectinib, respectively, developed high-grade adverse events. The treatment discontinuation rate was 9 and 21%, 16 and 60%, 0 and 0% with crizotinib, ceritinib, and alectinib in groups A and B, respectively.. In the elderly, crizotinib, ceritinib, and alectinib treatments are associated with similar efficacy but different safety profiles; alectinib is associated with a lower rate of high-grade adverse events and a lower treatment discontinuation rate.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Patient Safety; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Sulfones; Young Adult

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Gene Rearrangement; Genes, erbB-1; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Piperidines; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Topics: Adult; Anaplastic Lymphoma Kinase; Biomarkers; Carbazoles; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Lymphoma, Large-Cell, Anaplastic; Male; Molecular Targeted Therapy; Piperidines; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Retreatment; Tomography, X-Ray Computed; Treatment Outcome

Alectinib is a tyrosine kinase inhibitor currently used as a first-line treatment of anaplastic lymphoma kinase-positive metastatic nonsmall cell lung cancer (NSCLC). In the present work, we investigated possible interactions of this novel drug with ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 (P450) biotransformation enzymes that play significant roles in the phenomenon of multidrug resistance (MDR) of cancer cells as well as in pharmacokinetic drug-drug interactions. Using accumulation studies in Madin-Darby canine kidney subtype 2 (MDCKII) cells alectinib was identified as an inhibitor of ABCB1 and ABCG2 but not of ABCC1. In subsequent drug combination studies, we demonstrated the ability for alectinib to effectively overcome MDR in ABCB1- and ABCG2-overexpressing MDCKII and A431 cells. To describe the pharmacokinetic interaction profile of alectinib in a complete fashion, its possible inhibitory properties toward clinically relevant P450 enzymes (i.e., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP3A5) were evaluated using human P450-expressing insect microsomes, revealing alectinib as a poor interactor. Advantageously for its use in pharmacotherapy, alectinib further exhibited negligible potential to cause any changes in expression of

Topics: Animals; ATP-Binding Cassette Transporters; Biotransformation; Carbazoles; Cytochrome P-450 Enzyme System; Dogs; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Madin Darby Canine Kidney Cells; Piperidines; Protein Kinase Inhibitors

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Central Nervous System Neoplasms; Gene Rearrangement; Humans; Lymphoma, Large-Cell, Anaplastic; Male; Neoplasm Proteins; Piperidines; Recurrence

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood; treatments with greater effectiveness are required for NB, especially in advanced cases. This study aimed at evaluating the combined effect of anaplastic lymphoma kinase (ALK) inhibitor alectinib and histone deacetylase inhibitor vorinostat on NB cell lines harboring wild-type or mutated ALK.. Cytotoxicity was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Protein expression was analyzed using western blotting.. Combination treatment with alectinib and vorinostat had a synergistic effect on growth inhibition of the NB cell line with ALK R1275Q mutation. Cleavage of caspase-3 and poly-(ADP-ribose) polymerase increased, indicating enhanced caspase-dependent apoptosis. In addition, this combination reduced the protein levels of MYCN proto-oncogene and nuclear factor kappa B, both of which are important for NB tumorigenesis and progression.. Combined treatment with alectinib and vorinostat might be a novel therapeutic option for NB harboring the ALK R1275Q mutation.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Cell Line, Tumor; Cell Survival; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Mutation; N-Myc Proto-Oncogene Protein; Neuroblastoma; NF-kappa B; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Mas; Vorinostat

Topics: Adenocarcinoma of Lung; Bevacizumab; Carbazoles; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Topics: Antineoplastic Agents; Carbazoles; Crizotinib; Humans; Kidney Diseases, Cystic; Piperidines

The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples.. Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction.. ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes.. High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Erlotinib Hydrochloride; Humans; Kidney Neoplasms; Lactams; Lactams, Macrocyclic; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred NOD; Middle Aged; Mutation; Piperidines; Pyrazoles; Xenograft Model Antitumor Assays

1. The in vitro metabolism of alectinib, a potent and highly selective oral anaplastic lymphoma kinase inhibitor, was investigated. 2. The main metabolite (M4) in primary human hepatocytes was identified, which is produced by deethylation at the morpholine ring. Three minor metabolites (M6, M1a, and M1b) were also identified, and a minor peak of hydroxylated alectinib (M5) was detected as a possible precursor of M4, M1a, and M1b. 3. M4, an important active major metabolite, was produced and further metabolized to M6 by CYP3A, indicating that CYP3A enzymes were the principal contributors to this route. M5 is possibly produced by CYP3A and other isoforms as the primary step in metabolism, followed by oxidation to M4 mainly by CYP3A. Alternatively, M5 could be oxidized to M1a and M1b via an NAD-dependent process. None of the non-CYP3A-mediated metabolism appeared to be major. 4. In conclusion, this study suggests that involvement of multiple enzymes in the metabolism of alectinib reduces its potential for drug-drug interactions.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Cells, Cultured; Cytochrome P-450 CYP3A; Hepatocytes; Humans; Piperidines; Receptor Protein-Tyrosine Kinases

The penetration of the anaplastic lymphoma kinase (ALK) inhibitor alectinib in neuroblastomas and the relationship between alectinib and ALK expression are unknown. The aim of this study was to perform a quantitative investigation of the inter- and intra-tumoural distribution of alectinib in different neuroblastoma xenograft models using matrix-assisted laser desorption ionization MS imaging (MALDI-MSI).. The distribution of alectinib in NB1 (ALK amplification) and SK-N-FI (ALK wild-type) xenograft tissues was analysed using MALDI-MSI. The abundance of alectinib in tumours and intra-tumoural areas was quantified using ion signal intensities from MALDI-MSI after normalization by correlation with LC-MS/MS.. The distribution of alectinib was heterogeneous in neuroblastomas. The penetration of alectinib was not significantly different between ALK amplification and ALK wide-type tissues using both LC-MS/MS concentrations and MSI intensities. Normalization with an internal standard increased the quantitative property of MSI by adjusting for the ion suppression effect. The distribution of alectinib in different intra-tumoural areas can alternatively be quantified from MS images by correlation with LC-MS/MS.. The penetration of alectinib into tumour tissues may not be homogenous or influenced by ALK expression in the early period after single-dose administration. MALDI-MSI may prove to be a valuable pharmaceutical method for elucidating the mechanism of action of drugs by clarifying their microscopic distribution in heterogeneous tissues.

Topics: Animals; Carbazoles; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neuroblastoma; Pilot Projects; Piperidines; Protein Kinase Inhibitors; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Xenograft Model Antitumor Assays

Anaplastic lymphoma kinase (ALK) rearrangement is most commonly observed in lung adenocarcinoma in a subset of lung cancer. Large cell neuroendocrine carcinoma (LCNEC) harboring an ALK rearrangement is very rare. Based on the findings from a transbronchial lung biopsy, a 75-year-old non-smoking woman was diagnosed with LCNEC with multiple liver and bone metastases. After seven cycles of cytotoxic chemotherapy, her genotype testing demonstrated ALK rearrangement. Subsequently, she was administered alectinib and exhibited a partial response.

Topics: Aged; Anaplastic Lymphoma Kinase; Bone Neoplasms; Carbazoles; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Female; Gene Rearrangement; Humans; Liver Neoplasms; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Alectinib is a selective anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. Alectinib and its major active metabolite M4 exhibited drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8 in vitro. Clinical relevance of the DDI risk was investigated as part of a rapid development program to fulfill the breakthrough therapy designation. Therefore, a strategy with a combination of physiologically based pharmacokinetic (PBPK) modeling and limited clinical trials focused on generating informative data for modeling was made to ensure extrapolation ability of DDI risk. The PBPK modeling has provided mechanistic insight into the low victim DDI risk of alectinib through CYP3A4 by a novel two-dimensional analysis for fm

Topics: Activation, Metabolic; Carbazoles; Computer Simulation; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C8 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Approval; Drug Development; Drug Interactions; Humans; Models, Biological; Patient Safety; Piperidines; Protein Kinase Inhibitors; Risk Assessment; Substrate Specificity; United States; United States Food and Drug Administration

Alectinib, a highly selective next-genetation anaplastic lymphoma kinase (ALK) inhibitor, has demonstrated promising antitumor activity in patients with ALK-positive non-small cell lung carcinomas (NSCLC). However, the therapeutic benefits of alectinib is inescapably hampered by the development of acquired resistant mutations in ALK. Despite the availability of ample experimental mutagenesis data, the molecular origin and the structural motifs under alectinib binding affinity deficiencies are still ambiguous. Here, molecular dynamics (MD) simulations and molecular mechanics generalized born surface area (MM-GBSA) calculation approaches were employed to elucidate the mechanisms of alectinib resistance induced by the mutations I1171N, V1180L, and L1198F. The MD results reveal that the studied mutations could trigger the dislocation of alectinib as well as conformational changes at the inhibitor binding site, thus induce the interactional changes between alectinib and mutants. The most influenced regions are the ligand binding entrance and the hinge region, which are considered to be the dominant binding motifs accounting for the binding affinity loss in mutants. The "key and lock mechanism" between the ethyl group at position 9 of alectinib and a recognition cavity in the hinge region of ALK is presented to illustrate the major molecular origin of drug resistance. Our results provide mechanistic insight into the effect of ALK mutations resistant to alectinib, which could contribute to further rational design of inhibitors to combat the acquired resistance.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Molecular Dynamics Simulation; Mutation; Piperidines; Protein Conformation; Protein Kinase Inhibitors

　The aim of this study was to investigate the time-to-onset of drug-induced interstitial lung disease (DILD) following the administration of small molecule molecularly-targeted drugs via the use of the spontaneous adverse reaction reporting system of the Japanese Adverse Drug Event Report database. DILD datasets for afatinib, alectinib, bortezomib, crizotinib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, sorafenib, sunitinib, temsirolimus, and tofacitinib were used to calculate the median onset times of DILD and the Weibull distribution parameters, and to perform the hierarchical cluster analysis. The median onset times of DILD for afatinib, bortezomib, crizotinib, erlotinib, gefitinib, and nilotinib were within one month. The median onset times of DILD for dasatinib, everolimus, lapatinib, osimertinib, and temsirolimus ranged from 1 to 2 months. The median onset times of the DILD for alectinib, imatinib, and tofacitinib ranged from 2 to 3 months. The median onset times of the DILD for sunitinib and sorafenib ranged from 8 to 9 months. Weibull distributions for these drugs when using the cluster analysis showed that there were 4 clusters. Cluster 1 described a subgroup with early to later onset DILD and early failure type profiles or a random failure type profile. Cluster 2 exhibited early failure type profiles or a random failure type profile with early onset DILD. Cluster 3 exhibited a random failure type profile or wear out failure type profiles with later onset DILD. Cluster 4 exhibited an early failure type profile or a random failure type profile with the latest onset DILD.

Topics: Adverse Drug Reaction Reporting Systems; Afatinib; Bortezomib; Carbazoles; Cluster Analysis; Crizotinib; Dasatinib; Databases as Topic; Datasets as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Japan; Lung Diseases, Interstitial; Molecular Targeted Therapy; Particle Size; Piperidines; Pyrazoles; Pyridines; Quinazolines; Time Factors

Non-small-cell lung cancer (NSCLC) is currently the leading cause of cancer-related death. Accumulating evidences suggest that overcoming the therapeutic resistance in NSCLC is a big challenge. Recently, the outcomes of two independent phase 3 trials regarding Alectinib versus Crizotinib in ALK-positive NSCLC are encouraging. However, given the potential relevance of HGF-MET signaling and especially autophagy to the war against ALK-positive NSCLC between Alectinib and Crizotinib, it's too early to reach a convincing conclusion. Therefore, to further improve the therapeutic efficacy of ALK-positive NSCLC, this commentary highlights the negligence in design of relevant clinical trials, emphasizes the importance of molecular characteristics investigation, and discusses the prospect of combination therapy.

