ceritinib and Lung-Neoplasms

This study compares the safety and efficacy of first-line treatments for anaplastic lymphoma kinase (ALK)-mutated non-small cell lung cancer (NSCLC).. A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Abstracts related to lung cancer presented at important international conferences were also reviewed. Randomized clinical trials that qualified the inclusion criteria were subjected to Bayesian network meta-analysis and systematically reviewed.. The authors included a total of nine studies including 2441 patients and seven first-line treatments (ensartinib, brigatinib, crizotinib, lorlatinib, alectinib, ceritinib, and pemetrexed-based chemotherapy). Overall, lorlatinib appeared to confer the best progression-free survival (PFS) (probability of being the best [Prbest], 90%; surface under the cumulative ranking curve [SUCRA], 98%), and the same conclusion was obtained on paired comparisons (lorlatinib vs. ceritinib [hazard ratio (HR), 0.31; 95% confidence interval (CI), 0.20-0.47); lorlatinib vs. chemotherapy [HR, 0.17; 95% CI, 0.12-0.23]; crizotinib vs. lorlatinib [HR, 3.6; 95% CI, 2.4-5.2]; and brigatinib vs. lorlatinib [HR, 1.7; 95% CI, 1.0-2.8]). Alectinib conferred the best overall survival (OS) and safety profile. In the Asian population, ensartinib conferred the best PFS (Prbest 50%, SUCRA 87%), and for patients with brain metastases at baseline, lorlatinib showed the best PFS (Prbest 70%, SUCRA 93%).. For first-line treatment of patients with ALK-positive NSCLC, lorlatinib was associated with the best PFS and objective response rate, but poorer safety profile, whereas alectinib demonstrated the best OS and safety profile. In Asians, ensartinib conferred the best PFS benefit, and in the brain baseline metastasis population, lorlatinib conferred the best PFS benefit.. Among the many molecularly targeted drugs currently used to treat anaplastic lymphoma kinase mutation-positive non-small cell lung cancer, lorlatinib may be one of the most effective targeted drugs. Lung cancer has long been at the top of cancer rankings in terms of incidence and mortality. Today, the treatment of lung cancer has moved into the era of precision therapy. In this article, we use a statistical approach to compare the efficacy and safety of targeted drugs that have been used in the first-line treatment of anaplastic lymphoma kinase mutations to improve the reference for clinicians to make treatment decisions in the real world.

Topics: Anaplastic Lymphoma Kinase; Bayes Theorem; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams, Macrocyclic; Lung Neoplasms; Network Meta-Analysis; Protein Kinase Inhibitors

Lung cancer is the most common in incidence and mortality worldwide. With the development of next generation sequencing (NGS) detection technology, more and more patients with rare anaplastic lymphoma kinase (ALK) fusion mutations were detected. A case of advanced lung adenocarcinoma with rare COX7A2L-ALK (C2:A20) fusion detected by NGS was reported in Peking Union Medical College Hospital, and all cases with rare ALK fusion mutations were searched from medical datebase from January 1, 2014 to March 31, 2021, to investigate the treatment of rare ALK fusion mutations with ALK inhibitors. The best response of the patient was assessed as partial response (PR) with Ceritinib treatment. By literature review, 22 cases of rare ALK fusion were reported in 19 articles. Combined with this case, 23 cases were analyzed. The objective response rate (ORR) was 82.6% (19/23) and disease control rate (DCR) was 95.7% (22/23) for rare ALK fusions patients treated with ALK inhibitors. Lung adenocarcinoma patients with rare ALK fusion could benefit from ALK inhibitors.
.. 【中文题目：罕见COX7A2L-ALK融合突变
晚期肺腺癌1例病例报告并文献复习】 【中文摘要：肺癌是全世界发病率和死亡率最高的肿瘤，随着下一代测序（next generation sequencing, NGS）检测技术的发展，越来越多的罕见间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合突变患者被检测出来。本文报道了北京协和医院收治的1例罕见COX7A2L-ALK（C2:A20）融合突变的肺腺癌晚期患者，同时检索2014年1月1日-2021年3月31日发表的罕见ALK融合突变的病例报道，探讨ALK抑制剂对罕见ALK融合突变患者的疗效。本例患者一线给予口服塞瑞替尼后病情好转，疗效评价为部分缓解（partial response, PR）。通过上述检索方法检索出符合文献19篇，共报道22例罕见ALK融合突变，结合本例，对23例进行汇总分析。分析结果显示，ALK抑制剂对罕见ALK融合突变的客观有效率为82.6%（19/23），疾病控制率为95.7%（22/23）。罕见ALK融合突变晚期肺腺癌患者可以从ALK抑制剂治疗中受益。
】 【中文关键词：罕见ALK融合突变；ALK抑制剂；肺肿瘤；COX7A2L-ALK融合突变】.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Crizotinib; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors

To date, no direct comparisons have compared the effectiveness of all ALK inhibitors (ALKis) against ALK-positive non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the efficacy and safety of ALKis in ALK-positive NSCLC.. The effectiveness of ALKis was evaluated by assessing progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and PFS with baseline brain metastasis (BM). The serious adverse events (SAEs: Grade ≥ 3) and adverse events (AEs) leading to discontinuation were pooled to evaluate safety. We conducted an indirect treatment comparison between all ALKis by using a Bayesian model.. Twelve eligible trials including seven treatments were identified. All of the ALKis improved PFS and ORR relative to chemotherapy. Consistent with alectinib, brigatinib, lorlatinib, and ensartinib showed significant differences versus crizotinib and ceritinib. Lorlatinib seemed to prolong PFS compared with alectinib (0.64, 0.37 to 1.07), brigatinib (0.56, 0.3 to 1.05), and ensartinib (0.53, 0.28 to 1.02). No significant difference was found among them in OS except for alectinib versus crizotinib. Moreover, alectinib was significantly more effective than crizotinib (1.54, 1.02 to 2.5) in achieving the best ORR. Subgroup analyses based on BM indicated that PFS was dramatically lengthened by lorlatinib. Compared with other ALKis, alectinib notably reduced the rate of SAEs. There was no striking difference between discontinuation for AEs, except for ceritinib versus crizotinib. The ranking of validity showed that lorlatinib had the longest PFS (98.32%) and PFS with BM (85.84%) and the highest ORR (77.01%). The rank of probabilities showed that alectinib had the potentially best safety in terms of SAEs (97.85%), and ceritinib had less discontinuation (95.45%).. Alectinib was the first choice for patients with ALK-positive NSCLC and even for those with BM, whereas lorlatinib was the second choice. Long-term follow-up and prospective studies are warranted to compare ALKis and to verify our conclusions directly.

Topics: Anaplastic Lymphoma Kinase; Bayes Theorem; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Network Meta-Analysis; Protein Kinase Inhibitors

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are new treatment for advanced non-small cell lung cancer. Here, we quantified the toxicity profiles of different ALK-TKIs to guide clinical decision making.. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Data were analyzed using random effects and consistency models under the frequency framework.. Of 865 relevant studies, 13 RCTs (encompassing 3,353 patients) were finally included. A network meta-analysis of all-grade AEs, fatal AEs, and treatment discontinuation due to AEs revealed no significant differences among the six ALK-TKIs. The rates of grade 3-4 AEs were: alectinib (16.2%), crizotinib (46.4%), brigatinib (63.7%), ensartinib (75.6%), ceritinib (78.3%), and lorlatinib (91.6%). The toxicity spectra of ALK-TKIs were different. The most frequent AEs associated with crizotinib were gastrointestinal reactions, visual disorders, neutropenia, edema, fatigue, and elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, while those in the alectinib group were anemia and constipation. Diarrhea, hepatotoxicity, and increased serum creatinine were most common with ceritinib. The most frequent AEs in the brigatinib group were gastrointestinal reactions, hypertension, cough, headache, and elevated ALT or AST levels. The most significant toxicities of ensartinib were skin disorders, including pruritus and rash. Changes in lipid levels were the most frequent AEs associated with lorlatinib; weight gain, cognitive effects, and mood effects were lorlatinib-specific AEs.. The toxicity spectra of ALK-TKIs differed. Alectinib might be the safest ALK-TKI drug according to the combined evidence of grades 3-4 AEs and the combined incidence.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Network Meta-Analysis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Tyrosine Kinase Inhibitors

Epidermal growth factor receptor (EGFR) is a receptor for epithelial growth factor (EGF) cell proliferation and signaling, which is related to the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis, and apoptosis. Thus, it has become an important target for the treatment of non-small cell lung cancer (NSCLC). The first to the third-generation EGFR inhibitors have demonstrated powerful efficacy and brought a prospect to patients. Unfortunately, after 9-15 months of treatment, they all developed resistance without exception. As for the resistance of third-generation inhibitors, no major breakthrough has been made in this field. In this review, we discussed the recent advances in medicinal chemistry of fourth-generation EGFR-TKIs, as well as further discussed the clinical challenges and future prospects of treating patients with EGFR mutations resistant to third-generation EGFR-TKIs.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Chemistry, Pharmaceutical; ErbB Receptors; Humans; Lung Neoplasms; Molecular Structure; Mutation; Protein Kinase Inhibitors

Lung cancer is one of the most common malignant neoplasms. As a result of the disease's progression, patients may develop metastases to the central nervous system. The prognosis in this location is unfavorable; untreated metastatic lesions may lead to death within one to two months. Existing therapies-neurosurgery and radiation therapy-do not improve the prognosis for every patient. The discovery of Epidermal Growth Factor Receptor (EGFR)-activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes its dimerization and the activation of the intracellular signaling cascade. Signal transduction involves the activation of MAPK, AKT, and JNK, resulting in DNA synthesis and cell proliferation. In cancer cells, binding the ligand to the EGFR also leads to its dimerization and transduction of the signal to the cell interior. It has been demonstrated that activating mutations in the gene for EGFR-exon19 (deletion), L858R point mutation in exon 21, and mutation in exon 20 results in cancer cell proliferation. Continuous stimulation of the receptor inhibits apoptosis, stimulates invasion, intensifies angiogenesis, and facilitates the formation of distant metastases. As a consequence, the cancer progresses. These activating gene mutations for the EGFR are present in 10-20% of lung adenocarcinomas. Approximately 3-7% of patients with lung adenocarcinoma have the echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion gene. The fusion of the two genes EML4 and ALK results in a fusion gene that activates the intracellular signaling pathway, stimulates the proliferation of tumor cells, and inhibits apoptosis. A new group of drugs-small-molecule tyrosine kinase inhibitors-has been developed; the first generation includes gefitinib and erlotinib and the ALK inhibitor crizotinib. These drugs reversibly block the EGFR by stopping the signal transmission to the cell. The second-generation tyrosine kinase inhibitor (TKI) afatinib or ALK inhibitor alectinib block the receptor irr

Topics: Acrylamides; Aniline Compounds; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Pyrimidines; Sulfones

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

Ceritinib is a new, oral, potent and selective second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the Food and Drug Administration of the United States in April 2014. It is active in crizotinib-resistant patients, especially in patients with non-small cell lung cancer (NSCLC) and brain metastasis. The aim of this study was to analyse the effects and side effects of ceritinib in ALK-rearranged NSCLC.. We searched articles published from January 1980 to March 2019 in PubMed, EMBASE, Cochrane Library and Web of Science. The pooled estimate and 95% CI were calculated with DerSimonian-Laird method and the random effect model.. From 15 articles, 2,598 patients were included in the meta-analysis. Eleven studies reported the ORR, and the DCR was presented in 10 studies. The ORR and DCR of ceritinib were 0.48 (95% CI, 0.39-0.57) and 0.76 (95% CI, 0.69-0.82), respectively. The PFS and OS were presented in nine and three eligible studies, respectively. The PFS and OS of ceritinib were 7.26 months (95% CI, 5.10-9.43) and 18.73 months (95% CI; 14.59-22.87). These results suggested that ceritinib can effectively treat patients with ALK-rearranged NSCLC. Diarrhoea, nausea and vomiting were the three most common AEs and occurred in 69% (95% CI 51.7-87.1%), 66% (95% CI 47.0-85.8%) and 51% (95% CI 35.9-66.8%) of patients, respectively. Considering serious gastrointestinal AEs, antiemetic and antidiarrhoeal drugs should be considered to improve a patient's tolerance to ceritinib.. Ceritinib is effective in the treatment of patients with ALK-rearranged NSCLC with crizotinib resistance. The DCR was up to 76%, and PFS was extended to 7.6 months. The AEs were acceptable.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Pyrimidines; Sequence Analysis, DNA; Sulfones

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

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Humans; Lung Neoplasms; Progression-Free Survival; Pyrimidines; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Sulfones; Technology Assessment, Biomedical

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

The chimeric protein echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase, resulting from the rearrangement of the homonym genes, is one of the currently targetable oncogenic drivers in anaplastic lymphoma kinase-positive non-small-cell lung cancer. In fact, four first- and second-generation anaplastic lymphoma kinase tyrosine kinase inhibitors, crizotinib (PF-02341066), ceritinib (LDK378), alectinib (CH5424802), and brigatinib (AP26113), are presently approved for clinical practice; however, these agents are not devoid of complications and thus should be administered meaningfully. Furthermore, third-generation inhibitors are currently under development to overcome acquired resistance mechanisms inevitably resulting from treatment with first- and second-generation tyrosine kinase inhibitors. Therefore, this article aims to provide a comprehensive state-of-the-art review about the pharmacodynamics, pharmacokinetics, safety, and tolerability profiles of currently available and promising under-development anaplastic lymphoma kinase tyrosine kinase inhibitors.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Gastrointestinal Diseases; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Several reports attest the feasibility and the favorable outcomes of kinase inhibitors administration through feeding tubes or Percutaneous Endoscopic Gastrostomies (PEG), mainly in Non-Small Cell Lung Cancer (NSCLC) patients exposed to first-generation compounds. Here we present the case of an ALK-positive NSCLC patient who achieved cerebral and extra-cranial disease response with ceritinib (a novel ALK inhibitor) administered through a Nasogastric Tube (NGT). We moreover provide a review gathering clinical successes obtained with targeted agents intake through NGT or PEG.. A 53-year-old never-smoker woman was diagnosed with ALK-rearranged stage IV lung adenocarcinoma. After a brilliant response to crizotinib and several lines of systemic therapy, NGT positioning intended for ceritinib administration was required, given the development of a pleuro-esophageal fistula. Enteral drug administration allowed a significant reduction of hepatic and cerebral disease localizations.. The majority of kinase inhibitors administration through NGT or PEG accounts for EGFR-mutated (seven) or ALK-positive (seven, including our report) NSCLC patients. Five additional cases concerning different malignancies were described. Enteral drug administration was mostly required by disease-related respiratory impairment, requiring mechanical ventilation in the emergency setting. In our case, the cerebral and extra-cranial response obtained with enteral ceritinib intake suggests the proposition of novel inhibitors in these circumstances may take place after first-generation compounds failure or even upfront. Indeed, their grater potency and activity against brain metastases point out the role of their enteral administration in the first-line setting too, when a rapid systemic and intra-cerebral disease response is required.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Enteral Nutrition; Humans; Intubation, Gastrointestinal; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Sulfones; Treatment Outcome