Topics: Anaplastic Lymphoma Kinase; Autophagy; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Hepatocyte Growth Factor; Humans; Lung Neoplasms; Piperidines; Proto-Oncogene Proteins c-met; Signal Transduction

The recently completed ALEX trial demonstrated that alectinib improved progression-free survival, and delayed time to central nervous system progression compared with crizotinib in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer. However, the long-term clinical and economic impact of using alectinib vs. crizotinib has not been evaluated. The objective of this study was to determine the potential cost utility of alectinib vs. crizotinib from a US payer perspective.. A cost-utility model was developed using partition survival methods and three health states: progression-free, post-progression, and death. ALEX trial data informed the progression-free and overall survival estimates. Costs included drug treatments and supportive care (central nervous system and non-central nervous system). Utility values were obtained from trial data and literature. Sensitivity analyses included one-way and probabilistic sensitivity analyses.. Treatment with alectinib vs. crizotinib resulted in a gain of 0.91 life-years, 0.87 quality-adjusted life-years, and incremental costs of US$34,151, resulting in an incremental cost-effectiveness ratio of US$39,312/quality-adjusted life-year. Drug costs and utilities in the progression-free health state were the main drivers of the model in the one-way sensitivity analysis. From the probabilistic sensitivity analysis, alectinib had a 64% probability of being cost effective at a willingness-to-pay threshold of US$100,000/quality adjusted life-year.. Alectinib increased time in the progression-free state and quality-adjusted life-years vs. crizotinib. The marginal cost increase was reflective of longer treatment durations in the progression-free state. Central nervous system-related costs were considerably lower with alectinib. Our results suggest that compared with crizotinib, alectinib may be a cost-effective therapy for treatment-naïve patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cost-Benefit Analysis; Crizotinib; Disease-Free Survival; Drug Costs; Humans; Lung Neoplasms; Models, Economic; Piperidines; Protein Kinase Inhibitors; Quality-Adjusted Life Years

A 63-year-old woman with pulmonary adenocarcinoma (stage IIIB) that was positive for an epidermal growth factor receptor (EGFR) mutation and an anaplastic lymphoma kinase (ALK) rearrangement was treated with erlotinib as the first-line treatment, resulting in a stable disease. Due to skin rashes, fatigue and anorexia, erlotinib was suspended on erlotinib day 44. Alectinib was administered as the second-line treatment, exhibiting a partial response. On alectinib day 56, drug-induced lung injury forced suspension of alectinib, which was cured with corticosteroid therapy. ALK-tyrosine kinase inhibitors may be more effective for patients positive for both EGFR mutation and ALK rearrangement than other agents.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adrenal Cortex Hormones; Anaplastic Lymphoma Kinase; Carbazoles; Cough; ErbB Receptors; Erlotinib Hydrochloride; Female; Fever; Humans; Hypoxia; Lung Neoplasms; Middle Aged; Mutation; Piperidines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Topics: Adolescent; Antineoplastic Agents; Carbazoles; Drug Resistance, Neoplasm; Female; Humans; Neoplasm Recurrence, Local; Neuroblastoma; Piperidines; Protein Kinase Inhibitors

EML4-ALK alterations are more common in adenocarcinomas and are rarely found in squamous cell histology. In documented cases, the majority of EML4-ALK translocations are identified in squamous cell histology and occur in patients with no or light smoking history. We report an EML4-ALK4 translocation in a 50-year-old patient with squamous cell carcinoma and an 18 pack-year smoking history. The patient had a near complete response in the CNS to alectinib treatment. Our observation suggests that EML4-ALK genomic testing may be clinically useful in patients with heavy smoking history.

Topics: Carbazoles; Carcinoma, Squamous Cell; Crizotinib; Genetic Testing; Humans; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Patient Selection; Piperidines; Smoking; Treatment Outcome

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Choroid Neoplasms; Female; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Middle Aged; Neoplasm Staging; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Vision Disorders; Visual Fields

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carbazoles; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Piperidines

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Female; Gene Fusion; Humans; Lung Neoplasms; Middle Aged; Piperidines; Protein Kinase Inhibitors

Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3-39.0) for alectinib 600 mg twice daily (BID). We investigated exposure-response relationships from final pooled phase II OS and safety data to assess alectinib dose selection.. A semi-parametric Cox proportional hazards model analyzed relationships between individual median observed steady-state trough concentrations (C. Overall, 92% of patients (n = 207/225) had C. Alectinib 600 mg BID provides systemic exposures at plateau of response for OS while maintaining a well-tolerated safety profile. This analysis confirms alectinib 600 mg BID as the recommended global dose for patients with crizotinib-resistant ALK-positive NSCLC.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Crizotinib; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Gene Rearrangement; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Multicenter Studies as Topic; Piperidines; Proportional Hazards Models; Protein Kinase Inhibitors

Mutated anaplastic lymphoma kinase (ALK) drives the development of advanced non-small cell lung cancer (NSCLC). Most reported small-molecule inhibitors targeting the ALK domain do not display good inhibition of the G1202R solvent front mutation. The solvent front mutation was assumed to hinder drug binding. However, a different fact could be uncovered by the simulations reported in this study through a structural analog of alectinib (JH-VIII-157-02), which demonstrated potent effects against the G1202R mutation.. Molecular docking, conventional molecular dynamics (MD) simulations, free energy calculations, and umbrella sampling (US) simulations were carried out to make clear the principles of the binding preferences of alectinib and JH-VIII-157-02 toward ALK. JH-VIII-157-02 has similar binding affinities to both ALK. Both the binding affinity and the drug residence time should be emphasized in rational drug design to overcome the G1202R solvent front mutation in ALK resistance.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Drug Discovery; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Models, Molecular; Mutation; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Solvents; Structure-Activity Relationship; Thermodynamics

We determined the central nervous system (CNS) efficacy of alectinib by calculating time to CNS progression and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and death in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) enrolled in the J-ALEX phase III study.. Japanese patients aged ≥20 years with ALK-positive NSCLC who were ALK inhibitor-naïve and chemotherapy-naïve, or who had received one previous chemotherapy regimen, were enrolled. Patients with treated or untreated asymptomatic CNS metastases were eligible. Treatment comprised oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death or withdrawal. Imaging scans (computed tomography/magnetic resonance imaging) were taken at baseline and at regular intervals throughout the study. The CIRs for CNS progression, non-CNS progression and death were calculated for patients with and without baseline CNS metastases using a competing risks method.. The hazard ratio for time to CNS progression in patients with and without baseline CNS metastases was 0.51 (95% confidence interval [CI]: 0.16-1.64; P = 0.2502) and 0.19 (95% CI: 0.07-0.53; P = 0.0004), respectively. The CIRs of CNS progression and non-CNS progression were lower in the alectinib group than in the crizotinib group at all time points. The 1-year CIRs of CNS progression were 16.8% and 5.9% with crizotinib and alectinib, respectively, and the 1-year CIRs of non-CNS progression were 38.4% and 17.5%, respectively. Comparable findings were obtained in patients with or without baseline CNS metastases.. Alectinib appears to avert the progression of CNS metastases in patients with ALK-positive NSCLC and baseline CNS metastases, and to prevent the development of new CNS lesions in patients without baseline CNS disease.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System; Central Nervous System Neoplasms; Crizotinib; Disease Progression; Female; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Piperidines; Treatment Outcome

The mechanisms underlying anaplastic lymphoma kinase (ALK) resistance have not been well investigated in clinical practice. We herein report the case of a lung cancer patient with carcinomatous meningitis who had an ALK I1171T resistance mutation revealed by direct DNA sequencing of the cerebrospinal fluid after treatment with cytotoxic chemotherapy, crizotinib, and alectinib. I1171T is considered to be sensitive to ceritinib. Although ceritinib was not effective initially, we chose ceritinib again after whole-brain radiotherapy and ventriculoperitoneal shunting. Although the response duration was short, spinal magnetic resonance imaging revealed a marked response. The identification of an acquired ALK resistance mutation will aid in choosing the optimum sequence therapy.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Mutation; Piperidines; Pyrimidines; Sulfones

The second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib recently showed superior efficacy compared to the first-generation ALK inhibitor crizotinib in advanced ALK-rearranged NSCLC, establishing alectinib as the new standard first-line therapy. Brigatinib, another second-generation ALK inhibitor, has shown substantial activity in patients with crizotinib-refractory ALK-positive NSCLC; however, its activity in the alectinib-refractory setting is unknown.. A multicenter, retrospective study was performed at three institutions. Patients were eligible if they had advanced, alectinib-refractory ALK-positive NSCLC and were treated with brigatinib. Medical records were reviewed to determine clinical outcomes.. Twenty-two patients were eligible for this study. Confirmed objective responses to brigatinib were observed in 3 of 18 patients (17%) with measurable disease. Nine patients (50%) had stable disease on brigatinib. The median progression-free survival was 4.4 months (95% confidence interval [CI]: 1.8-5.6 months) with a median duration of treatment of 5.7 months (95% CI: 1.8-6.2 months). Among 9 patients in this study who underwent post-alectinib/pre-brigatinib biopsies, 5 had an ALK I1171X or V1180L resistance mutation; of these, 1 had a confirmed partial response and 3 had stable disease on brigatinib. One patient had an ALK G1202R mutation in a post-alectinib/pre-brigatinib biopsy, and had progressive disease as the best overall response to brigatinib.. Brigatinib has limited clinical activity in alectinib-refractory ALK-positive NSCLC. Additional studies are needed to establish biomarkers of response to brigatinib and to identify effective therapeutic options for alectinib-resistant ALK-positive NSCLC patients.

Topics: Adult; Aged; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Organophosphorus Compounds; Piperidines; Pyrimidines; Retrospective Studies; Young Adult

In current guidelines, the role of immune checkpoint inhibitors is not yet determined in the treatment strategy for NSCLC harboring ALK translocations.. A 51-year-old woman with lung adenocarcinoma harboring ALK translocation was treated with alectinib until PD. After the second (CDDP/PEM) and third (crizotinib) line treatment, a second biopsy was performed, revealing PD-L1 tumor proportion score of 70-80% and G1202R mutation of ALK. Pembrolizumab was selected for the fourth line, leading to PR for more than 6 months.. While alectinib might induce resistance to ALK-TKI, it could increase PD-L1 positive cells to become sensitive to PD-1/PD-L1 inhibitors.

Topics: Adenocarcinoma; Anaplastic Lymphoma Kinase; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; B7-H1 Antigen; Carbazoles; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Middle Aged; Molecular Targeted Therapy; Mutation; Piperidines; Receptor Protein-Tyrosine Kinases; Translocation, Genetic; Treatment Outcome; Up-Regulation

Alectinib is approved and recommended as the preferred first-line treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer. The effect of hepatic impairment on the pharmacokinetics (PK) of alectinib was assessed with physiologically based PK modeling prospectively and in a clinical study. An open-label study (NCT02621047) investigated a single 300-mg dose of alectinib in moderate (n = 8) and severe (n = 8) hepatic impairment (Child-Pugh B/C), and healthy subjects (n = 12) matched for age, sex, and body weight. Physiologically based PK modeling was conducted prospectively to inform the clinical study design and support the use of a lower dose and extended PK sampling in the study. PK parameters were calculated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Unbound concentrations were assessed at 6 and 12 hours postdose. Administration of alectinib to subjects with hepatic impairment increased the area under the plasma concentration-time curve from time 0 to infinity of the combined exposure of alectinib and M4 to 136% (90% confidence interval [CI], 94.7-196) and 176% (90%CI 98.4-315), for moderate and severe hepatic impairment, respectively, relative to matched healthy subjects. Unbound concentrations for alectinib and M4 did not appear substantially different between hepatic-impaired and healthy subjects. Moderate hepatic impairment had only a modest, not clinically significant effect on alectinib exposure, while the higher exposure observed in severe hepatic impairment supports a dose adjustment in this population.

Topics: Adult; Area Under Curve; Carbazoles; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Female; Half-Life; Humans; Liver; Liver Diseases; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

Primary lung adenocarcinoma is extremely rare in the pediatric age group. We report an 18-year-old man with non-small cell lung carcinoma stage IV with brain and bone metastatic. Lung biopsy showed expression of PDL1 along with rearrangement of ALK gene at chromosome 2p23. However, neither mutation of ROS1 nor epidermal growth factor receptor overexpression was seen. Second-generation anaplastic lymphoma kinase (ALK) inhibitor (alectinib) is initiated as first line of treatment. After 8 months of treatment with alectinib, F-NaF PET/CT demonstrated resolution of bone lesions. The present case show rapid and good response to alectinib in metastatic ALK-positive non-small cell lung carcinoma.

Topics: Adolescent; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Fluorine Radioisotopes; Humans; Lung Neoplasms; Male; Molecular Targeted Therapy; Neoplasm Metastasis; Piperidines; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Sodium Fluoride

Overexpression of insulin growth factor 1 receptor (IGF-1R) and its ligand, insulin growth factor 1 (IGF-1), is related to treatment resistance and worse prognosis in many types of tumors. We reported recently that IGF-1R activation by IGF induces resistance to alectinib and stimulates the production of vascular endothelial growth factor, which indicates that IGF induces alectinib resistance and angiogenesis. This study aimed to determine the effect of bigeminal inhibition of anaplastic lymphoma kinase (ALK) and angiogenesis on human insulin growth factor 1 receptor (hIGF-1)-triggered drug resistance in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-positive lung cancer. Human lung adenocarcinoma H3122 and H2228 cells were exposed to a combination of insulin growth factor 1 receptor (IGF-1), alectinib, or apatinib. The effects of the combination therapy were examined using cell the Cell Counting Kit-8 assay, the colony-forming assay, the scratch test, and flow cytometry analysis, and the molecular mechanism was assessed by western blot. At nontoxic concentrations, apatinib restored alectinib sensitivity by increasing drug-induced apoptosis and inhibiting viability, migration, and invasion in IGF-triggered drug resistant cells. Moreover, we found that apatinib restored sensitivity to alectinib mainly through suppression of the ALK downstream signaling pathway and antiangiogenesis signaling. Taken together, our results indicate that simultaneous inhibition of ALK and vascular endothelial growth factor R2 by the combination of alectinib with apatinib may be useful for controlling progression of EML4-ALK fusion gene lung cancer by reversing ALK-TKI resistance and inhibiting angiogenesis.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Apoptosis; Carbazoles; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Humans; Insulin-Like Growth Factor I; Lung Neoplasms; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Pyridines; Receptor, IGF Type 1; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and adjuvant targeted therapy has shown great benefits for the NSCLC patients with specific genomic mutations. Alectinib, a selective anaplastic lymphoma kinase (ALK) inhibitor, has been clinically used for the NSCLC patients with ALK-rearrangement, however, irreversible therapeutic resistance for the patients receiving alectinib treatment frequently occurs. Here we show that neuromedin U (NMU) may confer the alectinib resistance in NSCLC via multiple mechanisms based on the integrative bioinformatics analyses. Through employing the bioinformatics analyses of three microarray datasets, NMU, overexpressed in both NSCLC tissues and alectinib-resistant NSCLC cells, was initially identified as potential candidate for causing alectinib resistance in NSCLC. The resistance function of NMU in NSCLC was validated by performing protein/gene interactions and biological process annotation analyses, and further validated by analyzing the transcription factors targeting NMU mRNA. Collectively, these results indicated that NMU may confer alectinib resistance in NSCLC.

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Computational Biology; Databases, Genetic; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Lung Neoplasms; Neuropeptides; Oligonucleotide Array Sequence Analysis; Piperidines; Protein Kinase Inhibitors; Survival Analysis; Up-Regulation

Common gene fusion of the ALK gene is fusion of the ALK tyrosine kinase area and the 5'end of EML4. Seventeen EML4-ALK fusion variants have been reported. Herein, we report a novel EML4-ALK variant detected by next-generation sequencing in a 36-year-old female lung adenocarcinoma patient who experienced disease progression after six months of alectinib treatment. Second generation sequencing revealed an EML4-ALK fusion variant in which intron 19 of EML4 was fused to exon 20 of ALK. This is the first case of EML4-ALK (E19: A20) fusion to be reported. Alectinib may show unsatisfactory therapeutic effects for this kind of ALK fusion.

Topics: Adenocarcinoma of Lung; Carbazoles; Female; Humans; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

Topics: Aminopyridines; Animals; Carbazoles; Chromatography, Liquid; Drug Stability; Humans; Lactams; Lactams, Macrocyclic; Male; Mice; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tandem Mass Spectrometry; Tissue Distribution

The current study was carried out to compare the effectiveness and safety of different ALK inhibitors in treating ALK+ NSCLC.. Progression-free survival (PFS), disease control rate (DCR), overall response rate (ORR), and intracranial ORR and DCR have been aggregated to appraise the effectiveness of each ALKi. The discontinuation rate due to adverse events (AEs) was pooled to evaluate their safety. Bayesian network meta-analyses were used to compare the ORR, DCR, PFS, and discontinuation rate of patients treated with alectinib, ceritinib, crizotinib, and chemotherapy.. Compared with chemotherapy, ALK inhibitors significantly prolonged PFS [hazard ratio (HR) and 95% confidence interval (CI): alectinib, 0.50 (0.43-0.58); ceritinib, 0.75 (0.69-0.83); crizotinib, 0.71 (0.66-0.76)]. The ORRs were significantly higher for ALK inhibitors than for chemotherapy [odds ratio (OR) and corresponding 95% CI: alectinib, 11.69 (4.29-36.56); ceritinib, 7.85 (3.44-19.27); crizotinib, 6.04 (3.33-11.71)]. The discontinuation rates were lower for ALK inhibitors than for chemotherapy [OR and corresponding 95% CI: alectinib, 0.42 (0.12-1.36); ceritinib, 0.52 (0.20-1.35); crizotinib, 0.70 (0.30-1.62)].. ALK+ NSCLC patients treated with ALKi tend to have longer PFS than those treated with chemotherapy. ALKi-naïve patients tended to response better than their ALKi-pretreated counterparts. Alectinib appeared to be preferable for treating brain metastases due to its high intracranial efficacy. Patients treated with alectinib or ceritinib tended to have higher ORR and DCR than patients with similar baselines treated with crizotinib or chemotherapy. No significant differences in discontinuation rate were found for alectinib, ceritinib, crizotinib, and chemotherapy.

Topics: Anaplastic Lymphoma Kinase; Bayes Theorem; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Network Meta-Analysis; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Sulfones; Survival Analysis; Treatment Outcome

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Piperidines

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Pyrimidines; Receptor Protein-Tyrosine Kinases

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Disease Progression; Genetic Predisposition to Disease; Humans; Lung Neoplasms; Mutation; Phenotype; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Time Factors

The anaplastic lymphoma kinase (ALK) inhibitor alectinib is clinically used for the treatment of ALK positive non-small-cell lung cancer. At least in part the substance is effective by triggering suicidal death or apoptosis of tumor cells. Erythrocytes are lacking mitochondria and nuclei, key organelles of apoptosis but are, similar to apoptosis of nucleated cells, able to enter suicidal erythrocyte death or eryptosis. Stimulators of eryptosis include energy depletion, hyperosmotic shock, oxidative stress, and increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored, whether alectinib influences eryptosis.. Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding and cell volume from forward scatter. Measurements were made without or with energy depletion (glucose deprivation for 48 hours), hyperosmotic shock (+550mM sucrose for 6 hours), oxidative stress (50 min exposure to 0.3 mM tert-butylhydroperoxide), and Ca2+ loading (60 minutes treatment with 1 µM Ca2+ ionophore ionomycin).. A 48 hours exposure of human erythrocytes to alectinib (150-600 ng/ml) did not significantly modify the percentage of annexin-V-binding cells and forward scatter. Energy depletion, hyperosmotic shock, oxidative stress and Ca2+ loading were each followed by profound and significant increase of the percentage annexin-V-binding erythrocytes and a significant decrease of forward scatter. The effects of energy depletion and hyperosmotic shock, but not of oxidative stress or Ca2+ loading on annexin-V-binding were significantly blunted in the presence of alectinib (150-600 ng/ml). In none of the conditions was forward scatter significantly modified by alectinib.. Alectinib inhibits cell membrane scrambling following energy depletion and hyperosmotic shock.

Topics: Carbazoles; Energy Metabolism; Eryptosis; Erythrocyte Membrane; Erythrocytes; Humans; Osmotic Pressure; Oxidative Stress; Phosphatidylserines; Piperidines; Protein Kinase Inhibitors

Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carbazoles; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Doxorubicin; Female; Genetic Predisposition to Disease; Humans; Inhibitory Concentration 50; Mice, Nude; Mice, Transgenic; Mutation; N-Myc Proto-Oncogene Protein; Neuroblastoma; Phenotype; Phosphatidylinositol 3-Kinase; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Disease-Free Survival; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Topics: Adult; Carbazoles; Female; Humans; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

Heterozygous Neurofibromatosis 1 (NF1) loss of function mutations are found in 90% of patients with neurofibromatosis, a syndrome associated with disabling cognitive impairment. Drosophila studies have demonstrated a genetic interaction between Anaplastic Lymphoma Kinase (Alk) and NF1 in cognitive performance. In addition, pharmacologic inhibition of Alk improves cognitive performance in heterozygous NF1 mutant flies. In this study, we tested whether pharmacological inhibition of Alk in heterozygous NF1 mutant mice attenuates or rescues cognitive impairments. Cognitive impairment of spatial memory retention observed in heterozygous NF1 mutant mice was rescued by the Alk inhibitor. These data support the hypothesis that inhibition of Alk may cognitively benefit patients with Neurofibromatosis 1.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Cognitive Dysfunction; Disease Models, Animal; Female; Male; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Mice, Knockout; Neurofibromatosis 1; Nootropic Agents; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Spatial Memory; Swimming

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Piperidines; Receptor Protein-Tyrosine Kinases

Crizotinib, which is effective in patients with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer, is sometimes associated with the generation of complex renal cysts. A 56-year-old man with ALK positive adenocarcinoma received crizotinib. Ten months after the introduction of crizotinib, a cystic lesion developed from his right kidney to the iliopsoas muscle, accompanied by fever, anemia, and hypoproteinemia. After 17 months of treatment, crizotinib was switched to alectinib, followed by the recovery of hypoproteinemia and systemic inflammation. Switching to alectinib may be beneficial in patients demonstrating crizotinib-associated complex renal cysts with systemic inflammation and exhaustion.

Topics: Adenocarcinoma; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Kidney Diseases, Cystic; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Choroidal metastasis is rare in cancer patients and it may cause visual disturbances that reduce their quality of life. In non-small cell lung cancer (NSCLC), targeted therapy against actionable driver mutations has gradually replaced radiotherapy as the treatment of choice for choroidal metastasis. Recently, there have been several case reports of choroidal metastasis in patients with anaplastic lymphoma kinase (ALK)-rearranged NSCLC. We herein report the case of a 40-year-old Japanese woman diagnosed with choroidal metastasis of an ALK-rearranged NSCLC who received alectinib as the first-line chemotherapy. Alectinib may be the best treatment for choroidal metastasis in patients harboring an ALK translocation because of its favorable side effect profile involving visual disturbances.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Asian People; Carbazoles; Carcinoma, Non-Small-Cell Lung; Choroid Neoplasms; Female; Humans; Lung Neoplasms; Neoplasm Metastasis; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

A 36-year-old male was found two nodules in the right lower lobe of the lung. After the surgical resection, both lesions were diagnosed as invasive adenocarcinomas. One lesion was primarily lepidic growth component with EGFR-L858R mutation, and the other was micropapillary component with ALK translocation accompanying mediastinal lymphnode metastases. While he experienced disease recurrence, the disease was controlled by an ALK inhibitor, given based on the findings of surgical specimens. This is the first case who had two simultaneous lung cancers with EGFR mutation and ALK translocation in each respective lesion, and was successfully treated with ALK inhibitor at the post-surgical recurrence. J. Med. Invest. 64: 305-307, August, 2017.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Carbazoles; ErbB Receptors; Humans; Lung Neoplasms; Male; Mutation; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Translocation, Genetic

Inflammatory myofibroblastic tumor (IMT) is a neoplasm characterized by the proliferaton of myofibroblasts with the infiltration of inflammatory cells. There is no standard treatment for patients with recurrent or metastatic IMT. We describe here a patient with hyper-progressive IMT with an anaplastic lymphoma kinase (ALK) fusion gene that dramatically responded to alectinib without adverse events. His dramatic and enduring response supports the observation that alectinib may be considered a good treatment option for rare aggressive ALK-positive tumors.