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

Ceritinib shows a promising efficacy in patients with anaplastic lymphoma kinase (ALK)-rearrangement non-small-cell lung cancer (NSCLC). The present systematic review determined the whole body and intracranial effectiveness and safety of ceritinib in crizotinib-naive versus crizotinib-pretreated regimens in ALK-rearrangement NSCLC. A comprehensive search of databases, including PubMed, EMBASE, Ovid, Web of Science, and COCHRANE, was performed to identify clinical trials in English-language journals. We estimated the pooled progression-free survival (PFS) and overall response rate (ORR) for ceritinib in whole body and intracranial responses to find differences between crizotinib-naive and crizotinib-pretreated regimens. The intracranial disease control rate in both crizotinib-naive and crizotinib-pretreated regimens was also estimated. The pooled efficacy parameters were as follows: ORR, 56.9% (95% confidence interval [CI], 53.6%-60.1%); PFS, 8.26 months (95% CI, 6.18-11.07 months); intracranial ORR, 41.3% (95% CI, 35.3%-47.6%); and intracranial disease control rate, 79.8% (95% CI, 73.8%-84.7%). The pooled ceritinib for crizotinib-naive showed a trend toward greater ORR and longer PFS compared with ceritinib for crizotinib-pretreated (68.9% and 14.62 months vs. 48.2% and 6.32 months, respectively). The intracranial ORR for ceritinib as the initial regimen was 50.6% compared with 33.6% for crizotinib-pretreated. The discontinuation and dose reduction rates were 3.1% and 38.4%, respectively. The most common grade 3/4 adverse effects were increased alanine aminotransferase (25.5%), increased γ-glutamyltransferase (12.6%), and increased aspartate aminotransferase (11.1%). Ceritinib is an effective agent for both crizotinib-naive and crizotinib-pretreated patients with locally advanced or metastatic ALK-rearranged NSCLC. Ceritinib has significant activity in crizotinib-naive patients with brain metastases.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Gene Rearrangement; Humans; Lung Neoplasms; Neoplasm Metastasis; Pyrimidines; Sulfones; Survival Analysis

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Humans; Lactams; Lactams, Macrocyclic; Lung; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Receptor Protein-Tyrosine Kinases

Detection of molecular aberrations driving the biology and the clinical behavior of advanced non-small cell lung cancer (NSCLC) allows the adoption of specific therapeutic strategies dramatically impacting disease courses. Among these, ROS1 rearrangements are present in 1-2% of lung adenocarcinomas. Thanks to similarities between ALK and ROS1 oncogenes, lessons inferred from ALK can be applied to ROS1-positive NSCLC; nevertheless, disparities exist between diseases mastered by these two fusion genes. In the absence of more common genetic alterations detected in NSCLC (e.g. EGFR and KRAS mutations, ALK gene fusions), seeking for ROS1 rearrangements is crucial. Dedicated molecular diagnostics should be standardized, hopefully relying upon practical and efficient algorithms, comprehending immunohistochemistry and fluorescence in situ hybridisation. The major clinical impact exerted by crizotinib represents the main reason for which not even a sole ROS1-positive tumor should be undetected. The recent approval of the inhibitor by both American and European health agencies would hopefully boost the widespread testing for ROS1, eventually increasing the absolute number of positive cases, potential further source of information regarding molecular and clinical resistance. In vitro and clinical evidence have already been generated concerning crizotinib resistance and strategies to maintain patients under specific driver-inhibition are being successfully developed. Gathering data concerning diagnostics, preclinical evidence, clinical practice and ongoing studies, the present review depicts the current scenario of ROS1 inhibition in NSCLC.

Topics: Aminopyridines; Anilides; Antineoplastic Agents; Benzamides; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Indazoles; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Molecular Diagnostic Techniques; Oncogene Fusion; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyridines; Pyrimidines; Sulfones

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

The identification of echinoderm microtubule-associated protein-like 4 (

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Protein-Tyrosine Kinases; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Anaplastic lymphoma kinase rearrangement (ALK+) occurs in approximately 2-7% of patients with non-small cell lung cancer (NSCLC), contributing to a considerable number of patients with ALK+ NSCLC worldwide. Ceritinib is a next generation ALK inhibitor (ALKi), approved by the European Medicines Agency in 2015. In the first-in-human, phase I study, ceritinib demonstrated rapid and durable responses in ALK patients previously treated with a different ALKi and in those who were ALKi-naive. As ceritinib is starting to be used routinely for the treatment of patients with ALK+ NSCLC, experience is growing with regard to ideal therapy management. In this review we provide a brief background to the development of ceritinib. The optimal treatment management and adverse events associated with ceritinib in clinical trials and in clinical practice are then discussed in detail, and where applicable, an expert consensus on specific recommendations are made. In clinical trials, the most common adverse events related to ceritinib are nausea, vomiting, and diarrhea. However, the majority of these are mild and, in the opinion of the authors, can be effectively managed with dose modifications. Based on clinical data, ceritinib has demonstrated efficacy as a first-line therapy and in patients who have relapsed on crizotinib, including those with brain metastases at baseline. Unfortunately, at some point, all patients experience progressive disease, with the central nervous system being a common site of metastases. Recommendations are made for continuing treatment beyond disease progression as long as a clinical benefit to patients is observed. Here, we review management of ceritinib treatment and adverse events and make recommendations on optimal management of patients.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Disease Management; Disease Progression; Drug Interactions; Drug Resistance, Neoplasm; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Outcome

The discovery of ALK rearrangement in non-small-cell lung cancer (NSCLC) triggered rapid clinical development of a family of specific drugs targeting this alteration, called ALK inhibitors. Despite high rate of responses, the vast majority of patients treated with first-generation ALK inhibitor crizotinib will ultimately develop disease progression. The second-generation ALK inhibitor, ceritinib, is an oral, small-molecule that inhibits the ALK kinase activity with a potency 20-fold greater than crizotinib, being able to tackle some of the principal mechanisms of resistance to crizotinib. Evidences from five large prospective clinical trials have so far showed impressive activity of ceritinib in ALK inhibitor pretreated and naive NSCLC patients. This review will focus on the preclinical and clinical data available regarding ceritinib pharmacology, clinical efficacy and safety profile.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Staging; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

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

Clinical pharmacists are important contributors to the care of patients with cancer; it is therefore critical for oncology clinical pharmacists to stay current with new anticancer therapies. This review summarizes the epidemiology and pathogenesis of non-small cell lung cancer, including the most common genetic alterations, as well as the mechanism of action, clinical development, pharmacodynamics and pharmacokinetics of the anaplastic lymphoma kinase inhibitor ceritinib for the treatment of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer. Targeted therapies based on the presence of specific mutations are an important development in the treatment of non-small cell lung cancer. However, acquired resistance to the first anaplastic lymphoma kinase-inhibitor approved by the U.S. Food and Drug Administration, crizotinib, is observed in almost half of patients treated with it. Ceritinib is an oral anaplastic lymphoma kinase-inhibitor that has demonstrated more potent antitumor activity than crizotinib in preclinical models. It was granted accelerated approval in 2014 to treat anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer patients who have progressed on or are intolerant to crizotinib. Ceritinib represents an important alternative second-line therapy for patients with metastatic non-small cell lung cancer who have traditionally limited treatment options.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Pharmacists; Protein Kinase Inhibitors; Pyrimidines; Sulfones

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

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

Lung cancer is the leading cause of cancer death among both sexes in the United States and non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Over the last several decades, there have been many advances in both surgical approaches and systemic therapies for the treatment of NSCLC, but the prognosis for advanced disease remains poor. New research, however, is exploring the use of targeted therapies for the treatment of NSCLC. The anaplastic lymphoma kinase (ALK) is involved in normal mammalian central nervous system development. A novel fusion gene involving ALK and the echinoderm microtubule-associated protein-like 4 (EML4) gene has been associated with approximately 5% of NSCLCs and is mutually exclusive of other oncogenic driver mutations. Targeted therapies against this ALK rearrangement are a relatively new treatment modality that aims to improve the prognosis of patients with late-stage disease. Two such drugs have Food and Drug Administration (FDA) approval currently: Crizotinib and Ceritinib. Many other ALK inhibitors are currently being studied in clinical trials as well. The authors aim to provide a comprehensive review of ALK inhibitors for use in NSCLC as well as the future directions and challenges to developing these targeted therapies.

Topics: Anaplastic Lymphoma Kinase; Animals; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Crizotinib; Humans; Lung Neoplasms; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements representing one of the newest and most appealing. Crizotinib is now recognized as the standard of care in ALK-positive NSCLC due to the positive results of recently published trials. Unfortunately, resistance inevitably occurs within the first year of treatment. Overcoming resistance is the major challenge in clinical oncology, and novel potent ALK inhibitors are currently under evaluation, including ceritinib. Ceritinib is an oral, potent, second-generation ALK inhibitor demonstrating activity in patients who develop resistance to crizotinib. Recent data also suggested efficacy in ALK-inhibitor-naive population, thus supporting investigation of the drug in front-line setting.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Gene Order; Humans; Lung Neoplasms; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

In up to 5% of non-small cell lung cancer (NSCLC) patients, the EML4-ALK translocation drives tumor progression. Treatment with the ALK inhibitor crizotinib is more effective than standard chemotherapy. However, resistance to crizotinib occurs after approximately 8 months. Ceritinib is the first second-generation ALK inhibitor approved for treatment of crizotinib-resistant NSCLC. Ceritinib inhibits two of the most common ALK-mutants that confer resistance to crizotinib: L1196 M and G1269A. Cells with ALK expression are more sensitive to ceritinib than crizotinib (IC50 25 nM vs. 150 nM, respectively). Alternative second-generation ALK inhibitors such as Alectinib, Brigatinib and PF-06463922 are currently in development, each affecting different crizotinib-resistant ALK target mutations. Genetic identification of crizotinib-resistant mutants is essential for selecting the optimal treatment strategy in NSCLC patients to overcome resistance and to increase progression-free survival.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mutation; 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

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

Ceritinib (Zykadia™) is an oral, selective inhibitor of the anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase which, after genetic rearrangement, acts as an oncogenic driver in a proportion of non-small cell lung cancers (NSCLCs). The drug is approved in several countries worldwide for the treatment of patients with ALK-positive, advanced NSCLC who have previously received the first-generation ALK inhibitor crizotinib (indication details may vary by country). Approval was based on its clinical benefit in this setting in the phase I and II trials known as ASCEND-1 and -2. Across these noncomparative studies, 36-56 % of patients achieved a response with ceritinib (at the recommended dosage of 750 mg once daily) and the responses were durable, lasting up to a median of 10 months. Patients survived free from progression for a median of up to 7 months and had a median overall survival of up to 17 months. Moreover, efficacy outcomes in patients with brain metastases were generally consistent with those of the overall study populations. Ceritinib has an acceptable tolerability profile, with gastrointestinal issues, fatigue and liver test abnormalities being the most common adverse reactions. Thus, ceritinib is a valuable treatment option for patients with ALK-positive advanced NSCLC who have already received crizotinib therapy.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pyrimidines; Sulfones

To review ceritinib for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small-cell lung cancer (NSCLC).. Literature searches were conducted in PubMed, EMBASE (1974 to July week 5, 2014), and Google Scholar using the terms ceritinib, LDK378, and non-small-cell lung cancer.. One phase 1 trial and 2 abstracts were identified.. Ceritinib is approved for the treatment of ALK-positive metastatic NSCLC in patients who are intolerant to or have progressed despite therapy with crizotinib. In the phase 1 clinical trial, the maximum tolerated dose was determined to be 750 mg once daily. The overall response rate (ORR) was 58% (95% CI = 48-67) in patients who received ≥400 mg daily (n = 114). In this group, the ORR was 56% (95% CI = 41-67) and 62% (95% CI = 44-78) among crizotinib-exposed and -naïve patients, respectively. The ORR was 59% (95% CI = 47-70) in patients who received 750 mg daily (n = 78). The ORR was 56% (95% CI = 41-70) in crizotinib-treated patients and 64% (95% CI = 44-81) in crizotinib-naïve patients, respectively, in this subset. The median duration of response was 8.2 months. Median progression-free survival was 7.0 months. The most common adverse reactions included diarrhea, nausea, vomiting, abdominal pain, anorexia, constipation, fatigue, and elevated transaminases.. Ceritinib has activity in crizotinib-resistant and crizotinib-naïve patients and appears to be a viable alternative for ALK-positive NSCLC. Long-term data are needed to further define the role of ceritinib in the treatment of NSCLC.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Diarrhea; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Nausea; Protein Kinase Inhibitors; Pyrimidines; Sulfones; Vomiting

The success in identifying the chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) as an oncogenic driver has thoroughly changed the treatment of non-small-cell lung cancer. In the past decade, targeted drugs have emerged as an efficient personalized strategy for ALK-rearranged non-small-cell lung cancer. The accelerated approval of potent ALK inhibitors, such as crizotinib and more recently ceritinib (LDK378), based on the well designed phase I/II trials has been a landmark success in clinical cancer research and contributes a new era of oncogenic targeted therapy characterized by elegant clinical trial design. In this review, we aim to present the current knowledge on acquired resistance of crizotinib known as a first-in-class ALK inhibitor and potential solutions to improve the cost-effectiveness, and to review the difference between ceritinib and crizotinib; preclinical data and results of the elegant early clinical trial of ceritinib which promoted its accelerated approval, pharmacokinetics, safety profile, and tolerability, the updated results (eg, efficacy on brain metastases), and robust design of ongoing phase II/III trials, and future directions of ceritinib to be a potent alternative to crizotinib for ALK-rearranged non-small-cell lung cancer are also presented.

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

Over the past decade, the non-small cell lung cancer therapeutics landscape has been dominated by the increasing focus on identification and validation of molecular targets, as well as the identification of the best candidate agents to address these targets. Among the notable successes have been the approval of erlotinib, gefitinib, and afatinib for the EGFR mutation, and more recently crizotinib for anaplastic lymphoma kinase (ALK) gene rearrangement. Despite the excellent efficacy of crizotinib, several mechanisms of resistance, including secondary mutation in the ALK gene, eventually result in disease progression, and several second-generation ALK inhibitors, notably ceritinib, have demonstrated evidence of clinical activity in this setting. This review discusses the data associated with the recent accelerated approval of ceritinib for treatment of patients with ALK-positive, metastatic lung adenocarcinoma with disease progression on or who are intolerant to crizotinib.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pyrimidines; Sulfones

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

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

Research over the last decade has determined that the gene rearrangement involving the anaplastic lymphoma kinase (ALK) gene is an oncogenic driver in approximately 5% of patients with non-small cell lung carcinoma (NSCLC). This review describes the discovery of the ALK translocation, development of ALK directed therapy, and acquired resistance to ALK directed therapy with a focus on the clinical data and efficacy of the most recently approved ALK inhibitor, ceritinib.

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

Published data on the clinical efficacy, safety, dosage and administration, and costs of the anaplastic lymphoma kinase (ALK) inhibitors crizotinib and ceritinib in the treatment of non-small-cell lung cancer (NSCLC) are reviewed and compared.. The ALK protein functions as a transmembrane receptor tyrosine kinase; rearrangements of the ALK gene are associated with the development of NSCLC with adenocarcinoma histology. Crizotinib is an oral tyrosine kinase inhibitor approved in 2011 as a first-line therapy for patients with metastatic ALK mutation-driven NSCLC. Significantly improved response rates and progression-free survival (PFS) have been reported with the use of crizotinib therapy versus standard chemotherapy, but mutations conferring resistance to treatment develop in most cases. The second-generation ALK inhibitor ceritinib was approved in 2014 for the treatment of ALK-mutated NSCLC in patients who are intolerant or develop resistance to crizotinib. In a clinical trial of ceritinib involving 130 patients with ALK-positive NSCLC, the majority of whom had experienced disease progression during crizotinib use, patients receiving at least 400 mg of ceritinib daily had an overall response rate of 56% and median PFS of seven months. Adverse effects commonly reported with the use of either drug include visual disturbances, gastrointestinal disorders (e.g., diarrhea), and liver enzyme abnormalities.. The tyrosine kinase inhibitors crizotinib and ceritinib provide an effective treatment approach for patients with ALK-mutated NSCLC. Efficacy data for both crizotinib and ceritinib indicate improved response rates and PFS with the use of either drug as an alternative to standard chemotherapy.