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Granuloma, Plasma Cell; Humans; Inflammation; Male; Oncogene Proteins, Fusion; Piperidines; Receptor Protein-Tyrosine Kinases

Topics: Acetamides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antitoxins; Bridged Bicyclo Compounds, Heterocyclic; Carbazoles; Chenodeoxycholic Acid; Drug Approval; Humans; Indoles; Morpholinos; Oligonucleotides; Piperidines; Polydeoxyribonucleotides; Pyrazines; Sulfonamides; United States; United States Food and Drug Administration

Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, crizotinib, and recently the more highly potent alectinib and ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines. Src signaling was identified as an alectinib resistance mechanism, and combination treatment with ALK and Src inhibitors was highly effective for inhibiting the growth of ALK inhibitor resistant cells in vitro and in mouse xenograft models. Furthermore, phospho-receptor tyrosine kinase activation and downstream PI3K/AKT signaling was effectively blocked by inhibiting Src in alectinib resistant cells. Finally, we showed that the combined use of ALK and Src inhibitors inhibited the growth of other ALK-NSCLC cell lines, including those that were ceritinib or lorlatinib resistant. Our data suggest that targeting Src signaling may be an effective approach to the treatment of ALK-NSCLC with acquired resistance to ALK inhibitors.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Mice; Piperidines; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Signal Transduction; src-Family Kinases; Sulfones; Xenograft Model Antitumor Assays

Several second-generation inhibitors of anaplastic lymphoma kinase (ALK) have demonstrated potent activity in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Two of these agents, ceritinib, and alectinib, recently received approval for the treatment of ALK-rearranged NSCLC in Japan. The efficacy of treatment with a second-generation ALK inhibitor after failure with a different second-generation ALK inhibitor remains unclear. We present a series of eight patients with ALK-rearranged NSCLC treated with alectinib who experienced disease progression after ceritinib. Both crizotinib and ceritinib were administered to six patients, with four (29%) patients receiving crizotinib followed by ceritinib. Among the eight study patients, two (25%) had partial response, one (12%) stable disease, and five (63%) had progressive disease. The median progression-free survival was 3.6 months (95% confidence interval=0-7.1 months). The results of this study suggest that the second-generation ALK inhibitor alectinib has limited efficacy after initial treatment with the second-generation ALK inhibitor ceritinib.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Survival Analysis; Treatment Failure; Treatment Outcome

Genomic fusions of the anaplastic lymphoma kinase gene (. Comprehensive genomic profiling of 114,200 relapsed and metastatic malignancies, including both solid tumors and hematolymphoid cancers, was performed using a hybrid-capture, adaptor ligation-based next-generation sequencing assay.. Of 114,200 clinical samples, 21,522 (18.8%) were NSCLC and 92,678 (81.2%) were other tumor types. Of the 876 (0.8%) cases with. Rearrangements involving the

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Male; Molecular Targeted Therapy; Mutation; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Topics: Amino Acid Substitution; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carbazoles; Cell Line, Tumor; Crizotinib; Drug Design; Drug Resistance, Neoplasm; ERG1 Potassium Channel; Humans; Kinetics; Piperidines; Pyrazoles; Pyridines; Pyrimidines; Quinolines; Rats; Receptor Protein-Tyrosine Kinases; Signal Transduction; Structure-Activity Relationship; Sulfones

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Translocation, Genetic

Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, is a key drug for ALK rearranged lung adenocarcinoma. Interstitial lung disease (ILD) is an important adverse effect of alectinib, which generally requires termination of treatment. However, we treated two patients with drug-induced ILD who continued to receive alectinib.. Patient 1 was a 57-year-old male with an ALK-rearranged Stage IV lung adenocarcinoma who was administered alectinib as first-line therapy. Computed tomography (CT) detected asymptomatic ground-glass opacity (GGO) on day 33 of treatment. Alectinib therapy was therefore discontinued for 7 days and then restarted. GGO disappeared, and the progression of ILD ceased. Patient 2 was a 64-year-old woman with an ALK-positive lung adenocarcinoma who was administered alectinib as third-line therapy. One year later, CT detected GGO; and she had a slight, nonproductive cough. Alectinib therapy was continued in the absence of other symptoms, and GGO slightly diminished after 7 days. Two months later, CT detected increased GGO, and alectinib therapy was continued. GGO diminished again after 7 days. The patient has taken alectinib for more than 2 years without progression of ILD.. Certain patients with alectinib-induced ILD Grade 2 or less may continue alectinib therapy if they are closely managed.

Topics: Adenocarcinoma; Carbazoles; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Tomography, X-Ray Computed

1. Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor. 2. The absolute bioavailability, metabolism, excretion and pharmacokinetics of alectinib were studied in a two-period single-sequence crossover study. A 50 μg radiolabelled intravenous microdose of alectinib was co-administered with a single 600 mg oral dose of alectinib in the first period, and a single 600 mg/67 μCi oral dose of radiolabelled alectinib was administered in the second period to six healthy male subjects. 3. The absolute bioavailability of alectinib was moderate at 36.9%. Geometric mean clearance was 34.5 L/h, volume of distribution was 475 L and the hepatic extraction ratio was low (0.14). 4. Near-complete recovery of administered radioactivity was achieved within 168 h post-dose (98.2%) with excretion predominantly in faeces (97.8%) and negligible excretion in urine (0.456%). Alectinib and its major active metabolite, M4, were the main components in plasma, accounting for 76% of total plasma radioactivity. In faeces, 84% of dose was excreted as unchanged alectinib with metabolites M4, M1a/b and M6 contributing to 5.8%, 7.2% and 0.2% of dose, respectively. 5. This novel study design characterised the full absorption, distribution, metabolism and excretion properties in each subject, providing insight into alectinib absorption and disposition in humans.

Topics: Adult; Anaplastic Lymphoma Kinase; Biological Availability; Carbazoles; Cross-Over Studies; Healthy Volunteers; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Tissue Distribution

Alectinib and crizotinib have been approved for the therapy of NSCLC caused by anaplastic lymphoma kinase gene (ALK) rearrangement. The effect of alectinib or crizotinib on overall survival (OS) in patients with ALK-rearranged NSCLC remains unknown.. A multicenter retrospective study was conducted to compare OS between patients receiving alectinib and crizotinib and between patients treated with alectinib and those treated sequentially with crizotinib and then alectinib after crizotinib failure. The time to treatment failure (TTF), progression-free survival (PFS), and OS were compared.. Sixty-one patients with ALK-rearranged NSCLC were enrolled. Forty-six patients were treated with anaplastic lymphoma kinase (ALK) inhibitors (31 with crizotinib, 28 with alectinib, and 13 with both ALK inhibitors). The response rate was 66.7% for the crizotinib-treated group and 80.8% for the alectinib-treated group. Among all patients, TTF and PFS were significantly prolonged in the alectinib-treated group compared with in the crizotinib-treated group. Subgroup analyses revealed significantly prolonged TTF for alectinib compared with crizotinib therapy in the ALK inhibitor-naive population. OS was significantly longer in the alectinib-treated group than in the crizotinib-treated group. The TTF and OS of patients treated sequentially with crizotinib and then with alectinib after crizotinib failure tended to be longer than those of patients treated with alectinib alone.. Therapy with alectinib alone was significantly superior to therapy with crizotinib alone in terms of TTF, PFS, and OS, and sequential therapy with crizotinib and alectinib after crizotinib failure tended to provide a better OS benefit than did therapy with alectinib alone in patients with ALK-positive NSCLC. However, large-scale prospective studies are needed to confirm these observations.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Crizotinib; Female; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Piperidines; Prognosis; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Survival Rate

Currently, crizotinib is the first generation drug, which has been used in the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). However, more and more patients are found in crizotinib-resistance. In the last year, alectinib has been approved for treatment of patients with crizotinib-resistance. In this study, we aim to develop and validate a simple, rapid and sensitive tandem mass spectrometry (UHPLC-MS/MS) method for determination of alectinib in rat plasma. Diazepam was chosen as an internal standard (IS). Protein precipitation by acetonitrile was utilized to prepare plasma samples. Chromatographic separation was achieved on a RRHD Eclipse Plus C18 (2.1×50mm, 1.8μ) column with a gradient mobile phase consisting of acetonitrile and water (containing 0.1% formic acid). The analytes were detected by an electrospray ionization (ESI) source in positive mode. A dynamic multiple reaction monitoring (MRM) method was developed to detect specific precursor and product ions. The target fragment ions were m/z 483.2→396.1 for alectinib and m/z 285.0→192.9 for diazepam (IS). Linear calibration plots were achieved in the range of 1-500ng/ml for alectinib (R

Topics: Animals; Calibration; Carbazoles; Chromatography, High Pressure Liquid; Limit of Detection; Linear Models; Male; Piperidines; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry

1. A novel selective anaplastic lymphoma kinase (ALK) inhibitor, alectinib, has shown remarkable efficacy and safety in patients with ALK-positive non-small-cell lung cancer (NSCLC). The purpose of this study was to evaluate in vitro the potential to inhibit and induce cytochrome P450 (CYP) isoforms for alectinib and its major metabolite M4. 2. Alectinib and M4 did not show the meaningful direct inhibition of six major CYP isoforms (CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4) in human liver microsomes (HLM). Alectinib, but not M4, competitively inhibited CYP2C8, by which few marketed drugs are exclusively metabolized, with an inhibition constant of 1.98 μM. 3. Out of the seven CYP isoforms in HLM, alectinib and M4 showed time-dependent inhibition (TDI) of only CYP3A4, which suggests low TDI potential due to low inactivation efficiency. 4. Alectinib exhibited quite smaller induction of mRNA expression of CYP1A2, 2B6 and 3A4 genes in human hepatocytes compared to the respective positive controls, suggesting a low potential of enzyme induction. 5. In summary, the risk of alectinib causing drug-drug interactions with coadministered drugs is expected to be low due to the weak potential of CYP inhibition and induction estimated in the preclinical studies.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Induction; Piperidines; Receptor Protein-Tyrosine Kinases

Anaplastic lymphoma kinase (ALK) inhibition using crizotinib has become the standard of care in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but the treatment outcomes and duration of response vary widely. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most common translocation, and the fusion variants show different sensitivity to crizotinib in vitro. However, there are only limited data on the specific EML4-ALK variants and clinical responses of patients to various ALK inhibitors.. By multiplex reverse-transcriptase PCR, which detects 12 variants of known EML4-ALK rearrangements, we retrospectively determined ALK fusion variants in 54 advanced ALK rearrangement-positive NSCLCs. We subdivided the patients into two groups (variants 1/2/others and variants 3a/b) by protein stability and evaluated correlations of the variant status with clinical responses to crizotinib, alectinib, or ceritinib. Moreover, we established the EML4-ALK variant-expressing system and analyzed patterns of sensitivity of the variants to ALK inhibitors.. Of the 54 tumors analyzed, EML4-ALK variants 3a/b (44.4%) was the most common type, followed by variants 1 (33.3%) and 2 (11.1%). The 2-year progression-free survival (PFS) rate was 76.0% [95% confidence interval (CI) 56.8-100] in group EML4-ALK variants 1/2/others versus 26.4% (95% CI 10.5-66.6) in group variants 3a/b (P = 0.034) among crizotinib-treated patients. Meanwhile, the 2-year PFS rate was 69.0% (95% CI 49.9-95.4) in group variants 1/2/others versus 32.7% (95% CI 15.6-68.4) in group variants 3a/b (P = 0.108) among all crizotinib-, alectinib-, and ceritinib-treated patients. Variant 3a- or 5a-harboring cells were resistant to ALK inhibitors with >10-fold higher half maximal inhibitory concentration in vitro.. Our findings show that group EML4-ALK variants 3a/b may be a major source of ALK inhibitor resistance in the clinic. The variant-specific genotype of the EML4-ALK fusion allows for more precise stratification of patients with advanced NSCLC.