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

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

Around 4% of advanced non-small cell lung cancers (NSCLC) harbor a ALK rearrangement, with high sensitivity to ALK inhibitor as crizotinib. However, the vast majority of these tumors end with a tumor progression after several months of treatment with crizotinib. Ceritinib is a 2nd generation ALK inhibitor, which showed high efficiency in NSCLC with ALK rearrangement. Results from phase I trial showed a response rate at 58% in these tumors, with a similar rate for previously crizotinib-treated patients or crizotinib-naïve patients. Moreover, cerebral responses were observed with ceritinib. Preliminary date from a phase 2 trial confirmed these results. These promising results allowed a European marketing authorization (autorisation de mise sur le marché [AMM]) since May 2015 for the treatment of advanced NSCLC with ALK rearrangement and resistance or intolerance to crizotinib.

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

The anaplastic lymphoma kinase (ALK) gene plays a key role in the pathogenesis of selected tumors, including non-small-cell lung cancer (NSCLC). Patients with ALK-rearranged NSCLC are initially sensitive to the ALK inhibitor crizotinib but eventually become resistant, limiting its therapeutic potential. Ceritinib is an oral second-generation ALK inhibitor with greater preclinical antitumor potency than crizotinib in ALK-positive NSCLC. A Phase I trial of ceritinib in ALK-positive tumors demonstrated good activity in patients with advanced NSCLC, including those who had progressed on crizotinib. Adverse events are similar to those seen with other ALK tyrosine kinase inhibitors and are generally manageable. Ongoing trials are evaluating ceritinib in patients with ALK-rearranged NSCLC treated with prior chemotherapy and/or crizotinib.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Lung Neoplasms; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Ceritinib is an oral anaplastic lymphoma kinase (ALK) inhibitor developed by Novartis for the treatment of tumours characterised by genetic abnormalities in ALK. ALK is a member of the insulin receptor family of tyrosine kinases that can become oncogenic when fused to other proteins. Ceritinib has been approved in the US under 'Breakthrough Therapy' designation for the second-line treatment of ALK-positive non-small cell lung cancer (NSCLC). Regulatory submissions have also been made in the EU and other countries. Phase III development is ongoing worldwide to evaluate ceritinib both as a first- and second-line therapy for ALK-positive NSCLC. This article summarizes the milestones in the development of ceritinib leading to this first approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Approval; Humans; Lung Neoplasms; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment in human cancer. Several oncogenic alterations with druggable potential have been identified, with ALK rearrangements representing one of the newest and most appealing. Crizotinib is now recognized as the standard of care in chemotherapy-pretreated ALK-positive NSCLC due to the positive results of a recently published trial. Unfortunately, no patient exposed to crizotinib can be cured, and after a median time of 1 year, resistance inevitably occurs. Overcoming resistance is the major challenge in clinical oncology and many molecules are currently under evaluation, including ceritinib (LDK-378). Ceritinib is an oral, potent, second-generation ALK inhibitor recently approved by the U.S. Food and Drug Administration. Preclinical data showed impressive antitumor activity against crizotinib-resistant clones, and based on available data, ceritinib could represent a suitable option in crizotinib-resistant NSCLC.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Lung Neoplasms; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Outcome

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

Ceritinib is an orally bioavailable, small-molecule inhibitor of anaplastic lympoma kinase (ALK), insulin-like growth factor 1 receptor (IGFR1), and focal adhesion kinase (FAK), which are highly expressed in glioblastoma and many brain metastases. Preclinical and clinical studies indicate that ceritinib has antitumor activity in central nervous system (CNS) malignancies. This phase 0 trial measured the tumor pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in patients with brain metastasis or recurrent glioblastoma.. Preoperative patients with brain tumors demonstrating high expression of pSTAT5b/pFAK/pIGFR1 were administered ceritinib for 10 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at predefined timepoints following the final dose. Total and unbound drug concentrations were determined using LC-MS/MS. In treated tumor and matched archival tissues, tumor PD was quantified through IHC analysis of pALK, pSTAT5b, pFAK, pIGFR1, and pIRS1.. Ten patients (3 brain metastasis, 7 glioblastoma) were enrolled and no dose-limiting toxicities were observed. Ceritinib was highly bound to human plasma protein [median fraction unbound (Fu), 1.4%] and to brain tumor tissue (median Fu, 0.051% and 0.045% in gadolinium-enhancing and -nonenhancing regions respectively). Median unbound concentrations in enhancing and nonenhancing tumor were 0.048 and 0.006 μmol/L, respectively. Median unbound tumor-to-plasma ratios were 2.86 and 0.33 in enhancing and nonenhancing tumor, respectively. No changes in PD biomarkers were observed in the treated tumor samples as compared to matched archival tumor tissue.. Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations achieved in brain metastases and patients with recurrent glioblastoma were insufficient for target modulation.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Chromatography, Liquid; Glioblastoma; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines; Sulfones; Tandem Mass Spectrometry

Preclinical data show that the combination of an ALK inhibitor (ALKi) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) may act synergistically to overcome drug resistance mechanisms. Here, we assessed the safety, tolerability, and preliminary clinical activity of ceritinib, an ALKi in combination with ribociclib, a CDK4/6i, in patients with ALK-rearranged non-small cell lung cancer (NSCLC).. This was a multicenter, open-label, phase Ib/II dose-escalation study to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) for ceritinib plus ribociclib therapy.. Twenty-seven adult patients with ALK-rearranged advanced NSCLC with an ECOG PS ≤ 2 were enrolled into five cohorts to receive various dose combinations of ceritinib (range, 300-450 mg/day) and ribociclib (range, 100-300 mg/day). Median age of patients was 57 years. MTDs were not reached in this study. Enrollment into phase Ib was terminated early and phase II was not opened due to changes in the ALK-rearranged NSCLC treatment landscape. Ceritinib 300 mg/day and ribociclib 200 mg/day (3-weeks-on/1-week-off schedule) was identified as the RP2D. Among the 27 evaluable patients, the overall response rate (ORR) was 37.0% (95% CI, 19.4-57.6) and median progression-free survival (mPFS) was 21.5 months (95% CI, 5.5-25.0). At RP2D, the ORR was 50.0%, disease control rate was 75%, and mPFS was 24.8 months (95% CI, 5.5-25.1). Safety profile of the combination therapy was consistent with single-agent safety data.. Combination of ceritinib and ribociclib showed clinical activity with a manageable safety profile in patients with advanced ALK-rearranged NSCLC.

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Purines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug-drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively.. This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily.. Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC.. Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cross-Over Studies; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Drug Interactions; Female; Humans; Lung Neoplasms; Male; Midazolam; Middle Aged; Pyrimidines; Sulfones; Warfarin; Young Adult

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

Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients.. In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal.. In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9-99.6) in the 450-mg cohort and 60% (95% CI: 26.2-87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7-84.3) in the 450-mg cohort and 25% (95% CI: 5.5-57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1-87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0-58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported.. Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Nivolumab; Pyrimidines; Sulfones

The phase II, single-arm ASCEND-3 study assessed the efficacy and safety of ceritinib in anaplastic lymphoma kinase (ALK) inhibitor (ALKi)-naive patients with ALK-rearranged NSCLC who had received at least three previous lines of chemotherapy. Here, we report the final efficacy and safety results.. Eligible patients (including those with asymptomatic or neurologically stable brain metastases) received oral ceritinib (750 mg/day, fasted). The primary end point was investigator-assessed overall response rate (ORR). Secondary end points were Blinded Independent Review Committee-assessed ORR; investigator- and Blinded Independent Review Committee-assessed overall intracranial response rate, duration of response, time to response, disease control rate, and progression-free survival (PFS); overall survival (OS); and safety. Exploratory end points included patient-reported outcomes.. Of the 124 patients enrolled, 122 (98.4%) had received previous antineoplastic medications (31 patients [25.0%] received at least three regimens), and 49 (39.5%) had baseline brain metastases. The median follow-up time (data cutoff: January 22, 2018) was 52.1 (range, 48.4-60.1) months. The investigator-assessed ORR was 67.7% (95% confidence interval [CI]: 58.8-75.9), and the median PFS was 16.6 months (95% CI: 11.0-23.2). The median OS was 51.3 months (95% CI: 42.7-55.3). Most common adverse events (all grades, ≥60% of patients, all-causality) were diarrhea (85.5%), nausea (78.2%), and vomiting (71.8%). Overall, 18 patients (14.5%) had an adverse event leading to treatment discontinuation. Health-related quality of life was maintained during ceritinib treatment.. Ceritinib exhibited prolonged and clinically meaningful OS, PFS, and duration of response in chemotherapy-pretreated (at least three lines), ALKi-naive patients with ALK+ NSCLC. The safety profile was consistent with that reported in previous studies.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Quality of Life; Receptor Protein-Tyrosine Kinases; Sulfones

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

Ceritinib is a selective anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with unresectable advanced and/or recurrent ALK fusion gene-positive non-small cell lung cancer (NSCLC). As per the approval condition in Japan, this post-marketing surveillance (PMS) study evaluated the clinical safety (including adverse events [AEs], adverse drug reactions [ADRs] and priority investigation items) and efficacy (including ORR and PFS) of ceritinib in Japanese patients. Interim analysis was conducted ~ 2 years after the start of this non-interventional, multicentre, uncontrolled, open-label, special drug-use investigation and results are reported from March 28, 2016 to April 28, 2018. Each patient was followed up for 1 year. Most patients started treatment with 750 mg ceritinib. Safety profile was similar to that observed at the time of approval. No new AEs or ADRs with incidences higher than that at approval were identified. The rate of gastrointestinal ADRs (nausea, vomiting and diarrhoea) was 73.64%. Meaningful efficacy was observed in both post-crizotinib and post-alectinib settings, with ORR of 29.55% (95% CI 20.29-40.22) and disease control rate of 53.41% (95% CI 42.46-64.12). No concerns regarding the safety and efficacy of ceritinib were identified. No new measures, including modification of the PMS study protocol, are considered necessary.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Humans; Japan; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Product Surveillance, Postmarketing; Progression-Free Survival; Pyrimidines; Sulfones

Patients with anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC) treated with crizotinib inevitably relapse, with brain as common site of progression.. ASCEND-6, a phase 1/2, single-arm study, included adult Chinese patients with stage IIIB or IV ALK+ NSCLC pretreated with crizotinib as the last therapy (irrespective of prior chemotherapies [≤2]). Primary endpoints were pharmacokinetics (PK), safety, and tolerability. Key secondary endpoint was overall response rate (ORR; investigator assessed).. Ceritinib PK in Chinese patients is consistent with those observed in the global ASCEND-1 study. Ceritinib was well tolerated and showed durable responses in Chinese patients with ALK+ NSCLC who progressed after crizotinib and ≤2 prior lines of chemotherapy.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; China; Crizotinib; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Pharmaceutical Preparations; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Topics: Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Progression-Free Survival; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Sulfones

In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted.. Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1.. In total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]-positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9-86.9), 72.5% (95% CI: 58.3-84.1), and 75.7% (95% CI: 64.3-84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2-NE), 20.7 (95% CI: 15.8-NE), and 15.4 (95% CI: 8.3-NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%).. Ceritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Bone Neoplasms; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Fasting; Female; Follow-Up Studies; Food; Gene Rearrangement; Humans; Liver Neoplasms; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Prognosis; Pyrimidines; Response Evaluation Criteria in Solid Tumors; Sulfones; Young Adult

Ceritinib 750 mg/day was approved for the treatment of patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) based on ASCEND-4 study. The objective of this article is to introduce the use of time-dependent modeling approach in the updated exposure-efficacy analysis of ceritinib for the first-line indication.. Exposure-efficacy analyses, including data from 156 patients, were first conducted using time-independent logistic regression model for response of complete or partial response and Cox regression model for progression-free survival (PFS). The exposure measure used was average C. With exposure measure being average C. The drug effect on efficacy in clinical trials could be better characterized using time-dependent exposure-response models.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Female; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Prognosis; Pyrimidines; Sulfones; Survival Rate; Time Factors; Young Adult

Anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) is diagnosed in up to 126,000 patients worldwide annually. Ceritinib is a next-generation ALK-targeted tyrosine kinase inhibitor that is approved for the treatment of patients with metastatic ALK+ NSCLC. In December 2017, the US Food and Drug Administration-approved dose of ceritinib was changed from 750 mg/day under fasting conditions to 450 mg/day taken with food for the treatment of patients with ALK+ NSCLC. This change was implemented on the basis of data from studies designed to investigate ways to reduce the frequency of gastrointestinal adverse events noted in patients enrolled in several ASCEND clinical trials that evaluated a ceritinib 750-mg fasted dose as either first- or second/third-line treatment. This review highlights and discusses published findings from the ASCEND-8 food-effect trial and includes commentary from physicians regarding their own clinical cases of patients who were enrolled in the trial and treated with either the 750-mg fasted or 450-mg fed dose of ceritinib. The review also discusses the implications of using the recently approved ceritinib 450-mg dose in the clinical setting.

Topics: Administration, Oral; Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Disease Progression; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Protein Kinase Inhibitors; Pyrimidines; Sulfones; 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

In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study.. Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator's choice], every 21 days).. Among the 231 patients, 29 were Japanese, of which, 11 were treated with ceritinib and 18 were treated with chemotherapy (5 with pemetrexed and 13 with docetaxel). All the patients received prior crizotinib and one or two lines of prior chemotherapy for advanced disease. Median follow-up time was 16.6 months for ceritinib arm and 16.4 months for chemotherapy arm in the overall population. The median PFS by blinded independent review committee was 9.8 months (95% CI, 4.3-14.0) in ceritinib arm vs 1.6 months (95% CI, 1.4-3.0) in chemotherapy arm. Grade 3 or 4 adverse events, suspected to be study drug related, were reported in 36.4% of ceritinib arm and 72.2% of chemotherapy arm, respectively. No Grade 3 or 4 events of diarrhea, nausea and vomiting were reported in both the treatment arms. Adverse events leading to study drug discontinuation were reported in one patient in each arm: Grade 3 central-nervous system metastases in ceritinib-treated patient and Grade 3 febrile neutropenia in chemotherapy-treated patient.. Consistent with overall population, ceritinib demonstrated better efficacy compared with the standard second-line chemotherapy in Japanese patients with crizotinib-resistant ALK+ NSCLC.. NCT01828112.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Asian People; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Docetaxel; Female; Gene Rearrangement; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Pemetrexed; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Taxoids; Treatment Outcome

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

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

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer is sensitive to tyrosine kinase inhibitors; however, resistance can develop. Data are presented from the phase II trial (ASCEND-2) evaluating efficacy and safety in a subset of Japanese patients with ALK-rearranged non-small cell lung cancer previously treated with platinum-based chemotherapy, who experienced disease progression on crizotinib.. Patients with advanced ALK-rearranged non-small cell lung cancer, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/day. Whole-body and intracranial responses were assessed by investigator and Blinded Independent Review Committee (RECIST v1.1). Safety and tolerability were also investigated.. All 24 Japanese patients had received ≥2 previous treatment regimens, with crizotinib the last therapy received prior to ceritinib. Median duration of ceritinib exposure was 8.1 (range: 0.2-12.5) months. Overall response rate was 45.8% (95% confidence interval: 25.6-67.2). Other efficacy endpoints included disease control rate (79.2% [95% confidence interval: 57.8-92.9]), time to response (median 1.9 months [range: 1.7-3.5]), duration of response (median 9.2 months [95% confidence interval: 4.0-not estimable]) and progression-free survival (median 6.6 months [95% confidence interval: 3.7-9.3]). Of the four patients with active baseline target brain lesions, two achieved an intracranial partial response (50%). The most commonly reported adverse events (majority grade 1/2) were nausea (91.7%), diarrhea (83.3%) and vomiting (83.3%).. This study demonstrates the clinical activity and manageable tolerability of ceritinib in a Japanese subset of chemotherapy- and crizotinib-pretreated patients with ALK-rearranged non-small cell lung cancer who progressed on crizotinib, as was shown in the whole ASCEND-2 study population. ClinicalTrials.gov identifier: NCT01685060.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Asian People; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Female; Gene Order; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

The impact of proton pump inhibitors (PPIs) on the pharmacokinetics (PK) and efficacy of ceritinib was evaluated.. A healthy subject drug-drug interaction (DDI) study was conducted to assess the effect of esomeprazole on the PK of a single 750 mg dose of ceritinib. To further investigate the impact of PPIs on the PK and efficacy of ceritinib in ALK-positive cancer patients, two subgroup analyses were performed. Analysis 1 evaluated ceritinib steady-state trough concentration (C. In the healthy subject study, co-administration of a single 750 mg dose of ceritinib with esomeprazole 40 mg for 6 days decreased ceritinib AUC. Long-term administration of ceritinib with PPIs does not adversely affect the PK and efficacy of ceritinib in ALK-positive cancer patients.

Topics: Adolescent; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Drug Interactions; Esomeprazole; Female; Healthy Volunteers; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Proton Pump Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Outcome; Young Adult

Purpose ROS1 rearrangement is a distinct molecular subset of non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC. Patients and Methods We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization. Ceritinib 750 mg was administered once daily. The primary end point was objective response rate. The secondary end points were disease control rate; duration of response; progression-free survival; overall survival; toxicity; and concordance among fluorescent in situ hybridization, immunohistochemistry, and next-generation sequencing. Results Between June 7, 2013, and February 1, 2016, 404 patients underwent ROS1 prescreening, and 32 patients with ROS1 rearrangement were enrolled. All patients except two were crizotinib-naïve. At the time of data cutoff, the median follow-up was 14.0 months, and 18 patients (56%) had discontinued treatment. Of the 32 patients enrolled, 28 were evaluable for response by independent radiologic review. Objective response rate was 62% (95% CI, 45% to 77%), with one complete response and 19 partial responses; duration of response was 21.0 months (95% CI, 17 to 25 months); and disease control rate was 81% (95% CI, 65% to 91%). The median progression-free survival was 9.3 months (95% CI, 0 to 22 months) for all patients and 19.3 months (95% CI, 1 to 37 months) for crizotinib-naïve patients. The median overall survival was 24 months (95% CI, 5 to 43 months). Of the eight patients with brain metastases, intracranial disease control was reported in five (63%; 95% CI, 31% to 86%). The most common adverse events (majority, grade 1 or 2) for all treated patients were diarrhea (78%), nausea (59%), and anorexia (56%). Conclusion Ceritinib demonstrated potent clinical activity in patients with ROS1-rearranged NSCLC who were heavily treated previously with multiple lines of chemotherapy.

Topics: Adult; Aged; Anorexia; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Diarrhea; Disease-Free Survival; DNA, Neoplasm; Female; Gene Rearrangement; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Male; Middle Aged; Nausea; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrimidines; Sequence Analysis, DNA; Sulfones; Survival Rate

Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure.. ASCEND-8 is a multicenter, randomized, open-label, phase 1 study. Part 1 investigated the steady-state pharmacokinetics (PK) and safety of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg fasted in patients with advanced ALK-positive NSCLC who were either treatment naive or pretreated with chemotherapy and/or crizotinib. Part 2 will assess efficacy and safety of ceritinib in treatment-naive patients.. As of June 16, 2016, 137 patients were randomized (450 mg fed [n = 44], 600 mg fed [n = 47], and 750 mg fasted [n = 46]); 135 patients received ceritinib. Median follow-up duration was 4.14 months. At steady state, relative to 750 mg fasted, 450 mg with food demonstrated comparable PK as assessed by maximum (peak) concentration of drug in plasma and area under the plasma concentration-time curve from time zero to 24 hours, whereas 600 mg with food demonstrated approximately 25% higher PK. Relative to 750 mg fasted, 450 mg with food was associated with a lower proportion of patients with GI toxicities, mostly grade 1 (diarrhea [43.2%], nausea [29.5%], and vomiting [18.2%]); there were no grade 3 or 4 events, study drug discontinuations, or serious AEs due to GI toxicities.. Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than ceritinib, 750 mg in fasted patients with ALK-positive NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Fasting; Humans; Lung Neoplasms; Middle Aged; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Binding Sites; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lactams; Lactams, Macrocyclic; Liver Failure; Liver Neoplasms; Lung Neoplasms; Middle Aged; Molecular Structure; Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to EGFR and anaplastic lymphoma kinase (ALK) resistance to TKI therapy have been described in non-small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far.. A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)-ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib. Molecular analysis (whole-exome sequencing, CGH) and functional studies were undertaken to elucidate the mechanism of resistance. Based on this case, we took advantage of the structural homology of ROS1 and ALK to build a predictive model for drug sensitivity regarding future ROS1 mutations.. Sequencing revealed a dual mutation, S1986Y and S1986F, in the ROS1 kinase domain. Functional in vitro studies demonstrated that ROS1 harboring either the S1986Y or the S1986F mutation, while conferring resistance to crizotinib and ceritinib, was inhibited by lorlatinib (PF-06463922). The patient's clinical response confirmed the potency of lorlatinib against S1986Y/F mutations. The ROS1 S1986Y/F and ALK C1156Y mutations are homologous and displayed similar sensitivity patterns to ALK/ROS1 TKIs. We extended this analogy to build a model predicting TKI efficacy against potential ROS1 mutations.. Clinical evidence, in vitro validation, and homology-based prediction provide guidance for treatment decision making for patients with ROS1-rearranged NSCLC who progressed on crizotinib. Clin Cancer Res; 22(24); 5983-91. ©2016 AACR.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Mutation; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Phase I data (ASCEND-1) showed ceritinib efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC), regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein. Data are presented from a phase II trial (ASCEND-2) in which ceritinib efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during crizotinib treatment as their last prior therapy.. Patients with advanced ALK-rearranged NSCLC, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/d. Whole-body and intracranial responses were investigator assessed (according to RECIST version 1.1). Patient-reported outcomes were evaluated with the Lung Cancer Symptom Scale and European Organisation for Research and Treatment of Cancer surveys (the core-30 and the 13-item lung cancer-specific quality-of-life questionnaires).. All 140 patients enrolled had received two or more previous treatment regimens, and all patients had received crizotinib. The median duration of exposure and the follow-up time with ceritinib were 8.8 months (range, 0.1 to 19.4 months) and 11.3 months (range, 0.1 to 18.9 months), respectively. Investigator-assessed overall response rate was 38.6% (95% CI, 30.5% to 47.2%). Secondary end points, all investigator assessed, included disease control rate (77.1%; 95% CI, 69.3% to 83.8%), time to response (median, 1.8 months; range, 1.6 to 5.6 months), duration of response (median, 9.7 months; 95% CI, 7.1 to 11.1 months), and progression-free survival (median, 5.7 months; 95% CI, 5.4 to 7.6 months). Of 100 patients with baseline brain metastases, 20 had active target lesions at baseline; investigator-assessed intracranial overall response rate was 45.0% (95% CI, 23.1% to 68.5%). The most common adverse events (majority, grade 1 or 2) for all treated patients were nausea (81.4%), diarrhea (80.0%), and vomiting (62.9%). Patient-reported outcomes showed a trend toward improved symptom burden. The global quality-of-life score was maintained during treatment.. Consistent with its activity in ASCEND-1, ceritinib treatment provided clinically meaningful and durable responses with manageable tolerability in chemotherapy- and crizotinib-pretreated patients, including those with brain metastases.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Gene Order; Humans; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK inhibitors, but resistance develops. This study assessed the maximum-tolerated dose, safety, pharmacokinetics (PK), and antitumor activity of ceritinib, a novel ALK inhibitor (ALKi), in Japanese patients with ALK-rearranged malignancies.. This phase I, multicenter, open-label study (NCT01634763) enrolled adult patients with ALK-rearranged (by fluorescence in situ hybridization and/or immunohistochemistry) locally advanced/metastatic malignancy that had progressed despite standard therapy. The study comprised two parts: dose escalation and dose expansion. Ceritinib (single-dose) was administered orally in the 3-day PK run-in period, then once daily, in 21-day cycles. Adaptive dose escalations were guided by a Bayesian model.. Twenty patients (80% with ALKi treatment history [ALKi-pretreated]; 19 NSCLC; one inflammatory myofibroblastic tumor) received ceritinib 300 to 750 mg (19 during dose escalation, one in dose expansion). Two dose-limiting toxicities occurred: grade 3 lipase increase (600 mg); grade 3 drug-induced liver injury (750 mg). The most common adverse events were gastrointestinal (nausea: 95%; diarrhea, vomiting: 75%). Ceritinib PK profile was dose proportional across 300 to 750 mg dosages; steady state was reached by day 15. Overall response rate was 55% (11 of 20 patients). Among patients with NSCLC, partial response was observed in two of four ALKi-naive patients, five of nine crizotinib-pretreated patients, two of four alectinib-pretreated patients, and one of two crizotinib and alectinib/ASP3026 pretreated patients. The ASP3026-pretreated inflammatory myofibroblastic tumor patient achieved partial response.. Ceritinib maximum-tolerated dose was 750 mg once daily in Japanese patients. Antitumor activity was observed irrespective of prior ALKi treatment history. Dose expansion, examining the activity of ceritinib in alectinib-resistant patients, is ongoing.

Topics: Aged; Anaplastic Lymphoma Kinase; Antifreeze Proteins, Type I; Antineoplastic Agents; Asian People; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Female; Gene Rearrangement; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.. In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.. A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).. Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Recombination, Genetic; Sulfones; Treatment Outcome; Young Adult

Previous report from the ASCEND-8 trial showed consistent efficacy with less gastrointestinal (GI) toxicity in patients with anaplastic lymphoma kinase-rearranged (ALK+) advanced/metastatic non-small cell lung cancer (NSCLC) treated with ceritinib 450-mg with food compared with 750-mg fasted. In this subgroup analysis, we report outcomes in Asian patients of the ASCEND-8 trial.. Key efficacy endpoints were blinded independent review committee (BIRC)-assessed overall response rate (ORR) and duration of response (DOR) evaluated per Response Evaluation Criteria in Solid Tumors v1.1. Other efficacy endpoints were investigator-assessed ORR and DOR; BIRC- and investigator-assessed progression-free survival (PFS) and disease control rate; overall survival (OS). Safety was evaluated by frequency and severity of adverse events.. At final data cutoff (6 March 2020), 198 treatment-naïve patients were included in efficacy analysis, of which 74 (37%) comprised the Asian subset; 450-mg fed (n=29), 600-mg fed (n=19), and 750-mg fasted (n=26). Baseline characteristics were mostly comparable across study arms. At baseline, more patients in 450-mg fed arm (44.8%) had brain metastases than in 750-mg fasted arm (26.9%). Per BIRC, patients in the 450-mg fed arm had a numerically higher ORR, 24-month DOR rate and 24-month PFS rate than the 750-mg fasted arm. The 36-month OS rate was 93.1% in 450-mg fed arm and 70.9% in 750-mg fasted arm. Any-grade GI toxicity occurred in 82.8% and 96.2% of patients in the 450-mg fed and 750-mg fasted arms, respectively.. Asian patients with ALK+ advanced/metastatic NSCLC treated with ceritinib 450-mg fed showed numerically higher efficacy and lower GI toxicity than 750-mg fasted patients.

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

This real-world analysis describes treatment patterns, sequencing and clinical effectiveness, toxicities, and health utility outcomes in advanced-stage, incurable ALK-positive NSCLC patients across five different ALK-TKIs.. Clinicodemographic, treatment, and toxicity data were collected retrospectively in patients with advanced-stage ALK-positive NSCLC at Princess Margaret Cancer Centre. Patient-reported symptoms, toxicities, and health utilities were collected prospectively.. Of 148 ALK-positive NSCLC patients seen July 2009-May 2021, median age was 58.9 years; 84 (57%) were female; 112 (76%) never-smokers; 54 (47%) Asian and 40 (35%) white; 139 (94%) received at least one ALK-TKI: crizotinib (n = 74; 54%) and alectinib (n = 61; 44%) were administered mainly as first-line ALK-TKI, ceritinib, brigatinib and lorlatinib were administered primarily after previous ALK-TKI failure. Median overall survival (OS) was 54.0 months; 31 (21%) patients died within two years of advanced-stage diagnosis. Treatment modifications were observed in 35 (47%) patients with crizotinib, 19 (61%) with ceritinib, 41 (39%) with alectinib, 9 (41%) with brigatinib and 8 (30%) with lorlatinib. Prevalence of dose modifications and self-reported toxicities were higher with early versus later generation ALK-TKIs (P<.05). The presence of early treatment modification was not negatively associated with progression-free survival (PFS) and OS analyses.. Serial ALK-TKI sequencing approaches are viable therapeutic options that can extend quality of life and quantity-of-life, though a fifth of patients died within two years. No best single sequencing approach could be determined. Clinically relevant toxicities occurred across all ALK-TKIs. Treatment modifications due to toxicity may not necessarily compromise outcomes, allowing multiple approaches to deal with ALK-TKI toxicities.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Quality of Life; Receptor Protein-Tyrosine Kinases; Retrospective Studies

Anaplastic lymphoma kinase (ALK) inhibitors have significant efficacies in ALK-rearranged non-small cell lung cancers (NSCLC). In regard to pediatric NSCLC patients, however, there is a paradox in that on the one hand, they may have a higher probability of ALK-rearrangement positive, but on the other hand, there is no sufficient data for efficacies of ALK inhibitors in pediatric NSCLC patients. Here, we present an 11-year-old boy diagnosed with metastatic ALK-rearranged lung adenocarcinoma. He was treated with ceritinib 450 mg with food once daily and has obtained near complete response in 18th month, with a largely regressed intrathoracic lesion and only localized residual distant metastatic disease. Meanwhile, he showed continued good tolerance after a short period of side effects at the beginning of the dose. This is the first report of the use of ceritinib in pediatric patient with NSCLC.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Child; Humans; Lung Neoplasms; Male; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

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

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

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

Autoimmune disorders and some types of blood cancer originate when B lymphocytes malfunction. In particular, when B cells produce antibodies recognizing the body's proteins, it leads to various autoimmune disorders. Additionally, when B cells of various developmental stages transform into cancer cells, it results in blood cancers, including multiple myeloma, lymphoma, and leukemia. Thus, new methods of targeting B cells are required for various patient groups. Here, we used protein kinase inhibitors alectinib, brigatinib, ceritinib, crizotinib, entrectinib, and lorlatinib previously approved as drugs treating anaplastic lymphoma kinase (ALK)-positive lung cancer cells. We hypothesized that the same inhibitors will efficiently target leukocyte tyrosine kinase (LTK)-positive, actively protein-secreting mature B lymphocytes, including plasma cells. We isolated CD19-positive human B cells from the blood of healthy donors and used two alternative methods to stimulate cell maturation toward plasma cells. Using cell proliferation and flow cytometry assays, we found that ceritinib and entrectinib eliminate plasma cells from B cell populations. Alectinib, brigatinib, and crizotinib also inhibited B cell proliferation, while lorlatinib had no or limited effect on B cells. More generally, we concluded that several drugs previously developed to treat ALK-positive malignant cells can be also used to treat LTK-positive B cells.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; B-Lymphocytes; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Tyrosine Kinase Inhibitors