Topics: Adult; Aged; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Genotype; Humans; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Multiplex Polymerase Chain Reaction; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Protein Stability; Pyrazoles; Pyridines; Pyrimidines; Retrospective Studies; Sulfones

Second-generation anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib and ceritinib, have recently been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). An optimal strategy for using 2 or more ALK inhibitors has not been established. We sought to investigate the clinical impact of sequential use of ALK inhibitors on these tumors in clinical practice.. Patients with ALK-rearranged NSCLC treated from May 2010 to January 2016 at the National Cancer Center Hospital were identified, and their outcomes were evaluated retrospectively.. Fifty-nine patients with ALK-rearranged NSCLC had been treated and 37 cases were assessable. Twenty-six received crizotinib, 21 received alectinib, and 13 (35.1%) received crizotinib followed by alectinib. Response rates and median progression-free survival (PFS) on crizotinib and alectinib (after crizotinib failure) were 53.8% (95% confidence interval [CI], 26.7%-80.9%) and 38.4% (95% CI, 12.0%-64.9%), and 10.7 (95% CI, 5.3-14.7) months and 16.6 (95% CI, 2.9-not calculable), respectively. The median PFS of patients on sequential therapy was 35.2 months (95% CI, 12.7 months-not calculable). The 5-year survival rate of ALK-rearranged patients who received 2 sequential ALK inhibitors from diagnosis was 77.8% (95% CI, 36.5%-94.0%).. The combined PFS and 5-year survival rates in patients who received sequential ALK inhibitors were encouraging. Making full use of multiple ALK inhibitors might be important to prolonging survival in patients with ALK-rearranged NSCLC.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Follow-Up Studies; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Oncogene Proteins, Fusion; Piperidines; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Survival Analysis

Alectinib (Alecensa. An LC-MS/MS method using supported liquid extraction was developed for the determination of alectinib and M4 in human urine over the concentration range 0.5-500 ng/ml. Accuracy ranged from 92.0 to 112.2% and precision (CV) was below 9.6%.. The method was successfully employed to determine alectinib and M4 concentrations in urine samples from a clinical mass balance study. Addition of the surfactant Tween-20 to urine prevented nonspecific binding of the analytes.

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Chromatography, High Pressure Liquid; Humans; Piperidines; Protein Kinase Inhibitors; Quality Control; Tandem Mass Spectrometry

Alectinib, an inhibitor of anaplastic lymphoma kinase (ALK), was approved by the Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC). Here we investigated the reversal effect of alectinib on multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters, which is the primary cause of chemotherapy failure. We provide the first evidence that alectinib increases the sensitivity of ABCB1- and ABCG2-overexpressing cells to chemotherapeutic agents in vitro and in vivo. Mechanistically, alectinib increased the intracellular accumulation of ABCB1/ABCG2 substrates such as doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, alectinib stimulated ATPase activity and competed with substrates of ABCB1 or ABCG2 and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling bound to ABCB1 or ABCG2 but neither altered the expression and localization of ABCB1 or ABCG2 nor the phosphorylation levels of AKT and ERK. Alectinib also enhanced the cytotoxicity of DOX and the intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. These findings suggest that alectinib combined with traditional chemotherapy may be beneficial to patients with ABCB1- or ABCG2-mediated MDR.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Carbazoles; Drug Resistance, Neoplasm; HEK293 Cells; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Piperidines; Protein Kinase Inhibitors

We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and brain metastasis.. A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling.. Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001).. Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cranial Irradiation; Crizotinib; Disease-Free Survival; Female; Follow-Up Studies; Gene Rearrangement; Humans; Kaplan-Meier Estimate; Karnofsky Performance Status; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Piperidines; Prognosis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Radiosurgery; Receptor Protein-Tyrosine Kinases; Risk Assessment; Risk Factors; Smoking; Sulfones

Many acquired resistant mutations to the anaplastic lymphoma kinase (ALK) gene have been identified during treatment of ALK-rearranged non-small cell lung cancer (NSCLC) patients with crizotinib, ceritinib, and alectinib. These various acquired resistant ALK mutations confer differential sensitivities to various ALK inhibitors and may provide guidance on how to sequence the use of many of the second generation ALK inhibitors. We described a patient who developed an acquired ALK F1174V resistant mutation on progression from crizotinib that responded to alectinib for 18 months but then developed an acquired ALK I1171S mutation to alectinib. Both tumor samples had essentially the same genomic profile by comprehensive genomic profiling otherwise. This is the first patient report that demonstrates ALK F1174V mutation is sensitive to alectinib and further confirms missense acquired ALK I1171 mutation is resistant to alectinib. Sequential tumor re-biopsy for comprehensive genomic profiling (CGP) is important to appreciate the selective pressure during treatment with various ALK inhibitors underpinning the evolution of the disease course of ALK+NSCLC patients while on treatment with the various ALK inhibitors. This approach will likely help inform the optimal sequencing strategy as more ALK inhibitors become available. This case report also validates the importance of developing structurally distinct ALK inhibitors for clinical use to overcome non-cross resistant ALK mutations.

Topics: Anaplastic Lymphoma Kinase; Biopsy; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Remission Induction

A 56-year-old woman, a never-smoker, had postoperative recurrence of anaplastic lymphoma kinase rearranged lung cancer. She achieved a partial response to treatment with an anaplastic lymphoma kinase tyrosine kinase inhibitor, crizotinib. After the tumor regrowth, crizotinib was switched to alectinib; once again a partial response was observed. At the second recurrence, transbronchial needle aspiration of the right paratracheal node was performed, which revealed cytological findings of small-cell carcinoma. While treatment with cisplatin-irinotecan chemotherapy made reduction of some tumor shadows, including the biopsied mediastinal lymph nodes, new, small, nodular shadows, highly suggestive of pulmonary metastases, were detected in both lung fields. This case may show proof of the transformation to small-cell lung cancer as a mechanism of resistance to anaplastic lymphoma kinase tyrosine kinase inhibitors in anaplastic lymphoma kinase rearranged tumor. However, this transformation may also be only one part of the resistance mechanism of the heterogeneous tumor.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Transformation, Neoplastic; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Lymph Nodes; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Small Cell Lung Carcinoma

Alectinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the EML4-ALK gene rearrangement. The precise mechanism of acquired resistance to alectinib is not well defined. The purpose of this study was to clarify the mechanism of acquired resistance to alectinib in ALK-translocated lung cancer cells. We established alectinib-resistant cells (H3122-AR) from the H3122 NSCLC cell line, harboring the EML4-ALK gene rearrangement, by long-term exposure to alectinib. The mechanism of acquired resistance to alectinib in H3122-AR cells was evaluated by phospho-receptor tyrosine kinase (phospho-RTK) array screening and Western blotting. No mutation of the ALK-TK domain was found. Phospho-RTK array analysis revealed that the phosphorylation level of EGFR was increased in H3122-AR cells compared with H3122. Expression of TGFα, one of the EGFR ligands, was significantly increased and knockdown of TGFα restored the sensitivity to alectinib in H3122-AR cells. We found combination therapy targeting ALK and EGFR with alectinib and afatinib showed efficacy both in vitro and in a mouse xenograft model. We propose a preclinical rationale to use the combination therapy with alectinib and afatinib in NSCLC that acquired resistance to alectinib by the activation of EGFR bypass signaling.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gene Expression; Humans; Lung Neoplasms; Mice; Phosphorylation; Piperidines; Receptor Protein-Tyrosine Kinases; Signal Transduction; Transforming Growth Factor alpha; Translocation, Genetic; Tumor Burden; Xenograft Model Antitumor Assays

The FDA has approved a third ALK inhibitor, alectinib, for advanced ALK-positive non-small cell lung cancer. Two phase II studies show that patients who have become resistant to crizotinib respond well to alectinib; the drug is also effective against brain metastases, which are common in this disease subtype.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Neoplasm Metastasis; Piperidines; Receptor Protein-Tyrosine Kinases; Survival Analysis; Treatment Outcome

We report an anaplastic lymphoma receptor tyrosine kinase gene (ALK)-positive patient who showed a paradoxical response to the ALK inhibitor alectinib; the primary lesion increased in size, whereas other metastatic lesions decreased markedly. A biopsy of the primary lesion confirmed an ALK rearrangement; however, the tumor had transformed histologically into small cell lung cancer. The lack of reports of small cell lung cancer transformation in ALK-positive patients implies that this outcome was unusual; this patient was treated with alectinib, which is more selective and has a greater inhibitory effect than crizotinib. This case may reveal resistance mechanisms that differ according to the agent used for treatment.

Topics: Adenocarcinoma; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Cell Transformation, Neoplastic; Female; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Small Cell Lung Carcinoma

Topics: Adenocarcinoma; Adult; Anaplastic Lymphoma Kinase; Carbazoles; Cell Transformation, Neoplastic; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Small Cell Lung Carcinoma

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard dose alectinib (600 mg twice daily), but who subsequently experienced recurrences with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis.

Topics: Adult; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Alectinib is a highly selective next-generation anaplastic lymphoma kinase (ALK) inhibitor. Although alectinib shows inhibitory activity against various crizotinib-resistant ALK mutations in studies using cell-free kinase assays and Ba/F3 cell-based assays, it has not been tested for efficacy against non-small cell lung cancer (NSCLC) with the ALK mutations.. We conducted in vitro and in vivo investigations into the antitumor activity of alectinib against an ALK-positive NSCLC cell line, SNU-2535, which harbors an ALK G1269A mutation. The clinical efficacy of alectinib against a NSCLC patient harboring ALK G1269A mutation was evaluated in the phase I part of the North American study.. Alectinib exhibited antiproliferative activity against SNU-2535 cells in vitro with IC50 of 33.1 nM. Alectinib strongly inhibited phosphorylation of ALK and its downstream signaling molecules ERK1/2, AKT, and STAT3. In a mouse xenograft model, once-daily oral administration of alectinib for 21 days resulted in strong tumor regression. In addition, administration of alectinib for 100 days achieved continuous tumor regression without tumor regrowth in all mice. Notably, eradication of tumor cells was observed in half of the mice. In the clinical study, a patient with ALK G1269A mutation showed partial response to alectinib with a duration of response of 84 days.. These results indicated that alectinib has potent antitumor activity against NSCLC cells harboring the crizotinib-resistant mutation ALK G1269A. It is expected that alectinib would provide a valuable therapeutic option for patients with NSCLC having not only native ALK but also crizotinib-resistant ALK mutations.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Humans; Inhibitory Concentration 50; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Treatment Outcome; Xenograft Model Antitumor Assays

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown promising clinical activity in the treatment of non-small-cell lung cancer (NSCLC) that harbors ALK rearrangement. The next-generation ALK-TKI, alectinib, has been reported to have potent efficacy in ALK-positive NSCLC patients including on mutations that confer resistance to crizotinib, which was the first ALK-TKI approved for ALK-positive NSCLC. The efficacy and safety of ALK-TKIs, including crizotinib and alectinib, as the first-line treatment in critically ill patients is unclear. We report one ALK-positive NSCLC patient with poor performance status (PS) and disseminated intravascular coagulation because of respiratory failure and multiple metastases, and experienced the rapid and dramatic response to alectinib without adverse events that can lead to discontinuation and dose reduction of the drug. After a couple of months of treatment with alectinib, radiological review indicated a complete response. The present case is the first reported case of rapid and marked response to alectinib in ALK-positive NSCLC patients who had poor PS and severe organ dysfunction, such as disseminated intravascular coagulation. Further investigation of the safety and efficacy of ALK-TKI for ALK-positive NSCLC patients who are critically ill is warranted.