Recently, cases of cardiovascular toxicities, such as pericarditis, caused by anaplastic lymphoma kinase (ALK) inhibitors have been reported; however, whether these adverse events are common among all ALK inhibitors remains unclear.. This study aimed to clarify the cardiovascular toxicity profile of ALK inhibitors using an adverse event spontaneous report database.. We analyzed data from VigiBase, the WHO global database of individual safety reports, from its inception in 1968 to December 2021. We calculated the reporting odds ratio to evaluate the association between ALK inhibitors (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib) and 21 cardiovascular adverse events. Time to onset of pericarditis from ALK inhibitor administration was analyzed.. Of the 27,994,584 reports, 19,911 involved treatment with ALK inhibitors. Among the 21 cardiovascular toxicities, only pericarditis signals were detected with all five ALK inhibitors (crizotinib [reporting odds ratios (ROR), 4.7; 95% CI 3.63-6.15], ceritinib [ROR, 12.9; 95% CI 9.37-17.79], alectinib [ROR, 4.8; 95% CI 3.15-7.42], brigatinib [ROR, 3.5; 95% CI 1.33-9.46], and lorlatinib [ROR, 6.4; 95% CI 3.60-11.22]). For torsade de pointes/QT prolongation, signals were detected with crizotinib (ROR, 5.0; 95% CI 3.72-6.77) and ceritinib (ROR, 4.2; 95% CI 2.17-8.05), whereas for hypertension, they were identified only with brigatinib (ROR, 3.9; 95% CI 2.88-5.20), and for heart failure, they were detected with alectinib (ROR, 2.2; 95% CI 1.60-2.90), crizotinib (ROR, 2.1; 95% CI 1.72-2.48), and lorlatinib (ROR, 2.0; 95% CI 1.27-3.23). Regarding time-to-onset analysis from drug administration to adverse event reporting, for pericarditis, it ranged from 52.5 days for alectinib to 166.5 days for crizotinib.. Systematic evaluation of ALK inhibitor-associated adverse events revealed differences in the cardiotoxicity profiles among ALK inhibitors. Understanding the differences in the cardiovascular toxicity profile of each ALK inhibitor will contribute to safe drug therapy when switching between ALK inhibitors.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Pericarditis; Pharmacovigilance; Protein Kinase Inhibitors; World Health Organization

Targeting the Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene is a promising therapeutic strategy for non-small-cell lung cancer (NSCLC) patients. With the advent of the first- and second-generation ALK inhibitors, the mortality rate of lung cancer has shown a downward trend, but almost inevitably, patients will eventually develop resistance, which severely limits the clinical application. Hence, developing new ALK inhibitors which can overcome resistance is essential. Here, we synthesized a novel ALK inhibitor 1-[4-[[5-Chloro-4-[[2-[(1-methylethyl)sulfonyl]phenyl]amino]-2-pyrimidinyl]amino]-3-methoxyphenyl]-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-imidazolidinone (ZYY-B-2) based on the structure of the second-generation ALK inhibitor ceritinib. ZYY-B-2 exhibited impressive anti-proliferative effect in the EML4-ALK positive H2228 cells and ceritinib-resistant H2228 (H2228/Cer) cells. Meanwhile, ZYY-B-2 inhibited the activation of p-ALK in a concentration-dependent manner, and inactivated its downstream target proteins p-AKT and p-ERK to inhibit cell proliferation. Subsequently, we found that ZYY-B-2 blocked H2228 cells and H2228/Cer cells in G0/G1 phase and induced cells to undergo apoptosis through the mitochondrial pathway. The ability of its anti-proliferation and pro-apoptosis was significantly stronger than the second generation ALK inhibitor ceritinib. In addition, high expression of P-gp was found in H2228/Cer cells compared with H2228 cells. ZYY-B-2 could inhibit the expression of P-gp in a dose-dependent manner to overcome ceritinib resistance, and the suppression effect of ZYY-B-2 on P-gp might be related to its inhibition of PI3K/AKT signaling pathway. In summary, ZYY-B-2, a promising ALK inhibitor, shows potent activity against ceritinib-resistant cells, which provides experimental and theoretical basis for the further development of new ALK inhibitors.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Lung Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases

As a second-generation selective oral anaplastic lymphoma kinase inhibitor, ceritinib is an effective first-line treatment for c-ros oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC). Its efficacy and safety for the treatment of crizotinib-resistant ROS1-rearranged NSCLC were explored in the study. A retrospective single-center study was conducted to investigate the efficacy of ceritinib in crizotinib-resistant ROS1-rearranged NSCLC. The objective response rate was the primary objective, while the disease control rate, progression-free survival and adverse events were secondary objectives. From December 2015 to October 2021, a total of 246 patients with ROS1-rearranged NSCLC were screened, 12 (4.9%) of whom were treated with ceritinib after the development of crizotinib resistance. Among the 12 crizotinib-resistant patients included, 3 displayed the efficacy of partial response and 3 had the efficacy of stable condition. The objective response rate, disease control rate and median progression-free survival of all patients were 25% (95% confidence interval [CI]: -3.7% to 53.7%; 3 of 12 patients), 50% (95% CI: 16.8% to 83.2%; 6 of 12 patients), and 10.5 months (95% CI, 5.7 to 15.3 months), respectively. In addition, of the 6 patients with brain metastases, an intracranial disease control rate of 66.7% (95% CI:12.5% to 120.9%) was obtained. The research results reveal that ceritinib can be a treatment option for ROS1-rearranged NSCLC patients after the development of crizotinib resistance.

Topics: Carcinoma, Non-Small-Cell Lung; Crizotinib; Gene Rearrangement; Humans; Lung Neoplasms; Oncogenes; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Retrospective Studies

We conducted a post-marketing surveillance of Zykadia® in patients with ALK-positive unresectable, advanced or recurrent non-small cell lung cancer. There were 573 patients included in the safety analysis, of which 54.62% were female, and their mean age was 59.9 years. Overall, 473 patients(82.55%)experienced side effects, which were mainly diarrhea in 43.46%, nausea in 34.38%, vomiting in 18.67%, and hepatic dysfunction in 16.40%. Side effects led to treatment discontinuation in 24.78%. Among 455 patients included in the efficacy analysis, the response rate was 30.99%. The median progression- free survival was approximately 4 months. The safety and efficacy were similar to those of previous reports, and this study confirmed that there are no problems requiring additional precautions in clinical use of Zykadia®.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Product Surveillance, Postmarketing; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Epidermal growth factor receptor (EGFR) is of great significance in mediating cell signaling transduction and tumor behaviors. Currently, third-generation inhibitors of EGFR, especially osimertinib, are at the clinical frontier for the treatment of EGFR-mutant non-small-cell lung cancer (NSCLC). Regrettably, the rapidly developing drug resistance caused by EGFR mutations and the compensatory mechanism have largely limited their clinical efficacy. Given the synergistic effect between EGFR and other compensatory targets during tumorigenesis and tumor development, EGFR dual-target inhibitors are promising for their reduced risk of drug resistance, higher efficacy, lower dosage, and fewer adverse events than those of single-target inhibitors. Hence, we present the synergistic mechanism underlying the role of EGFR dual-target inhibitors against drug resistance, their structure-activity relationships, and their therapeutic potential. Most importantly, we emphasize the optimal target combinations and design strategies for EGFR dual-target inhibitors and provide some perspectives on new challenges and future directions in this field.

Topics: Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

To better understand genetic determinants of response to ceritinib, an exploratory analysis was conducted using tumor biopsies from anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients treated with ceritinib at doses of ≥ 300 mg in the ASCEND-1 study.. ASCEND-1 was an open-label, multicentre, phase 1, dose-escalation and expansion study of ceritinib (fasted) in ALK inhibitor (ALKi)-naïve or ALKi-pretreated patients with locally advanced or metastatic ALK + NSCLC. Biopsies were assayed by next-generation sequencing (NGS) using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14-Apr-2014). A total of 285 ALK + NSCLC patients were treated with ceritinib at doses ≥ 300 mg.. NGS data were generated for 85 pts (ALKi-pretreated [n = 54]; ALKi-naïve [n = 31]), 57 were collected from patients before exposure to any ALKi. NGS did not detect ALK rearrangement in 14 of 85 patients; several of these ALK NGS negative cases harbored alternative drivers, e.g. EGFR mutation. Of the 71 biopsies with NGS confirmed ALK rearrangement, the most frequently detected rearrangements were EML4-ALK variant 1 (V1) and EML4-ALK V3 (36.6% [26/71] and 32.4% [23/71] respectively). Eight (six crizotinib-pretreated and two pretreated with crizotinib followed by alectinib) of the 21 ALKi-pretreated patients carried a point mutation of the ALK TKD, and had the biopsy collected between 1 and 14 days before ceritinib; with the exception of one patient with a G1202R point mutation, all patients derived clinical benefit from ceritinib treatment. Of the 14 ALKi-naïve patients, ceritinib was effective in almost all patients, including a patient carrying a concomitant ERBB4 and HGF amplification.. This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients.. ClinicalTrials.gov, NCT01283516. Registered January 26, 2011, https://clinicaltrials.gov/ct2/show/NCT01283516.

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

The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene occurs in approximately 5% of non-small-cell lung cancers (NSCLCs). The development of ALK tyrosine kinase inhibitors (ALK-TKIs) is a major advance in treating NSCLC with the ALK fusion gene. Nevertheless, acquired resistance to ALK-TKIs ultimately limits their use. A prevalent mechanism of drug resistance in kinases occurs through the mutation of G1202R in ALK. However, the mechanisms underlying G1202R resistance to ceritinib are not fully understood. Here, we demonstrated that the expression of EML4-ALK G1202R mutation in A549 cells induced an epithelial-mesenchymal transition (EMT) phenotype and significantly increased the migration and invasion abilities. These phenomena may be due to the upregulation of signal transducer and activator of transcription 3 (STAT3), accompanied by the elevated expression of Slug in EML4-ALK G1202R mutant cells. Furthermore, the combination of ALK and STAT3 inhibitors restored the sensitivity of EML4-ALK G1202R mutant cells to ceritinib. In conclusion, these data indicate that the EML4-ALK G1202R mutation mediates the EMT phenotype by activating the STAT3/Slug signaling pathway, resulting in resistance to ceritinib, and that the combination of STAT3 and ALK inhibitors may overcome ALK mutation-driven drug resistance in the clinic.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Humans; Lung Neoplasms; Mutation; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrimidines; Signal Transduction; STAT3 Transcription Factor; Sulfones

Central nervous system metastases are a prominent cause of morbidity and mortality in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with ALK+ NSCLC metastatic to the brain and/or leptomeninges.. Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKi-pretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naïve; arm 4: no radiotherapy/ALKi-naïve). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses.. Per investigator assessment, in arms 1 (n = 42), 2 (n = 40), 3 (n = 12), and 4 (n = 44), respectively: whole-body ORRs [95% confidence interval (CI)] were 35.7% (21.6-52.0), 30.0% (16.6-46.5), 50.0% (21.1-78.9), and 59.1% (43.2-73.7); whole-body DCR (95% CI): 66.7% (50.5-80.4), 82.5% (67.2-92.7), 66.7% (34.9-90.1), and 70.5% (54.8-83.2); intracranial ORRs (95% CI): 39.3% (21.5-59.4), 27.6% (12.7-47.2), 28.6% (3.7-71.0), and 51.5% (33.5-69.2). In arm 5 (n = 18), whole-body ORR was 16.7% (95% CI, 3.6-41.4) and DCR was 66.7% (95% CI, 41.0-86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood-brain barrier.. Ceritinib showed antitumor activity in patients with ALK+ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease. See related commentary by Murciano-Goroff et al., p. 2477.

Topics: Anaplastic Lymphoma Kinase; Brain; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Central Nervous System; Humans; Lung Neoplasms; Neoplasms, Second Primary; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Central nervous system (CNS) metastases constitute a challenge for the design of anaplastic lymphoma kinase (ALK) fusion-positive lung cancer trials. The ASCEND-7 study of ceritinib demonstrates the feasibility of broadening CNS eligibility criteria to include symptomatic brain and leptomeningeal disease and highlights design features that contemporary trials will need to incorporate. See related article by Chow et al., p. 2506.

Topics: Anaplastic Lymphoma Kinase; Brain; Carcinoma, Non-Small-Cell Lung; Central Nervous System; Central Nervous System Neoplasms; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Anaplastic lymphoma kinase (ALK) fusion is a prognostic indicator for patients with non-small cell lung cancer (NSCLC) receiving tyrosine kinase inhibitors (TKIs). The real-world data of ALK TKIs remain a major concern.. Patients with ALK-positive advanced NSCLC, who received crizotinib or alectinib treatment in first line, were retrospectively reviewed. ALK status was detected using immunohistochemistry (IHC) or next-generation sequencing (NGS). Clinical outcomes have been comprehensively analyzed between TKIs, ALK fusions, EML4-ALK variants, and next-generation TKIs after crizotinib failure.. One hundred sixty-eight patients were successively enrolled (crizotinib, n = 109; alctinib, n = 59). Alectinib showed consistent superiority in progressive-free survival (PFS) over crizotinib (hazard ratio [HR]: 0.43, 95% confidential interval [CI]: 0.24-0.77, p = 0.004). Multivariate Cox regression showed chemotherapy (CT) prior to TKIs or synchronous chemotherapy seemed not to improve PFS compared to ALK inhibitors alone (p > 0.05). And, alectinib was superior to crizotinib in prolonging intracranial PFS (HR 0.12, 95% CI: 0.03-0.49, p = 0.003). Patients in EML4 group had a better prognosis than those in non-EML4 group after alectinib administration (HR 0.13, 95% CI: 0.03-0.60, p = 0.009). TP53 co-mutations were relatively common (34.0%) and associated with adverse outcome in ALK-positive patients (adjusted HR 2.22, 95% CI: 1.00-4.92, p = 0.049). After crizotinib failure, 33 patients received a sequential application of next-generation ALK TKIs. Compared to ceritinib and brigatinib, alectinib might have better PFS (p = 0.043).. Our results revealed alectinib had better PFS and higher intracranial efficacy compared to crizotinib in ALK-positive NSCLC, and might improve PFS by comparison with ceritinib and brigatinib after crizotinib failure.