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Critical Illness; Humans; Lung Neoplasms; Male; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Lung cancers with anaplastic lymphoma kinase rearrangements are highly sensitive to anaplastic lymphoma kinase tyrosine kinase inhibition, underscoring the notion that such cancers are addicted to anaplastic lymphoma kinase activity. Several anaplastic lymphoma kinase inhibitors have been identified and are being evaluated in clinical trials. However patients with poor performance status (3 or 4) were not involved in these clinical trials, it has been unclear to use anaplastic lymphoma kinase-tyrosine kinase inhibitors for these patients. Here, we report an anaplastic lymphoma kinase-positive non small cell lung cancer patient with performance status 4, who was successfully treated with alectinib.. We report on a 52-year-old patient diagnosed as non small cell lung cancer harboring echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene. His performance status was 4 because of severe respiratory failure. We treated this patient with alectinib as the first line therapy. Dramatic response was obtained and his performance status improved from 4 to 1 without severe adverse events.. Alectinib is a therapeutic option for the anaplastic lymphoma kinase positive patients with poor performance status.

Topics: Anaplastic Lymphoma Kinase; Bronchoscopy; Carbazoles; Carcinoma, Non-Small-Cell Lung; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Receptor Protein-Tyrosine Kinases; Tomography, X-Ray Computed; Treatment Outcome

Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non-small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Gene Expression Regulation, Neoplastic; Glial Cell Line-Derived Neurotrophic Factor Receptors; Humans; Mutation; Neuregulin-1; Oncogene Proteins, Fusion; Piperidines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Receptor, ErbB-3; Signal Transduction; Sulfones

In the development of anticancer drugs, drug concentration measurements in the target tissue have been thought to be crucial for predicting drug efficacy and safety. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is commonly used for determination of average drug concentrations; however, complete loss of spatial information in the target tissue occurs. Mass spectrometry imaging (MSI) has been recently applied as an innovative tool for detection of molecular distribution of pharmacological agents in heterogeneous targets. This study examined the intra-brain transitivity of alectinib, a novel anaplastic lymphoma kinase inhibitor, using a combination of matrix-assisted laser desorption ionization-MSI and LC-MS/MS techniques. We first analyzed the pharmacokinetic profiles in FVB mice and then examined the effect of the multidrug resistance protein-1 (MDR1) using Mdr1a/b knockout mice including quantitative distribution of alectinib in the brain. While no differences were observed between the mice for the plasma alectinib concentrations, diffuse alectinib distributions were found in the brain of the Mdr1a/b knockout versus FVB mice. These results indicate the potential for using quantitative MSI for clarifying drug distribution in the brain on a microscopic level, in addition to suggesting a possible use in designing studies for anticancer drug development and translational research.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Brain; Carbazoles; Male; Mice, Knockout; Neuroimaging; Piperidines; Tandem Mass Spectrometry; Tissue Distribution

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Mutation; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Alectinib is a second generation ALK inhibitor that has significant clinical activity in central nervous system (CNS) metastases in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Pseudoprogression (PsP) due to radiation necrosis during alecitnib treatment of central nervous system (CNS) metastases from ALK-rearranged NSCLC as been reported. Hence, distinguishing radiation-related PsP from alectinib-induced radiographic changes is important to avoid erroneous early trial discontinuation and abandonment of an effective treatment. However, it remains difficult to assess casuality of radiation necrosis is related to recent direct radiation or induced by alectinib treatment or both. It is also unknown how long from previous radiation can alectinib still induce radiation necrosis. Here we reported a crizotinib-refractory ALK-positive NSCLC patient who develop radiation necrosis in one of his metastatic CNS lesions after approximately 12 months of alectinib treatment who otherwise had on-going CNS response on alectinib. His most recent radiation to his CNS metastases was 7 years prior to the start of alectinib. This case illustrates that in the setting of pror CNS radiation, given the significant clinical activity of alectinib in CNS metastases in ALK-positive NSCLC patients the risk of CNS radiation necrosis remains long after previous radiation to the CNS metastases has been completed and can occur after durable response of treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Brain; Brain Neoplasms; Carbazoles; Crizotinib; Disease Progression; Humans; Lung Neoplasms; Male; Middle Aged; Necrosis; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiation Injuries; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show marked therapeutic efficacy in patients with non-small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4-ALK fusion gene. The effect on overall survival (OS) of sequential treatment with the first- and second-generation ALK-TKIs crizotinib and alectinib, respectively, has remained unknown. We have examined the clinical outcome of such sequential treatment in a retrospective analysis of patients with ALK-rearranged NSCLC.. Eleven patients with ALK-rearranged NSCLC treated with crizotinib followed by alectinib were identified. The progression-free survival (PFS) and OS for these patients were determined from a retrospective review of their medical records.. The median PFS on crizotinib or alectinib was 6.1 months (range, 1.0-15.4 months) and 15.2 months (range, 1.0-28.3 months), respectively. The median combined PFS for both crizotinib and alectinib was 18.2 months (range, 10.4-43.7 months). Crizotinib was continued beyond radiographic evidence of progressive disease in 6 of the 11 patients, with a median duration of postprogression crizotinib treatment of 9.4 months (range, 0-20.5 months). The OS period from the diagnosis of metastatic disease or the initiation of crizotinib treatment was 51.1 months (range, 20.9-69.5 months) and 48.6 months (range, 19.8-50.1 months), respectively.. Our retrospective study has revealed durable survival for alectinib treatment after crizotinib failure in patients with ALK-rearranged NSCLC.

Topics: Adenocarcinoma; Adult; Aged; Anaplastic Lymphoma Kinase; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; Female; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Survival Rate; Young Adult

In the present study we assessed the activity of the next-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) alectinib, in patients with ALK-postive, advanced non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. NSCLCs with ALK-positive disease, as assessed by fluorescence in situ hybridization, and CNS metastases were treated with alectinib 600 mg BID. Included patients were followed prospectively in order to evaluate the efficacy of the drug, with particular emphasis on activity in the CNS. Eleven consecutive patients were enrolled. The majority of them were pretreated with crizotinib (n = 10, 90.9 %), and cranial radiotherapy (n = 8, 72.7 %). Six of the seven patients with measurable CNS disease experienced a CNS response, including three patients who were naïve for cranial radiation. Median duration of response was 8 months. For the whole population, median CNS-progression-free survival (-PFS), systemic-PFS, overall-PFS, overall survival, and 1-year survival were 8, 11, 8, 13 months, and 31.1 %, respectively. Two patients experiencing a CNS response were assessed for alectinib's concentrations in serum and cerebro-spinal fluid (CSF), and showed a CSF-to-serum ratio ranging from 0.001 to 0.003 ng/mL. Alectinib is highly active against CNS metastases from ALK-positive NSCLCs, irrespective of prior treatment(s) with ALK-TKI(s) and/or cranial radiotherapy. The low CSF-to-serum ratio of alectinib suggests that measuring the concentrations of the drug in the CSF may not be a reliable surrogate of its distribution into the CNS.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Brain; Carbazoles; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Retrospective Studies

Alectinib is a novel anaplastic lymphoma kinase (ALK) inhibitor for treatment of patients with ALK-positive non-small-cell lung cancer who have progressed on or are intolerant to crizotinib. To support clinical development, concentrations of alectinib and metabolite M4 were determined in plasma from patients and healthy subjects.. LC-MS/MS methods were developed and validated in two different laboratories: Chugai used separate assays for alectinib and M4 in a pivotal Phase I/II study while Roche established a simultaneous assay for both analytes for another pivotal study and all other studies.. Cross-validation assessment revealed a bias between the two bioanalytical laboratories, which was confirmed with the clinical PK data between both pivotal studies using the different bioanalytical methods.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Chromatography, High Pressure Liquid; Equipment Design; Humans; Limit of Detection; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Tandem Mass Spectrometry

On December 11, 2015, the FDA granted accelerated approval to alectinib (Alecensa; Genentech) for the treatment of patients with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This approval was based on two single-arm trials including 225 patients treated with alectinib 600 mg orally twice daily. The objective response rates (ORR) by an independent review committee in these studies were 38% [95% confidence interval (CI), 28-49] and 44% (95% CI, 36-53); the median durations of response (DOR) were 7.5 months and 11.2 months. In a pooled analysis of 51 patients with measurable disease in the central nervous system (CNS) at baseline, the CNS ORR was 61% (95% CI, 46-74); the CNS DOR was 9.1 months. The primary safety analysis population included 253 patients. The most common adverse reactions were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). The most common laboratory abnormalities were anemia (56%), increased aspartate aminotransferase (51%), increased alkaline phosphatase (47%), increased creatine phosphokinase (43%), hyperbilirubinemia (39%), hyperglycemia (36%), increased alanine aminotransferase (34%), and hypocalcemia (32%). Dose reductions due to adverse reactions occurred in 12% of patients, whereas 27% of patients had alectinib dosing interrupted for adverse reactions. Permanent discontinuation of alectinib due to adverse reactions occurred in only 6% of patients. With the clinically meaningful ORR and DOR as well as the safety profile observed in these trials, alectinib was determined to have a favorable benefit-risk profile for the treatment of the indicated population. Clin Cancer Res; 22(21); 5171-6. ©2016 AACR.

Topics: Anaplastic Lymphoma Kinase; Aspartate Aminotransferases; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Approval; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; United States; United States Food and Drug Administration

Chromosomal rearrangements involving rearranged during transfection gene (RET) occur in 1% to 2% of NSCLCs and may confer sensitivity to rearranged during transfection (RET) inhibitors. Alectinib is an anaplastic lymphoma kinase tyrosine kinase inhibitor (TKI) that also has anti-RET activity in vitro. The clinical activity of alectinib in patients with RET-rearranged NSCLC has not yet been reported.. We have described four patients with advanced RET-rearranged NSCLC who were treated with alectinib (600 mg twice daily [n = 3] or 900 mg twice daily [n = 1]) as part of single-patient compassionate use protocols or off-label use of the commercially available drug.. Four patients with metastatic RET-rearranged NSCLC were identified. Three of the four had received prior RET TKIs, including cabozantinib and experimental RET inhibitors. In total, we observed two (50%) objective radiographic responses after treatment with alectinib (one confirmed and one unconfirmed), with durations of therapy of 6 months and more than 5 months (treatment ongoing), respectively. Notably, one of these two patients had his dose of alectinib escalated to 900 mg twice daily and had clinical improvement in central nervous system metastases. In addition, one patient (25%) experienced a best response of stable disease lasting approximately 6 weeks (the drug discontinued for toxicity). A fourth patient who was RET TKI-naive had primary progression while receiving alectinib.. Alectinib demonstrated preliminary antitumor activity in patients with advanced RET-rearranged NSCLC, most of whom had received prior RET inhibitors. Larger prospective studies with longer follow-up are needed to assess the efficacy of alectinib in RET-rearranged NSCLC and other RET-driven malignancies. In parallel, development of more selective, potent RET TKIs is warranted.