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

The real-world intracranial efficacy data of ceritinib at a dose of 450 mg quaque die (QD) are currently unavailable. Therefore, we evaluated the intracranial efficacy of ceritinib (450 mg QD) in anaplastic lymphoma kinase (ALK)-rearrangement NSCLC patients in China.. In total, 57 ALK-rearrangement NSCLC patients with brain metastases (BM) were enrolled retrospectively in this real-world study. Of these, 53 patients experienced progression at baseline during or after prior crizotinib administration, and 24 patients received prior brain radiotherapy. Patients received ceritinib (450 mg QD) treatment. Intracranial efficacy [objective response rate (ORR) and disease control rate (DCR)] was evaluated according to the Response Assessment in Neuro-Oncology (RANO) standard; progression-free survival (PFS) and adverse events (AEs) data were obtained through follow-ups.. The intracranial ORR and DCR of ceritinib were 73.7% and 93.0%, respectively. The median intracranial PFS in patients reaching the endpoint was 8.75 months, whereas the median intracranial PFS in all patients was not reached and predicted to be not evaluable (NE) (95% CI: 12.9-NE). The estimated 12-month event-free probability (EFP) of intracranial lesions was 68.1%. A subgroup analysis revealed that the estimated 12-month EFP of intracranial lesions was relatively higher in patients with prior brain radiotherapy (93.8% vs. 47.1%, P = 0.0006).. Ceritinib administered at 450 mg QD to ALK-rearrangement NSCLC patients with BM in China exhibited superior ORR and DCR, as well as PFS and event free probability. The estimated 12-month EFP for intracranial lesions improved in patients with prior brain radiotherapy.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Chromosome Aberrations; Humans; Lung Neoplasms; Pyrimidines; Retrospective Studies; Sulfones

Ceritinib is a new anaplastic lymphoma kinase (ALK) inhibitor that has shown greater potency in patients with advanced ALK-rearranged non-small cell lung cancer, including those who had disease progression in crizotinib treatment. Here we reported, after several months of ceritinib treatment, two patients with advanced ALK-rearranged pulmonary adenocarcinoma exhibited a spectrum of respiratory symptoms like cough and dyspnea, with significantly higher inflammatory indicators. Chest computed tomography (CT) showed multiple bilateral and peripheral lesions in lungs. The prior considerations taken into account were disease progression or infection. However, biopsies of the pulmonary nodules revealed features of granulomatous inflammation without definite cancer cells. We documented for the first time that ceritinib might be associated with pulmonary granulomatous inflammation, and clinicians should be alert to the possibility that the rare adverse event emerged during ceritinib treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease Progression; Humans; Inflammation; Lung; Lung Neoplasms; Pneumonia; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Here, we first report a case of neoadjuvant ceritinib for locally advanced lung adenosquamous carcinoma. In this study, a locally advanced adenosquamous carcinoma (ASC) patient with EML4-ALK fusion who achieved a partial response with neoadjuvant ceritinib treatment after a cycle of neoadjuvant chemotherapy did not show significant efficacy. A complete surgical resection was performed with mild adhesions and a small amount of bleeding intraoperatively. The EML4-ALK fusion was detected by targeted next-generation sequencing (NGS) in both pretreatment biopsy and the postoperative tissue specimens with a dramatic decrease in the allele frequency (26.2% [pre]-2.3% [post]). Pathological examination of the postoperative specimens indicated a diagnosis of ASC but the proportions of adenocarcinoma and squamous cell carcinoma cells in the primary lung tumor and metastatic lymph node site were different, suggesting the various responses to ceritinib. Thus, with the case presented here, we provide the clinical evidence for ALK-positive locally advanced ASC patients benefiting from neoadjuvant ceritinib treatment with a tolerable safety profile, whereas further cohort studies of the efficacy and safety of neoadjuvant ceritinib in such patients are needed.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Adenosquamous; Humans; Lung Neoplasms; Neoadjuvant Therapy; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%-5% of patients with non-small cell lung cancer (NSCLC) and confers sensitivity to ALK-tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK-rearranged NSCLC, various additional ALK-TKIs have been developed. Ceritinib is a second-generation ALK-TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib (a first-generation ALK-TKI)-refractory ALK-rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib-resistant, echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive H3122 cells and ceritinib-resistant patient-derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib-resistant patient-derived specimens confirmed that tyrosine-protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counteractivated EGFR and/or Her3 and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be overcome by identifying precise resistance mechanisms.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Receptor, Fibroblast Growth Factor, Type 3

An important mechanism, by which cancer cells achieve immune escape, is the release of extracellular adenosine into their microenvironment. Adenosine activates adenosine A. We pursued a repurposing approach by screening a self-compiled collection of approved, mostly ATP-competitive protein kinase inhibitors, on human CD39. The best hit compound was further characterized and evaluated in various orthogonal assays and enzyme preparations, and on human immune and cancer cells.. The tyrosine kinase inhibitor ceritinib, a potent anticancer drug used for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer, was found to strongly inhibit CD39 showing selectivity versus other ectonucleotidases. The drug displays a non-competitive, allosteric mechanism of CD39 inhibition exhibiting potency in the low micromolar range, which is independent of substrate (ATP) concentration. We could show that ceritinib inhibits ATP dephosphorylation in peripheral blood mononuclear cells in a dose-dependent manner, resulting in a significant increase in ATP concentrations and preventing adenosine formation from ATP. Importantly, ceritinib (1-10 µM) substantially inhibited ATP hydrolysis in triple negative breast cancer and melanoma cells with high native expression of CD39.. CD39 inhibition might contribute to the effects of the powerful anticancer drug ceritinib. Ceritinib is a novel CD39 inhibitor with high metabolic stability and optimized physicochemical properties; according to our knowledge, it is the first brain-permeant CD39 inhibitor. Our discovery will provide the basis (i) to develop more potent and balanced dual CD39/ALK inhibitors, and (ii) to optimize the ceritinib scaffold towards interaction with CD39 to obtain potent and selective drug-like CD39 inhibitors for future in vivo studies.

Topics: Adenosine; Adenosine Triphosphate; Antigens, CD; Antineoplastic Agents; Apyrase; Carcinoma, Non-Small-Cell Lung; Humans; Immunotherapy; Leukocytes, Mononuclear; Lung Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Tumor Microenvironment

Anaplastic lymphoma kinase (ALK) gene fusion, an important driver gene alteration leading to the development of lung cancer, occurs in 5% of nonsmall cell lung cancer (NSCLC) cases in China. In addition to echinoderm microtubule-associated protein-like 4 (EML4)-ALK, which is the most common type of ALK fusion, various fusion partner genes have been identified in recent years. However, ALK intergenic breakpoint fusions confound fusion detection and targeted treatment.. A 40-year-old woman presented to our hospital with a 2-month history of a cough.. Based on the right hilar lymph node biopsy and positron emission tomography computed tomography (PET-CT) examination, the patient was diagnosed with "stage IV lung adenocarcinoma" showing metastases in the mediastina, right hilar lymph nodes, and C7 vertebral body. A rare solute carrier family 8 member A1 (SLC8A1) downstream intergenic region ALK fusion was identified in biopsy specimens using next-generation sequencing (NGS).. The patient received first-line molecular-targeted therapy (ceritinib).. After nearly 9 months, the best evaluation of partial remission (PR) was obtained.. This is the first clinical evidence of advanced NSCLC due to a rare SLC8A1 downstream intergenic region ALK fusion that has been effectively treated with ceritinib. Whether this finding represents an inherent property of this fusion protein or its unique clinicopathological characteristics in patients carrying this fusion protein remains to be investigated. Moreover, the patient's durable response to ceritinib and future resistance mechanisms require further follow-up.

Topics: Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; DNA, Intergenic; Female; Gene Fusion; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Brigatinib is a potent next-generation ALK tyrosine kinase inhibitor approved for treatment-naive and crizotinib-refractory advanced ALK-positive (ALK+) NSCLC. We evaluated brigatinib after other next-generation ALK tyrosine kinase inhibitors.. In this single-arm, phase 2, ALK in Lung Cancer Trial of brigAtinib-2 (NCT03535740), patients with advanced ALK+ NSCLC whose disease progressed on alectinib or ceritinib received brigatinib 180 mg once daily (after 7-d 90-mg lead-in). Primary end point was independent review committee (IRC)-assessed overall response rate (ORR). Circulating tumor DNA (ctDNA) was analyzed.. Among 103 patients (data cutoff: September 30, 2020; median follow-up [range]: 10.8 [0.5-17.7] mo), confirmed IRC-ORR was 26.2% (95% confidence interval [CI]: 18.0-35.8), median duration of response, 6.3 months (95% CI: 5.6-not reached), and median progression-free survival (mPFS), 3.8 months (95% CI: 3.5-5.8). mPFS was 1.9 months (95% CI: 1.8-3.7) in patients with ctDNA-detectable baseline ALK fusion (n = 64). Among 86 patients who progressed on alectinib, IRC-ORR was 29.1% (95% CI: 19.8-39.9); mPFS was 3.8 months (95% CI: 1.9-5.4). Resistance mutations were present in 33.3% (26 of 78) of baseline ctDNA; 54% (14 of 26) of mutations were G1202R; 52% (33 of 64) of patients with detectable ALK fusion had EML4-ALK variant 3. Most common all-grade treatment-related adverse events were increased creatine phosphokinase (32%) and diarrhea (27%). The mean dose intensity of brigatinib (180 mg once daily) was 85.9%.. In ALK in Lung Cancer Trial of brigAtinib-2, brigatinib was found to have a limited activity in patients with ALK+ NSCLC post-ceritinib or post-alectinib therapy. mPFS was longer with brigatinib in patients without baseline detectable plasma ALK fusion.

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

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 real-world treatment and outcomes of patients with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer treated with ALK Tyrosine Kinase Inhibitor (TKI) drugs in Sweden is not well described.. A retrospective population-based cohort study was conducted using Swedish national registers. All patients with a filled prescription for an ALK TKI between January 2012 and October 2020 were included. The sequencing of ALK TKI and duration of treatment (DOT) were described, and overall survival (OS) was estimated using the Kaplan-Meier method. Patients were stratified based on treatment with frontline chemotherapy, presence of CNS metastases prior to the first ALK TKI, and generation of ALK TKI agent.. Among the total of 579 patients, 549 (95%) underwent a therapy sequence in line with current clinical practice with 204 (37%) patients receiving frontline chemotherapy. Single-line ALK TKI was given to 366 patients (crizotinib: 211; alectinib: 146; ceritinib: 9), whereas 128 patients received two different ALK TKI (frontline crizotinib: 100, alectinib: 24, ceritinib: 4); 40 patients received three lines and 15 patients four ALK TKI lines or more. With frontline chemotherapy, the mean (standard deviation) DOT was 1.07 (1.25) years for the entire TKI therapy sequence compared to 1.23 (1.28) years with frontline ALK TKI. The median (95% confidence interval) OS was 1.83 (1.48-2.13) years for the entire cohort, 1.44 (0.89-1.98) years for patients given frontline chemotherapy, and 2.02 (1.60-2.58) years for patients given frontline ALK TKI.. This study provides a unique overview of the patient population treated with ALK TKI in Sweden and reveals the treatment patterns applied in real clinical practice. More research is needed when longer follow-up data are available for later-generation ALK TKI, to fully understand ALK TKI sequencing and its effect on patient survival in a real-world setting.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Crizotinib; Duration of Therapy; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Retrospective Studies; Sweden

Ceritinib is used for the treatment of patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), who are at the risk of developing bone metastasis. During bone metastasis, tumor cells release factors that induce osteoclast formation, resulting in osteolysis. However, the effect of ceritinib on osteoclast formation remains unclear.. Osteoclastogenesis was induced to assess the effect of ceritinib on osteoclast formation and osteoclast-specific gene expression. Western blotting was used to examine the molecular mechanisms underlying the effect of ceritinib on osteoclast differentiation. An. The differentiation of osteoclasts and the expression of osteoclast-specific genes were inhibited upon ceritinib stimulation. Ceritinib suppressed Akt and p65 phosphorylation during the receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis. The administration of ceritinib to ovariectomized mice ameliorated trabecular bone loss by inhibiting osteoclast formation.. Ceritinib is beneficial in preventing bone loss by suppressing osteoclastic Akt and nuclear factor κB (NF-κB) signaling.

Topics: Animals; Bone Diseases, Metabolic; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mice; NF-kappa B; Osteoclasts; Proto-Oncogene Proteins c-akt

As a tumor suppressor in lung cancer, FAT atypical cadherin 4 (FAT4) has a critical role in epithelial-mesenchymal transition (EMT). However, the role of FAT4 in ceritinib-resistant anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) EMT has not been reported. It is necessary to discuss the role of FAT4 in this process and its potential mechanism of interaction. We found that the expression level of FAT4 was downregulated markedly in ceritinib-resistant NCI-H2228 (H2228/Cer) cells. Jujuboside A, a FAT4 activator, diminished EMT and metastasis of H2228/Cer cells. Importantly, autophagy inhibition inverted the inhibitory effect of FAT4 activation on EMT. Furthermore, we found the regulatory action of FAT4 on autophagy was related to proteasome 26S subunit ubiquitin receptor and non-ATPase 4 (PSMD4) and proteasome 20S subunit beta 4 (PSMB4), and the inhibitory effect of autophagy on EMT might be related to ROS/NF-κB/IκB-α and Wnt/β-catenin pathways. In conclusion, FAT4 activation can inhibit the process of EMT in H2228/Cer cells by promoting autophagy, which provides a potential target for ceritinib-resistant ALK positive NSCLC therapy.

Topics: Autophagy; Cadherins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Humans; Lung Neoplasms; Proteasome Endopeptidase Complex; Receptor Protein-Tyrosine Kinases; Tumor Suppressor Proteins

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

Immunogenic cell death (ICD) has initially been discovered in the context of chemotherapy. High-dose crizotinib also stimulates ICD, as we described for non-small cell lung cancer lacking activating chromosomal aberrations of ALK or ROS1, the usual targets of crizotinib, indicating that crizotinib may act through off-target effects. However, we found that low-dose of ALK inhibitors, crizotinib and ceritinib, may stimulate ICD in anaplastic large cell lymphoma, in which ALK is activated due to a chromosomal translocation, suggesting on target ICD-promoting effects.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Immunogenic Cell Death; Lung Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrimidines; Sulfones

Patients with

Topics: Adenocarcinoma of Lung; Adult; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Immune Checkpoint Inhibitors; Lactams; Lung Neoplasms; Male; Mutation; Neoplasm Staging; Nivolumab; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyrimidines; Sulfones; Time Factors; Treatment Outcome; Tumor Microenvironment

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Humans; Lung Neoplasms; Mesothelioma; Protein Kinase Inhibitors; Pyrimidines; Sulfones

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

ALK inhibitors effectively target EML4-ALK positive non-small cell lung cancer, but their effects are hampered by treatment resistance. In the present study, we asked whether ALK inhibition affects autophagy, and whether this may influence treatment response. Whereas the impact of targeted therapies on autophagic activity previously have been assessed by surrogate marker proteins such as LC3B, we here thoroughly examined effects on functional autophagic activity, i.e. on the sequestration and degradation of autophagic cargo, in addition to autophagic markers. Interestingly, the ALK inhibitor Ceritinib decreased mTOR activity and increased GFP-WIPI1 dot formation in H3122 and H2228 EML4-ALK

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Autophagy; Autophagy-Related Protein-1 Homolog; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Class III Phosphatidylinositol 3-Kinases; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Microtubule-Associated Proteins; Oncogene Proteins, Fusion; Pyrimidines; Sulfones

The echinoderm microtubule associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) were fractured and fused to become EML4-ALK. Most of these EML4-ALK-positive non-small cell lung cancer patients respond well to the ALK inhibitor. Many patients can benefit from drug target therapy for a long time, and some patients can achieve long-term survival of more than 7 years under the optimized treatment mode. This patient has lung adenocarcinoma positive for EML4-ALK fusion gene, but the treatment outcome is obviously different from that of other patients with lung cancer positive for EML4-ALK fusion gene. After the first to third generations of ALK inhibitor targeted therapy and chemotherapy, the disease progresses rapidly, the drug resistance time is short, the survival time is short, and the benefit is limited. The patient received targeted therapy of Crizotinib, Ceritinib and Lorlatinib successively from July 15, 2019, followed by two chemotherapy courses of Bevacizumab combined with Pemetrexed and Carboplatin. The patient died on September 10, 2020, with a survival of 15 months. At the same time, the treatment showed common adverse reactions of ALK inhibitors. This paper analyzed the therapeutic effect and treatment dilemma of this patient, and provided an exploration direction for the treatment of patients with EML4-ALK fusion gene positive lung cancer.
.. 【中文题目：经3种ALK抑制剂及化疗治疗的
1例非小细胞肺癌病例报道】 【中文摘要：棘皮动物微管相关蛋白4（echinoderm microlubule-associated protein-like 4, EML4）和间变淋巴瘤激酶基因（anaplastic lymphoma kinase, ALK）可发生断裂后融合为EML4-ALK基因。对于EML4-ALK阳性非小细胞肺癌（non-small cell lung cancer, NSCLC），一代至三代的ALK抑制剂的使用已显示出显著疗效，很多患者可以从药物治疗中实现长期获益，部分患者在优化的治疗模式下可取得超过7年的长期生存。本例患者为EML4-ALK融合基因阳性肺腺癌，治疗结局却明显不同于其他EML4-ALK融合基因阳性肺癌患者，经过一代至三代ALK抑制剂靶向治疗和化学治疗疾病进展快，耐药时间短，生存期短，获益有限。患者2019年7月15日开始先后口服克唑替尼、色瑞替尼、劳拉替尼靶向治疗，行贝伐珠单抗联合培美曲塞、卡铂化疗2个疗程，于2020年9月10日患者死亡，生存期15个月。同时治疗中表现出ALK抑制剂的常见不良反应。本文分析本例患者的治疗疗效及治疗困境，为EML4-ALK融合基因阳性肺癌患者治疗提供探索方向。
】 【中文关键词：EML4-ALK融合基因；AIK抑制剂；肺肿瘤】.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Crizotinib; Female; Humans; Lactams; Lung Neoplasms; Microtubule-Associated Proteins; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Serine Endopeptidases; Sulfones

The treatment of stage IIIB non-small cell lung cancer (NSCLC) is complicated, the best strategy is chosen individually and surgery is usually not recommended. A 50-year-old female was diagnosed with locally advanced lung adenocarcinoma (stage IIIB, T2bN3M0). Fluorescence in situ hybridization (FISH) analysis revealed an ALK rearrangement. Crizotinib was administered and progression was seen after five months. The patient then received ceritinib with a palliative intent, which led to downstaging (IIIA[N2]) with a radiological and metabolic response. Right lower lobe lobectomy was performed at 12 months post-surgery, and the patient is still disease-free according to the last computed tomography (CT) scan. The unintended downstaging from ceritinib provided a chance for resection in our patient who had ALK-positive stage IIIB NSCLC after the failure of first-line crizotinib, indicating potential usage of ceritinib in the neoadjuvant setting. Future perspective trials are warranted to investigate the role of ceritinib in earlier stages as a primary drug.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Middle Aged; Neoadjuvant Therapy; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sulfones

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

Anaplastic lymphoma kinase (ALK) inhibitors have been approved for patients with ALK-rearrangement lung cancer. The effect is superior to the standard first-line therapy of pemetrexed plus platinum-based chemotherapy. However, ALK inhibitors are associated with rare and sometimes fatal adverse events. Organizing pneumonitis (OP) is a rare and serious adverse event usually caused by ceritinib, and it is easily misdiagnosed as infectious pneumonia, metastasis, or cancer progression.. A 56-year-old female presented with chest tightness and dyspnea for more than 10 days. She was previously healthy with no significant medical history. Workup including chest computed tomography (CT), pathological examination of a biopsy specimen, and next-generation sequencing was consistent with a diagnosis of IVA ALK-rearrangement lung adenocarcinoma. She was treated with pemetrexed plus platinum-based chemotherapy and crizotinib concurrently, followed by maintenance therapy with crizotinib alone and she had an almost complete response. However, about 26 months after beginning treatment she developed multiple brain metastases. Crizotinib was discontinued and she was begun on ceritinib. After about 3 months the brain metastases had almost complete response. After 5 months of ceritinib, however, multiple patchy lesions appeared in the bilateral upper lungs.. Treatment with antibiotics had no effect and blood and sputum cultures are negative. A CT-guided biopsy of the upper lung was performed, and pathological hematoxylin-eosin staining and immunohistochemical studies were consistent with OP.. Ceritinib was discontinued, she was begun on prednisone 0.5 mg/kg orally every day, and regular follow-up is necessary.. CT of the chest 2 and 4 weeks after beginning prednisone showed the lung lesions to be gradually resolving, and she was continued on prednisone for 2 months and gradually reduced the dose of prednisone every 2 weeks. No related adverse events were occurred in patient.. OP must be differentiated from infectious pneumonia, metastasis, or cancer progression. The mechanism of OP is still unknown and needs further research. Biopsy plays a role in making a diagnosis of OP. In our patient, discontinuing ceritinib and treating her with prednisone resulted in a good outcome.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biopsy; Brain Neoplasms; Crizotinib; Cryptogenic Organizing Pneumonia; Drug Substitution; Enzyme Inhibitors; Female; High-Throughput Nucleotide Sequencing; Humans; Lung; Lung Neoplasms; Middle Aged; Pemetrexed; Prednisone; Pyrimidines; Sulfones; Tomography, X-Ray Computed; Treatment Outcome

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

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

A 40-year-old Japanese man with advanced pulmonary adenocarcinoma harboring anaplastic lymphoma kinase (ALK)-rearranged was administered the selective ALK inhibitor ceritinib as a third-line treatment and continued treatment for nine months. After fourth-line treatment, we performed rechallenge with ceritinib as a fifth-line treatment. On day 54 after rechallenge, the patient developed acutely deteriorating dyspnea. Chest computed tomography showed extensive ground-glass opacities. We diagnosed him with ceritinib-induced interstitial lung disease (ILD) and initiated methylprednisolone pulse therapy. To our knowledge, this is the first report of ceritinib-induced ILD in a Japanese patient. Since it may newly emerge with rechallenge therapy, close attention is necessary.

Topics: Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Tomography, X-Ray Computed

Genetic rearrangements of anaplastic lymphoma kinase contribute to the pathogenesis of non-small-cell lung cancer; the anaplastic lymphoma kinase inhibitor, ceritinib, is widely used, as it is effective even in patients with non-small-cell lung cancer resistant to other anaplastic lymphoma kinase inhibitors. Although a case of possible ceritinib-induced hyperglycemia was reported, the association of ceritinib with hyperglycemia remains to be investigated. Disproportionality analysis was carried out using the Japanese Adverse Drug Event Report database, which contains all pharmacovigilance data based on spontaneous reports of adverse events between April 2004 and November 2018 to the Pharmaceuticals and Medical Devices Agency. The reporting odds ratio of ceritinib for hyperglycemia was 2.25 (95% confidence interval [CI] 1.24-4.08], whereas those of crizotinib and alectinib were 0.07 (95% CI 0.01-0.40) and 0.94 (95% CI 0.30-2.94), respectively. Among reported events without antidiabetes agent use, the reporting odds ratio of ceritinib was still 2.54 (95% CI 1.27-5.12). Thus, the possibility of hyperglycemia should be carefully monitored in patients receiving ceritinib.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Databases, Factual; Female; Humans; Hyperglycemia; Japan; Lung Neoplasms; Male; Odds Ratio; Protein Kinase Inhibitors; Pyrimidines; Sulfones

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

Targeted therapies are a standard of care for first-line treatment of Anaplastic lymphoma kinase (ALK)-rearranged non small cell lung cancer (NSCLC). Giving the rapid pace of drug discovery and development in this area, reporting of adverse effects of ALK inhibitors is crucial. Here, we report a case of osteitis induced by an ALK inhibitor mimicking bone metastasis, a previously undescribed side effect of crizotinib.. A 31-year-old woman with stage IV ALK-rearranged NSCLC presented with back pain after 3 months of crizotinib treatment. Diagnostic work-up showed osteitis on the 4th and 5th thoracic vertebrae, anterior soft tissue infiltration and epiduritis, without any sign of infection. Spinal cord decompression, histological removal and osteosynthesis were performed. Histologic examination showed necrosis with abundant peripheral neutrophils, no microorganism nor malignant cell. Symptoms and Computarized Tomography-abnormalities rapidly diseappeared after crizotinib withdrawal and did not recur after ceritinib onset.. This is the first report of crizotinib-induced osteitis. Crizotinib differs from other ALK inhibitors as it targets other kinases as well, which may have been responsible for the osteitis. Crizotinib can induce rapidly extensive osteitis, which can mimic tumor progression.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Bone Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Osteitis; Protein Kinase Inhibitors; Pyrimidines; Sulfones; Tomography, X-Ray Computed

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 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: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Nivolumab; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor for mainly treating non-small cell lung cancer (NSCLC). This investigation focused on to clarify in detail the binding behavior between human α-1 acid glycoprotein (HAG) and ceritinib by means of multi-spectroscopic and molecular modeling approaches. Fluorescence data obtained at four different temperatures indicated ceritinib quenched the endogenous fluorescence of HAG by a static quenching mechanism. Based on the K

Topics: Antineoplastic Agents; Binding Sites; Carcinoma, Non-Small-Cell Lung; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Lung Neoplasms; Molecular Dynamics Simulation; Orosomucoid; Protein Binding; Protein Conformation; Pyrimidines; Sulfones; Thermodynamics

Topics: Algorithms; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Both ceritinib (CER) and programmed cell death (PD)-1/PD ligand-1 (PD-L1) have brought significant breakthroughs for anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). However, the overall clinical efficacy of either CER or PD-1/PD-L1 inhibitor monotherapy has been limited to a large extent. In addition, the antitumor effect of combined CER and PD-L1 inhibitor in ALK-rearranged NSCLC is not fully understood. In H2228 cells, we examined the tumor killing effect of CER plus PD-L1 inhibitor in vitro by quantitative RT-PCR, flow cytometry, ELISA, western blot analysis, PBMC coculture system, and plasmid and transfection experiments. A Ba/F3 (EML4-ALK-WT) xenograft mouse model was also utilized to further evaluate the synergistic anticancer effects of CER and PD-L1 inhibitor in vivo. The coculture system of PBMCs with H2228 cells promotes the expression of PD-L1 and phospho-ERK, and combined treatments facilitate lymphocyte proliferation and activation, inhibit PD-L1 expression, and enhance lymphocyte cytotoxicity and cell death. In the in vivo NSCLC xenograft model, the volumes of tumors treated with CER and PD-L1 inhibitor in combination were significantly smaller than those treated with CER or PD-L1 alone. The relative tumor growth inhibitions were 84.9%, 20.0%, and 91.9% for CER, PD-L1 inhibitor, and CER plus PD-L1 groups, respectively. Ceritinib could synergize with PD-1/PD-L1 blockade to yield enhanced antitumor responses along with favorable tolerability of adverse effects. Ceritinib and PD-L1 inhibitor combined produced a synergistic antineoplastic efficacy in vitro and in vivo, which provides a key insight and proof of principle for evaluating CER plus PD-L1 blockade as combination therapy in clinical therapeutic practice.

Topics: Anaplastic Lymphoma Kinase; Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Synergism; Humans; Lung Neoplasms; Mice; Pyrimidines; Sulfones; 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

Ceritinib is a selective second-generation ALK inhibitor that is highly sensitive to echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) molecule.. In this paper, we report a 68-year-old female that was diagnosed with stage 4 ALK-positive non-small cell lung cancer (NSCLC).. Cases achieving complete response with ceritinib treatment are rare. In this paper, we aimed to emphasize the complete response in stage 4 NSCLC in an elderly patient.

Topics: Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Sulfones

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

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

Ceritinib is a potent selective ALK inhibitor with a manageable safety profile. In anecdotal reports, ceritinib was associated with organizing pneumonia (OP), which could be confused with disease progression.. We aimed to delineate the characteristics of OP that occurs during treatment with ceritinib, and evaluate its clinical implications.. We retrospectively analyzed 44 lung cancer patients whose tumors harbored ALK or ROS1 fusions and who had received ceritinib. OP diagnosis was based on radiographic and clinical features. Four OP cases were pathologically confirmed.. Among 44 patients, 22 OP events occurred in 16 (36.4%) patients. The median time to the first event was 17.2 weeks (range 6.7-68.7 weeks). All events were grade 1 or 2. Radiographic features were categorized into four patterns: nodular (54.6%), consolidation (27.3%), parenchymal band (4.5%), and ground-glass opacity (GGO) (13.6%). OP improved in 20 events with drug interruption or corticosteroids. The median duration of OP was 11.3 weeks (range 2-24 weeks). Tumor response rate was 75% in OP-positive and 42.9% in OP-negative groups. The median progression-free survival was 16.7 months [95% confidence interval (CI) 10.1-not applicable (NA)] in OP-positive and 5.4 months (95% CI 3.6-8.4) in OP-negative patients (P = 0.004). The median overall survival was 46.2 months (95% CI 38.1-NA) in OP-positive and 10.5 months (95% CI 6.2-18.9) in OP-negative patients (P < 0.001).. OP occurs frequently during ceritinib treatment and must be distinguished from disease progression. OP could be reversible without fatal complications and its occurrence is associated with better survival outcomes.

Topics: Female; Humans; Lung Neoplasms; Male; Pneumonia; Pyrimidines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Sulfones

Anaplastic lymphoma kinase (ALK) rearrangement is a common driver gene of non-small cell lung cancer (NSCLC). Ceritinib is a second-generation ALK inhibitor, which can bring survival benefits to ALK-positive metastatic NSCLC. However, few studies focus on the safety and efficacy of ceritinib in China. Therefore, this study intends to investigate the safety and preliminary efficacy of ceritinib 450 mg with meals in Chinese patients with ALK-positive NSCLC through a real world study.. From October 2018 to December 2019, patients with ALK-positive NSCLC from 8 medical centers in Sichuan province were recruited in this study. All of these participants received ceritinib 450 mg/d with food. The basic characteristics, adverse effects (AEs) and responses were collected and analyzed in order to evaluate the safety and efficacy of ceritinib.. A total of 109 patients were included in this study. Data cutoff was January 23, 2020. The median duration of treatment exposure was 5.87 mon (range: 0.4 mon-15.7 mon). Total AEs were reported in 98 (89.9%) of 109 patients and grade 3 or 4 AEs were reported in 22.9% of patients. Most common AEs (mainly grade 1 or 2) were diarrhea (60.6%), elevated alanine aminotransferase (ALT)(38.5%) and aspartate aminotransferase (AST)(37.6%). As of data cutoff, 45 patients discontinued ceritinib. The overall response rate (ORR) was 37.6% (95%CI: 28.5%-47.4%) and disease control rate (DCR) was 86.2% (95%CI: 78.3%-92.1%).. The treatment of ceritinib 450 mg with food for Chinese ALK-positive NSCLC patients had a good safety profile and favorable DCR in real-world setting. However, this conclusion needs to be further verified by large sample, prospective trials.. 【中文题目：塞瑞替尼450 mg随餐服用治疗中国ALK阳性非小细胞肺癌患者的安全性及近期疗效分析】 【中文摘要：背景与目的 间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）染色体易位为非小细胞肺癌（non-small cell lung cancer, NSCLC）常见的驱动基因。塞瑞替尼为第二代的ALK抑制剂，可为ALK阳性转移性NSCLC患者带来生存获益，但国内尚无塞瑞替尼用药安全性及疗效的研究报道。因此本研究拟通过真实世界研究来探讨塞瑞替尼450 mg随餐服用治疗中国ALK阳性NSCLC患者的安全性及近期疗效。方法 回顾性分析2018年10月-2019年12月期间就诊于四川省8家医疗机构口服塞瑞替尼450 mg/d随餐治疗的ALK阳性NSCLC患者，收集患者基本信息、治疗期间不良事件（adverse effects, AEs）及疗效数据等资料，评价其安全性及初步疗效。结果 研究共纳入109例患者，随访至2020年1月23日，中位服药时间为5.87个月（范围：0.4个月-15.7个月），总体不良事件发生率为89.9%，3级-4级不良事件发生率为22.9%。最常见AEs（主要为1级-2级）为腹泻（60.6%）、丙氨酸氨基转移酶（alanine aminotransferase, ALT）升高（38.5%）及门冬氨酸氨基转移酶（aspartate aminotransferase, AST）升高（37.6%）。至随访截止，共45例患者停药，总体客观缓解率（objective response rate, ORR）为37.6%（95%CI: 28.5%-47.4%），疾病控制率（disease control rate, DCR）为 86.2%（95%CI: 78.3%-92.1%）。结论 真实世界中，塞瑞替尼450 mg随餐服用的给药方式在中国ALK阳性NSCLC患者中具有良好的安全性及疾病控制率，但需要更大样本量的前瞻性研究来进一步验证。】 【中文关键词：塞瑞替尼；间变性淋巴瘤激酶；肺肿瘤；安全性；疗效】.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sulfones

The ALK gene (anaplastic lymphoma kinase) encodes a highly conserved tyrosine kinase receptor whose physiological function has not yet been fully established; in particular the fusion of ALK (mainly EML4-ALK) is the gene alteration that most frequently involves 3-7% of all non-small cell lung cancers. Neuroblastoma in adults (NB) is a rare tumor that can present somatic activating mutations in the ALK gene in 8-9% of patients (and up to 14% of high-risk NBs); these mutations occur in the tyrosine kinase domain in three key positions (F1174, F1245 and R1275), which account for approximately 85% of all ALK mutations in NB. In this article, we report the case of an adult patient with advanced mutation-positive NB treated with an ALK inhibitor ceritinib showing a therapeutic opportunity due to the molecular diagnostic techniques now available.