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines

Alectinib has been approved for the treatment of patients with anaplastic lymphoma kinase (ALK) gene rearrangement-positive advanced non-small cell lung cancer. In terms of adverse effects, the occurrence of a severe skin rash induced by alectinib is reportedly rare, compared with the occurrence of skin rash induced by epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). In the present case report, a 76-year-old woman with ALK-positive lung adenocarcinoma experienced disease progression after undergoing first-line chemotherapy. Subsequently, alectinib was administered as a second-line therapy. However, she discontinued alectinib therapy after 11days because of the occurrence of an alectinib-induced skin rash. Since the skin rash improved within one week, we attempted to perform oral desensitization to alectinib. The patient has not shown any recurrence of the rash or disease progression for 7 months since the successful oral desensitization to alectinib. Here, we describe the first case of successful oral desensitization against a skin rash induced by alectinib in a patient with ALK-positive lung adenocarcinoma. Desensitization to overcome adverse effects and to enable sustained treatment with alectinib should be considered in patients who develop alectinib sensitivities.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biopsy; Carbazoles; Desensitization, Immunologic; Exanthema; Female; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Over the last 2 years, our therapeutic armamentarium against genomically defined subgroups of non-small cell lung cancer (NSCLC) has extended to patients with acquired resistance to front-line targeted therapy. Alectinib (Alecensa; Roche/Genentech), a second-generation, orally active, potent, and highly selective inhibitor of anaplastic lymphoma kinase (ALK), is indicated for patients with metastatic, ALK rearrangement-positive NSCLC whose disease has worsened after treatment with crizotinib or who became intolerant to the drug. Alectinib received orphan drug designation, breakthrough therapy designation, priority review status, and accelerated approval by the FDA. Clin Cancer Res; 22(21); 5177-82. ©2016 AACR.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Disease Progression; Drug Approval; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Piperidines; Precision Medicine; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; United States; United States Food and Drug Administration

Patients with lung cancers harboring anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors, but acquired resistance inevitably arises. A better understanding of proximal ALK signaling mechanisms may identify sensitizers to ALK inhibitors that disrupt the balance between prosurvival and proapoptotic effector signals. Using affinity purification coupled with mass spectrometry in an ALK fusion lung cancer cell line (H3122), we generated an ALK signaling network and investigated signaling activity using tyrosine phosphoproteomics. We identified a network of 464 proteins composed of subnetworks with differential response to ALK inhibitors. A small hairpin RNA screen targeting 407 proteins in this network revealed 64 and 9 proteins that when knocked down sensitized cells to crizotinib and alectinib, respectively. Among these, knocking down fibroblast growth factor receptor substrate 2 (FRS2) or coiled-coil and C2 domain-containing protein 1A (CC2D1A), both scaffolding proteins, sensitized multiple ALK fusion cell lines to the ALK inhibitors crizotinib and alectinib. Collectively, our data set provides a resource that enhances our understanding of signaling and drug resistance networks consequent to ALK fusions and identifies potential targets to improve the efficacy of ALK inhibitors in patients.

Topics: Adaptor Proteins, Signal Transducing; Anaplastic Lymphoma Kinase; Carbazoles; Cell Cycle Proteins; Cell Line, Tumor; Crizotinib; DNA-Binding Proteins; Humans; Lung Neoplasms; Membrane Proteins; Microtubule-Associated Proteins; Piperidines; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; RNA Interference; Serine Endopeptidases

A 75-year-old woman with anaplastic lymphoma kinase (ALK)-rearranged Stage IV lung adenocarcinoma was administered the selective anaplastic lymphoma kinase inhibitor, alectinib, as a third-line treatment in a Phase 1-2 study. On the 102nd day, chest computed tomography showed diffuse ground glass opacities. Laboratory data revealed high serum levels of KL-6, SP-D and lactate dehydrogenase without any clinical symptoms. There was no evidence of infection. Marked lymphocytosis was seen in bronchoalveolar lavage fluid analysis, and transbronchial lung biopsy showed mild thickening of alveolar septa and lymphocyte infiltration. Interstitial lung disease was judged to be related to alectinib based on improvements in imaging findings and serum biomarkers after discontinuation of alectinib. To our knowledge, this is the first reported case of alectinib-induced interstitial lung disease. Alectinib is a promising drug for ALK-rearranged non-small cell lung cancer. Clinical trials of this selective anaplastic lymphoma kinase inhibitor will facilitate the meticulous elucidation of its long-term safety profile.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Bronchoalveolar Lavage Fluid; Carbazoles; Female; Humans; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Tomography, X-Ray Computed

Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK-positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK-positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Hepatocyte Growth Factor; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Signal Transduction

Leptomeningeal metastases (LM) are an increasingly frequent and devastating complication of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). Currently, the optimal management of LM in ALK-positive patients remains poorly understood as these patients have been routinely excluded from clinical trials.. We describe four ALK-positive patients with LM who were treated with the next-generation ALK inhibitor alectinib through single-patient, compassionate use protocols at two institutions. All patients had previously been treated with both FDA-approved ALK inhibitors--crizotinib and ceritinib. Patients received alectinib at a starting dose of 600 mg twice daily.. Four ALK-positive NSCLC patients with symptomatic leptomeningeal disease were identified. Three of four patients experienced significant clinical and radiographic improvements in LM upon treatment with alectinib. A fourth patient had stable intracranial disease for 4 months before eventual systemic disease progression. Overall, alectinib was well tolerated. One patient required dose reduction due to grade 2 hyperbilirubinemia.. Alectinib is active in ALK-rearranged NSCLC patients with LM, including in patients previously treated with crizotinib and ceritinib. Additional prospective studies of alectinib in ALK-positive patients with LM are warranted.

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Humans; Lung Neoplasms; Male; Meningeal Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Crizotinib is a potent and specific small-molecule inhibitor of both anaplastic lymphoma kinase (ALK) and c-MET tyrosine kinases, and patients with ALK rearrangement tumor benefit from crizotinib treatment; however, its penetration into calculated cerebrospinal fluid (CSF) is considered to be poor. Alectinib is a highly selective, next-generation ALK inhibitor, and both preclinical and clinical studies have indicated that alectinib is also effective in crizotinib-resistant tumors. A recent in vitro study demonstrated significant antitumor activity of alectinib for brain metastases using mouse models of ALK-positive non-small-cell lung cancer. In this paper, we report a first case alectinib was highly effective against brain metastases refractory to crizotinib. Further investigation of alectinib in this setting would be particularly valuable.

Topics: Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Pyrazoles; Pyridines

Topics: Activin Receptors, Type II; Adult; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cerebellum; Crizotinib; Female; Humans; Meningeal Carcinomatosis; Neoplasm Staging; Piperidines; Pyrazoles; Pyridines; Radiography; Randomized Controlled Trials as Topic

EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Bone Neoplasms; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; Crizotinib; Female; Humans; Lung Neoplasms; Male; Mice; Mice, SCID; Microtubule-Associated Proteins; Oncogene Proteins, Fusion; Piperidines; Pleural Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiography; Receptor Protein-Tyrosine Kinases; Serine Endopeptidases

Crizotinib was the first clinically available anaplastic lymphoma kinase (ALK) inhibitor, showing remarkable activity against ALK-rearranged non-small-cell lung cancer (NSCLC). Despite initial responses, acquired resistance to crizotinib inevitably develops, with the brain being a common site of relapse. Alectinib is a highly selective, next-generation ALK inhibitor with potent inhibitory activity also against ALK mutations conferring resistance to crizotinib, including the gatekeeper L1196M substitution. In a Phase I/II study from Japan, alectinib was found to be highly active and safe in crizotinib-naïve, ALK-rearranged NSCLC patients. Alectinib also demonstrated promising antitumor activity in crizotinib-resistant patients, including those with CNS metastases. Based on these data, the drug received Breakthrough Therapy Designation by the US FDA and has been recently approved in Japan for the treatment of ALK-positive, advanced NSCLC patients. However, patients may eventually develop resistance to alectinib, highlighting the need for novel therapeutic strategies to further improve the management of ALK-rearranged NSCLC.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Treatment Outcome

We describe a case of dysgeusia that developed gradually over one week after initiation of crizotinib administration for treatment of ALK-positive non-small cell lung cancer, necessitating discontinuation of the agent. The symptom was accompanied by progressive loss in appetite and body weight. Alectinib, a novel alternative ALK inhibitor, was administered and has been successfully continued without any toxicity, including dysgeusia. The present case indicates that dysgeusia is an important toxicity associated with crizotinib, which could adversely affect nutritional condition and quality of life. We describe the clinical course and present a review of crizotinib-induced dysgeusia.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Substitution; Dysgeusia; Female; Humans; Lung Neoplasms; Middle Aged; Piperidines; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Acquired resistance mutations to anaplastic lymphoma kinase (ALK) inhibitors such as crizotinib and alectinib have been documented in non-small cell lung cancer (NSCLC) patients harboring ALK rearrangement (ALK+). Of note I1171T/N/S mutations in the ALK kinase domain have recently been described by several groups to confer resistance to alectinib, a second-generation ALK inhibitor. Additionally one of these reports demonstrated one ALK+ NSCLC patient harboring an I1171T acquired mutation has responded to ceritinib, another second-generation ALK inhibitor.. We reported the presence of an ALK I1171N resistance mutation from comprehensive genomic profiling from a liver biopsy of a progressing metastatic lesion in an ALK+ patient on alectinib after an initial partial response. The patient then responded to ceritinib 750 mg orally once daily but required dose reduction to 600 mg once daily. She initially had grade 3 elevation of liver enzymes from crizotinib necessitating the original switch to alectinib but experienced no transaminase elevations with alectinib or ceritinib.. This is the fifth patient case to date demonstrating that ALK I1171 mutation confers resistance to alectinib and the second reported case of ALK I1171 mutation being sensitivity to ceritinib. Substitutions of isoleucine at amino acid 1171 in the ALK kinase domain may distinguish which second generation ALK inhibitor will be effective after crizotinib failure. This case also provides evidence that transaminase elevations is likely a unique adverse event associated with crizotinib and unlikely a "class" effect involving all ALK inhibitors.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Middle Aged; Mutation, Missense; Piperidines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Crizotinib was the first clinically available inhibitor of the tyrosine kinase ALK, and next-generation ALK inhibitors, such as alectinib, are now under development. Although crizotinib is generally well tolerated, severe esophageal injury has been reported as a rare but serious adverse event of crizotinib therapy. We now describe the successful treatment with alectinib of a patient who developed crizotinib-induced esophageal ulceration.

Topics: Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Endoscopes; Esophageal Diseases; Female; Humans; Lung Neoplasms; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Tomography, X-Ray Computed; Treatment Outcome; Ulcer

Topics: Aged; Carbazoles; Carcinoma, Squamous Cell; Humans; Lung Neoplasms; Male; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Treatment Failure

Molecular target therapy for cancer is characterized by unique adverse effects that are not usually observed with cytotoxic chemotherapy. For example, the anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor crizotinib causes characteristic visual disturbances, whereas such effects are rare when another ALK-tyrosine kinase inhibitor, alectinib, is used. To elucidate the mechanism responsible for these visual disturbances, the responses to light exhibited by retinal ganglion cells treated with these agents were evaluated using a C57BL6 mouse ex vivo model. Both crizotinib and alectinib changed the firing rate of ON and OFF type retinal ganglion cells. However, the ratio of alectinib-affected cells (15.7%) was significantly lower than that of crizotinib-affected cells (38.6%). Furthermore, these drugs changed the response properties to light stimuli of retinal ganglion cells in some of the affected cells, i.e., OFF cells responded to both ON and OFF stimuli, etc. Finally, the expressions of ALK (a target receptor of both crizotinib and alectinib) and of MET and ROS1 (additional target receptors of crizotinib) were observed at the mRNA level in the retina. Our findings suggest that these drugs might target retinal ganglion cells and that the potency of the drug actions on the light responses of retinal ganglion cells might be responsible for the difference in the frequencies of visual disturbances observed between patients treated with crizotinib and those treated with alectinib. The present experimental system might be useful for screening new molecular target agents prior to their use in clinical trials.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Crizotinib; Female; In Vitro Techniques; Male; Mice; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retina; Retinal Ganglion Cells

Alectinib, the second generation anaplastic lymphoma kinase (ALK) inhibitor, has significant potency in patients with ALK rearrangement positive non-small cell lung cancer (NSCLC), and its toxicity is generally well tolerable. We report a patient who developed severe acute interstitial lung disease after alectinib treatment. An 86-year-old woman with stage IV lung adenocarcinoma positive for rearrangement of ALK gene was treated with alectinib. On the 215th day after initiation of alectinib administration, she was admitted to our hospital with the symptom of progressive dyspnea. Computed tomography (CT) revealed diffuse ground glass opacities and consolidations in both lungs, and analysis of bronchoalveolar lavage fluid revealed pronounced lymphocytosis. There was no evidence of infection or other specific causes of her condition, and she was therefore diagnosed with interstitial lung disease induced by alectinib. Her CT findings and respiratory condition improved after steroid pulse therapy. As far as we are aware, this is the first reported case of alectinib-induced severe interstitial lung disease (ILD). We should be aware of the possibility of such a severe adverse event and should therefore carefully monitor patients treated with this drug.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adrenal Cortex Hormones; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Piperidines; Receptor Protein-Tyrosine Kinases

We herein report a case of a 46-year-old woman with anaplastic lymphoma kinase (ALK)-rearranged stage IV lung adenocarcinoma who received the ALK inhibitor crizotinib as second-line therapy. On the 47th day following crizotinib initiation, a chest computed tomography scan revealed ground-glass opacities with a clinical manifestation of desaturation, although a partial response to treatment was detected. The diagnosis of crizotinib-induced interstitial lung disease (ILD) was confirmed, and crizotinib was discontinued, followed by the initiation of corticosteroid therapy. After improvement of ILD with corticosteroid therapy, alectinib was administered as salvage therapy, resulting in tumor shrinkage without any recurrence of ILD. To the best of our knowledge, this is the first report of successful alectinib treatment following crizotinib-induced ILD. Our results indicate that alectinib could be a promising alternative treatment option in patients with crizotinib-induced ILD.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Carbazoles; Crizotinib; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiography, Thoracic; Tomography, X-Ray Computed; Treatment Outcome

The treatment of patients with advanced non-small-cell lung cancer harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small-molecule inhibitor of ALK, ROS1, and MET. However, resistance to crizotinib inevitably develops through a variety of mechanisms, leading to relapse both systemically and in the central nervous system (CNS). This has motivated the development of "second-generation" ALK inhibitors, including alectinib and ceritinib, that overcome some of the mutations leading to resistance. However, most of the reported ALK inhibitors do not show inhibition of the G1202R mutant, which is one of the most common mutations. Herein, we report the development of a structural analogue of alectinib (JH-VIII-157-02) that is potent against the G1202R mutant as well as a variety of other frequently observed mutants. In addition, JH-VIII-157-02 is capable of penetrating the CNS of mice following oral dosing.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lung; Lung Neoplasms; Mice; Molecular Docking Simulation; Neuroblastoma; NIH 3T3 Cells; Piperidines; Point Mutation; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Crizotinib, the first FDA-approved ALK inhibitor, showed significant antitumor activity in young patients with anaplastic large-cell lymphoma (ALCL) frequently displaying ALK rearrangement. However, long-term therapeutic benefits of crizotinib are limited due to development of drug resistance. CH5424802--more potent and selective ALK inhibitor--comprises a good candidate for second-line treatment in crizotinib-relapsed patients. The aim of this study was to determine possible mechanisms of resistance to ALK inhibitors that can appear in ALCL patients.. ALK+ ALCL cell lines resistant to crizotinib (Karpas299CR) and to CH5424802 (Karpas299CHR) were established by long-term exposure of Karpas299 cells to these inhibitors. Next, alterations in their sensitivity to ALK, HSP90 and mTOR inhibitors were investigated by cell viability and BrdU incorporation assays and immunoblot analysis.. cDNA sequencing of ALK kinase domain revealed activating mutations-I1171T in Karpas299CR and F1174C in Karpas299CHR. The resistant cells displayed diminished sensitivity to structurally unrelated ALK inhibitors-crizotinib, CH5424802 and TAE684. Nevertheless, CH5424802 and TAE684 were still more potent against the resistant cells than crizotinib. Moreover, Karpas299CR and Karpas299CHR cells remained sensitive to HSP90 or mTOR inhibitors.. Resistance mediated by activating mutations in ALK kinase domain may emerge in ALCL patients during ALK inhibitors treatment. However, more potent second-generation ALK inhibitors, HSP90 or mTOR inhibitors may represent an effective therapy for relapsed ALK+ ALCL patients.

Topics: Anaplastic Lymphoma Kinase; Apoptosis; Blotting, Western; Carbazoles; Cell Cycle; Cell Proliferation; Crizotinib; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins; Humans; Lymphoma, Large-Cell, Anaplastic; Mutation; Phosphoproteins; Piperidines; Protein Array Analysis; Protein Kinase Inhibitors; Protein Structure, Tertiary; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Topics: Carbazoles; Crizotinib; Disseminated Intravascular Coagulation; Drug Resistance, Neoplasm; Gene Amplification; Humans; Liver Neoplasms; Piperidines; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines

Acquired secondary mutations in the anaplastic lymphoma kinase (ALK) gene have been identified in ALK-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients who developed disease progression while on crizotinib treatment. Here, we identified a novel secondary acquired NSCLC ALK F1174V mutation by comprehensive next-generation sequencing in one ALK+ NSCLC patient who progressed on crizotinib after a prolonged partial response to crizotinib. In a second case, we identified a secondary acquired ALK G1202R, which also confers resistance to alectinib (CH5424802/RO5424802), a second-generation ALK inhibitor that can inhibit ALK gatekeeper L1196M mutation in vitro. ALK G1202R is located at the solvent front of the ALK kinase domain and exhibits a high level of resistance to all other ALK inhibitors currently in clinical development in vitro. Comprehensive genomic profiling of resistant tumor is increasingly important in tailoring treatment decisions after disease progression on crizotinib in ALK+ NSCLC given the promise of second-generation ALK inhibitors and other therapeutic strategies.

Topics: Adenocarcinoma; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Gene Rearrangement; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Staging; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

The clinical efficacy of the ALK inhibitor crizotinib has been demonstrated in ALK fusion-positive NSCLC; however, resistance to crizotinib certainly occurs through ALK secondary mutations in clinical use. Here we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in models of crizotinib resistance. Alectinib led to tumor size reduction in EML4-ALK-positive xenograft tumors that failed to regress fully during the treatment with crizotinib. In addition, alectinib inhibited the growth of some EML4-ALK mutant-driven tumors, including the G1269A model. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with ALK secondary mutations.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Apoptosis; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Crizotinib; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mice; Mice, SCID; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Random Allocation; Receptor Protein-Tyrosine Kinases; Treatment Outcome; Xenograft Model Antitumor Assays

Ceritinib and other second-generation inhibitors have demonstrated promising anticancer activity in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Specifically, they can overcome resistance due to certain gatekeeper mutations acquired following crizotinib exposure. These agents now provide new options for the management of ALK-positive NSCLC.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 (EML4)--anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK.

Topics: Benzoquinones; Blotting, Western; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Epidermal Growth Factor; ErbB Receptors; Hepatocyte Growth Factor; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Ligands; Lung Neoplasms; Mutation; Oncogene Proteins, Fusion; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Transforming Growth Factor alpha; Triazoles

Topics: Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Piperidines

The clinical efficacy of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been demonstrated in ALK fusion-positive non-small cell lung cancer (NSCLC); however, brain metastases are frequent sites of initial failure in patients due to poor penetration of the central nervous system by crizotinib. Here, we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in preclinical models of intracranial tumors.. We established intracranial tumor implantation mouse models of EML4-ALK-positive NSCLC NCI-H2228 and examined the antitumor activity of alectinib in this model. Plasma distribution and brain distribution of alectinib were examined by quantitative whole-body autoradiography administrating a single oral dose of (14)C-labeled alectinib to rats. The drug permeability of alectinib was evaluated in Caco-2 cell.. Alectinib resulted in regression of NCI-H2228 tumor in mouse brain and provided a survival benefit. In a pharmacokinetic study using rats, alectinib showed a high brain-to-plasma ratio, and in an in vitro drug permeability study using Caco-2 cells, alectinib was not transported by P-glycoprotein efflux transporter that is a key factor in blood-brain barrier penetration.. We established intracranial tumor implantation models of EML4-ALK-positive NSCLC. Alectinib showed potent efficacy against intracranial EML4-ALK-positive tumor. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with brain metastases.

Topics: Anaplastic Lymphoma Kinase; Animals; Brain Neoplasms; Caco-2 Cells; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Luciferases; Luminescent Measurements; Lung; Lung Neoplasms; Mice, Nude; Mice, SCID; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Rats; Receptor Protein-Tyrosine Kinases; Tissue Distribution; Xenograft Model Antitumor Assays

The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged non-small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance.. We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure-activity relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE.. We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib.. We have identified two novel ALK mutations arising after alectinib exposure that are sensitive to other next-generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs.

Topics: Anaplastic Lymphoma Kinase; Benzoquinones; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; DNA Mutational Analysis; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins; Humans; Inhibitory Concentration 50; Lactams, Macrocyclic; Lung Neoplasms; Models, Molecular; Mutation; Piperidines; Protein Conformation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Tomography, X-Ray Computed

Alectinib/CH5424802 is a known inhibitor of anaplastic lymphoma kinase (ALK) and is being evaluated in clinical trials for the treatment of ALK fusion-positive non-small cell lung cancer (NSCLC). Recently, some RET and ROS1 fusion genes have been implicated as driver oncogenes in NSCLC and have become molecular targets for antitumor agents. This study aims to explore additional target indications of alectinib by testing its ability to inhibit the activity of kinases other than ALK. We newly verified that alectinib inhibited RET kinase activity and the growth of RET fusion-positive cells by suppressing RET phosphorylation. In contrast, alectinib hardly inhibited ROS1 kinase activity unlike other ALK/ROS1 inhibitors such as crizotinib and LDK378. It also showed antitumor activity in mouse models of tumors driven by the RET fusion. In addition, alectinib showed kinase inhibitory activity against RET gatekeeper mutations (RET V804L and V804M) and blocked cell growth driven by the KIF5B-RET V804L and V804M. Our results suggest that alectinib is effective against RET fusion-positive tumors. Thus, alectinib might be a therapeutic option for patients with RET fusion-positive NSCLC.

Topics: Animals; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cytoskeletal Proteins; Disease Models, Animal; Gene Rearrangement; Humans; Lung Neoplasms; Male; Mice; Models, Molecular; Molecular Conformation; Mutation; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Receptor Protein-Tyrosine Kinases; Signal Transduction; Xenograft Model Antitumor Assays

Huntingtin-interacting protein 1 (HIP1) has recently been identified as a new fusion partner fused to anaplastic lymphoma kinase (ALK) in non-small-cell lung cancer (NSCLC). To date, two variants of HIP1-ALK (H21; A20) and (H28; A20) have been identified in NSCLC. However, the response of patients with NSCLC harboring HIP1-ALK to ALK inhibitors and potential resistance mechanisms to such remain unknown. Here, we report a patient with NSCLC harboring a novel HIP1-ALK fusion variant (H30; A20). This patient and another patient with EML4-ALK variant 3a/b initially responded sequentially to crizotinib and then alectinib, a next-generation ALK inhibitor, but developed acquired resistance to alectinib with the presence of a mutation in amino acid residue 1171 (I1171N and I1171S respectively) located in the hydrophobic regulatory spine (R-spine) of the ALK kinase in both the cases as identified by a comprehensive next-generation sequencing-based assay performed on biopsies of new liver metastases that developed during alectinib treatment.

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; DNA-Binding Proteins; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Topics: Adult; Anaplastic Lymphoma Kinase; Bone Neoplasms; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Drug Resistance, Multiple; Female; Gene Fusion; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases

Topics: Adenocarcinoma; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Gene Rearrangement; Humans; Lung Neoplasms; Male; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.

Topics: Administration, Oral; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carbazoles; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Mice; Mice, Nude; Mice, SCID; Models, Molecular; Mutation; Neoplasms; Piperidines; Protein Conformation; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Recombinant Fusion Proteins; Time Factors; Transfection; Tumor Burden; Xenograft Model Antitumor Assays