Topics: Adult; Humans; Lung Neoplasms; Mutation; Neuroblastoma; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for development of various tumor types. In this study, we synthesized a series of novel 2,4-diarylaminopyrimidine derivatives possessing a unique N-(3-pyridinylmethyl)urea moiety as ALK inhibitors. The most promising analog 5m bearing a 3-methoxy-4-morpholinophenyl substituent significantly inhibited proliferation of ALK positive H3122 and Karpas-299 cells with IC

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Drug Stability; Female; Fibroblasts; Humans; Lung Neoplasms; Mice, Inbred BALB C; Microsomes, Liver; Molecular Docking Simulation; Molecular Structure; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Structure-Activity Relationship; Xenograft Model Antitumor Assays

A trial-based assessment was completed to evaluate the cost-effectiveness of ceritinib as a first-line treatment for advanced non-small cell lung cancer (NSCLC) with rearrangement of anaplastic lymphoma kinase.. Based on the disease situation of advanced NSCLC, a Markov model was constructed to estimate the costs and benefits of ceritinib and platinum-based chemotherapy. The cost information and health utilities were obtained from published literature. The incremental cost-effectiveness ratio was calculated. The stability of the model was verified by sensitivity analyses.. The base case analysis results indicated that compared with platinum-based chemotherapy, ceritinib therapy would increase benefits in a 5-, 10- and 15-year time horizon, with extra costs of $230,661.61, $149,321.52 and $136,414.43 per quality-adjusted life-year gained, respectively. The most sensitive parameter in the model analysis was the cost of ceritinib. Probabilistic sensitivity analysis suggested that at the current price of ceritinib, the chance of ceritinib being cost-effective was 0 at the willingness-to-pay threshold of $27,142.85 per quality-adjusted life-year (three times the per capita gross domestic product of China).. As a first-line treatment for advanced NSCLC with rearrangement of anaplastic lymphoma kinase, ceritinib is unlikely to be cost-effective at the current price from the Chinese healthcare perspective. To meet the treatment demands of patients, it may be a better option to reduce the price or provide appropriate drug assistance policies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; China; Cost-Benefit Analysis; Disease-Free Survival; Humans; Lung Neoplasms; Models, Economic; Platinum; Pyrimidines; Quality-Adjusted Life Years; Sulfones

Approximately 3%-5% of lung adenocarcinoma is driven by anaplastic lymphoma kinase (ALK) fusion oncogene, whose activity can be suppressed by multiple ALK inhibitors. Crizotinib and ceritinib have demonstrated superior efficacy to platinum-based chemotherapy as front-line treatment for patients with ALK-positive advanced non-small cell lung cancer (NSCLC). However, the direct comparison between them in the front-line setting remains lacking.. A total of 48 patients with ALK-positive, previously untreated advanced NSCLC, who received crizotinib and ceritinib as front-line treatment were retrospectively investigated. The efficacy and pattern of disease progression were analyzed.. Patients receiving ceritinib treatment were significantly younger than those receiving crizotinib treatment (52.0 vs. 63.0, P = 0.016). The median progression-free survival (PFS) was significantly longer with ceritinib than with crizotinib treatment (32.3 vs. 12.9 months; log-rank P = 0.020); the hazard ratio for disease progression or death, 0.27 (95% CI, 0.08-0.90; P = 0.033). An objective response was noted in all patients in the ceritinib group and in 23 patients in the crizotinib group (74.2%; 95% CI, 59.0 to 88.5). The rate of systemic progression was significantly lower over time with ceritinib treatment compared to crizotinib treatment (cause-specific hazard ratio, 0.21; 95% CI 0.06-0.73; P = 0.014). Serious adverse events were noted in one (2.9%) patient showing elevated liver function in the crizotinib group and three (23.1%) patients showing diarrhea in the ceritinib group. Dose reduction was needed in five out of 13 (38.5%) patients receiving ceritinib treatment.. Ceritinib showed higher efficacy associated with a better control of systemic progression compared to crizotinib for the front-line treatment of ALK-positive advanced NSCLCs.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Oncogene Proteins, Fusion; Prognosis; Pyrimidines; Sulfones

Topics: Aged; Anilides; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyridines; Pyrimidines; Retreatment; Sulfones

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

We herein report a 75-year-old woman with insulin-treated diabetes and metastatic anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who received ceritinib, a second-generation ALK inhibitor, and achieved dramatic tumor reduction. However, her fasting blood glucose increased, particularly markedly in the first two weeks after ceritinib administration, and did not normalize even increasing the total insulin dose. After discontinuing ceritinib, her glucose levels rapidly reduced. Ceritinib can aggravate hyperglycemia in patients with diabetes who lack compensatory insulin secretion, due to its inhibitory effects on the insulin receptor. Careful monitoring for ceritinib-induced hyperglycemia should be performed, especially in the first two weeks after ceritinib administration.

Topics: Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers; Biomarkers, Tumor; Blood Glucose; Carcinoma, Non-Small-Cell Lung; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulins; Lung Neoplasms; Neoplasm Metastasis; Pyrimidines; Sulfones

Alectinib has shown a greater efficacy to ALK-rearranged non-small-cell lung cancers in first-line setting; however, most patients relapse due to acquired resistance, such as secondary mutations in ALK including I1171N and G1202R. Although ceritinib or lorlatinib was shown to be effective to these resistant mutants, further resistance often emerges due to ALK-compound mutations in relapse patients following the use of ceritinib or lorlatinib. However, the drug for overcoming resistance has not been established yet.. We established lorlatinib-resistant cells harboring ALK-I1171N or -G1202R compound mutations by performing ENU mutagenesis screening or using an in vivo mouse model. We performed drug screening to overcome the lorlatinib-resistant ALK-compound mutations. To evaluate these resistances in silico, we developed a modified computational molecular dynamic simulation (MP-CAFEE).. We discovered lorlatinib-resistant multiple ALK-compound mutations and an L1256F single mutation as well as the potential therapeutic strategies for these ALK mutations. Our original computational simulation to calculate the binding affinity may be applicable for predicting resistant mutations and for overcoming drug resistance in silico. FUND: This work was mainly supported by MEXT/JSPS KAKENHI Grants and AMED Grants.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Dynamics Simulation; Mutation, Missense; Protein Binding; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Software; Sulfones

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: Aged; Humans; Lung Neoplasms; Male; Mutation; Organophosphorus Compounds; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Meningeal Neoplasms; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Spinal Cord Neoplasms; Sulfones; Treatment Outcome

Tyrosine kinase inhibitors are now major actors for the treatment of non-small-cell metastatic lung cancers where ROS 1 gene rearrangement is present. Because of the rapid development of these new therapies, developing information about their monitoring and knowledge about their potential toxicities is essential. We describe the case of a patient who was treated with ceritinib as a third line approach for a metastatic lung adenocarcinoma with ROS1 rearrangement. After two months, the patient developed acute respiratory distress with pericarditis and pleurisy. A hypersensitivity reaction was suggested and supported by favorable clinical and radiological outcomes within three days following ceritinib discontinuation and systemic corticosteroid introduction. Pleural effusion, pericarditis and diffuse pulmonary infiltration associated to ceritinib have not often been described previously. Despite few data of pulmonary toxicity related to ceritinib, the current observation highlights the need for caution and regular monitoring when using these inhibitors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Drug Hypersensitivity; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Neoplasm Metastasis; Pericarditis; Pleural Effusion; Pyrimidines; Respiratory Distress Syndrome; Sulfones

The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein-797 to serine-790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current irreversible EGFR TKIs. In this Miniperspective, we present key mechanisms of resistance in response to third-generation EGFR TKIs, and emerging reports on novel EGFR TKIs to combat the resistance. Specifically, we analyze the allosteric and ATP-competitive inhibitors in terms of drug discovery, binding mechanism, and their potency and selectivity against EGFR harboring C797S mutations. Lastly, we provide some perspectives on new challenges and future directions in this field.

Topics: Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitors

Anaplastic lymphoma kinase (ALK) activation has been associated with many types of human cancer. Significant efforts have been devoted to the development of ALK inhibitors to antagonize the kinase activity of ALK. Four ALK inhibitors have been approved by the FDA to date for treating patients with ALK-positive non-small cell lung cancers (NSCLC). However, drug resistance has been observed in the majority of patients treated with these inhibitors. New therapeutic strategies (e.g., compounds with novel mechanisms of action) are needed to overcome the drug resistance issue. The emerging PROTAC (Proteolysis Targeting Chimera) technology has been successfully applied to selective degradation of multiple protein targets, but not ALK. Since ALK protein levels are not important for viability in mammals, ALK PROTACs could lead to novel therapeutics with minimal toxicity. Here we report the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. MS4077 (5) and MS4078 (6) potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds 5 and 6 was cereblon and proteasome dependent. In addition, compounds 5 and 6 potently inhibited proliferation of SU-DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. We also developed MS4748 (7) and MS4740 (8), very close analogs of 5 and 6 respectively, which are incapable to degrade the ALK fusion proteins, as negative controls. Compounds 5-8 are valuable chemical tools for investigating effects of ALK pharmacological degradation. Our study paved the way for developing the next generation of ALK PROTACs.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Humans; Lung Neoplasms; Lymphoma; Male; Mice; Protein Kinase Inhibitors; Proteolysis; Receptor Protein-Tyrosine Kinases; Signal Transduction

We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1).

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Proteolysis; Pyrimidines; Sulfones

ALK, RET and ROS1 fusions have been identified as treatable targets in 5%-15% of non-small-cell lung cancers, and thanks to the advanced sequencing technologies, their new partner genes have been steadily detected. Here we identified a rare fusion of ALK (GCC2-ALK) in a patient with advanced lung adenocarcinoma and monitored the treatment efficacy of ALK inhibitors on this patient. We further performed in vitro functional studies of this fusion protein for evaluating its oncogenic potential.. The GCC2-ALK fusion gene was identified by targeted next generation sequencing (NGS) from the tumor DNA samples, and its fusion product was confirmed by Sanger sequencing the cDNA product. The functional study of GCC2-ALK was performed in Ba/F3 cells with cell proliferation and viability assays. The activation of downstream signaling pathways of ALK and their responses to crizotinib inhibition were studied in HEK-293 and 293T cells with ectopic expression of GCC2-ALK. In parallel, disease progression in the patient was monitored by computed tomography scanning and targeted NGS of either liquid or tissue biopsy samples throughout and after crizotinib treatment.. Similarly to EML4-ALK, the GCC2-ALK fusion protein promotes IL-3-independent growth of Ba/F3 cells. Ectopic expression of GCC2-ALK leads to hyper-activation of ALK downstream signaling that can be inhibited by crizotinib. Crizotinib treatment of the patient resulted in 18 months of progression free survival without any trace of GCC2-ALK fusion in the liquid biopsies. Re-biopsy of a lung lesion at progression identified the re-occurrence of GCC2-ALK. The patient was then administrated with a second-generation ALK inhibitor, ceritinib, and received partial response until the last follow-up.. We identified and functionally validated GCC2-ALK as a constitutively activated fusion in NSCLC. The patient was benefited from crizotinib treatment initially and then ceritinib after progression, suggesting GCC2-ALK as a novel therapeutic target for ALK inhibitors.

Topics: Adenocarcinoma; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Cell Line, Tumor; Crizotinib; Female; Golgi Matrix Proteins; HEK293 Cells; Humans; Lung Neoplasms; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrimidines; Sulfones

In lung adenocarcinoma, canonical EML4-ALK inversion results in a fusion protein with a constitutively active ALK kinase domain. Evidence of ALK rearrangement occurs in a minority (2-7%) of lung adenocarcinoma, and only ~60% of these patients will respond to targeted ALK inhibition by drugs such as crizotinib and ceritinib. Clinically, targeted anti-ALK therapy is often initiated based on evidence of an ALK genomic rearrangement detected by fluorescence in situ hybridization (FISH) of interphase cells in formalin-fixed, paraffin-embedded tissue sections. At the genomic level, however, ALK rearrangements are heterogeneous, with multiple potential breakpoints in EML4, and alternate fusion partners. Using next-generation sequencing of DNA and RNA together with ALK immunohistochemistry, we comprehensively characterized genomic breakpoints in 33 FISH-positive lung adenocarcinomas. Of these 33 cases, 29 (88%) had detectable DNA level ALK rearrangements involving EML4, KIF5B, or non-canonical partners including ASXL2, ATP6V1B1, PRKAR1A, and SPDYA. A subset of 12 cases had material available for RNA-Seq. Of these, eight of eight (100%) cases with DNA rearrangements showed ALK fusion transcripts from RNA-Seq; three of four cases (75%) without detectable DNA rearrangements were similarly negative by RNA-Seq, and one case was positive by RNA-Seq but negative by DNA next-generation sequencing. By immunohistochemistry, 17 of 19 (89%) tested cases were clearly positive for ALK protein expression; the remaining cases had no detectable DNA level rearrangement or had a non-canonical rearrangement not predicted to form a fusion protein. Survival analysis of patients treated with targeted ALK inhibitors demonstrates a significant difference in mean survival between patients with next-generation sequencing confirmed EML4-ALK rearrangements, and those without (20.6 months vs 5.4 months, P<0.01). Together, these data demonstrate abundant genomic heterogeneity among ALK-rearranged lung adenocarcinoma, which may account for differences in treatment response with targeted ALK inhibitors.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Chromosome Breakpoints; Crizotinib; Female; Gene Rearrangement; High-Throughput Nucleotide Sequencing; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrimidines; Sulfones; Survival Analysis

To assess the cost-effectiveness of first-line ceritinib vs crizotinib and platinum doublet chemotherapy for anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) from a US third-party payer's perspective.. A partitioned survival model with three health states (stable disease, progressive disease, death) was developed over a 20-year time horizon. Ceritinib's efficacy inputs (progression-free and overall survival) were estimated from ASCEND-4; parametric survival models extrapolated data beyond the trial period. The relative efficacy of ceritinib vs chemotherapy was obtained from ASCEND-4, the relative efficacy of ceritinib vs crizotinib was estimated using a matching-adjusted indirect comparison based on ASCEND-4 and PROFILE 1014. Drug acquisition, treatment administration, adverse event management, and medical costs were obtained from publicly available databases and the literature, and inflated to 2016 US dollars. Treatment-specific stable-state utilities were derived from trials and progressive-state utility from the literature. Incremental costs per quality-adjusted life year (QALY) were estimated for ceritinib vs each comparator. Cost-effectiveness was assessed based on US willingness-to-pay thresholds. Deterministic and probabilistic sensitivity analyses were performed to test model robustness.. In the base case, first-line ceritinib was associated with total direct costs of $299,777 and 3.28 QALYs (from 4.61 life years gained [LYG]) over 20 years. First-line crizotinib and chemotherapy were associated with 2.73 and 2.41 QALYs, 3.92 and 3.53 LYG, and $263,172 and $228,184 total direct costs, respectively. The incremental cost per QALY gained was $66,064 for ceritinib vs crizotinib and $81,645 for ceritinib vs chemotherapy. In the first 2 years following treatment initiation, ceritinib dominated crizotinib by conferring greater health benefits at reduced total costs. Results were robust to deterministic and probabilistic sensitivity analyses.. In the absence of head-to-head trials, an indirect comparison method was used.. Ceritinib is cost-effective compared to crizotinib and chemotherapy in the treatment of previously untreated ALK-positive metastatic NCSLC in the US.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cost of Illness; Cost-Benefit Analysis; Crizotinib; Disease-Free Survival; Humans; Lung Neoplasms; Models, Econometric; Pyrazoles; Pyridines; Pyrimidines; Quality-Adjusted Life Years; Receptor Protein-Tyrosine Kinases; Sulfones; Survival Analysis; United States

The advent of anaplastic lymphoma kinase(ALK)inhibitors has revolutionized treatment of ALK fusion gene-positive nonsmall cell lung cancer(NSCLC). Nevertheless, it has become clear that cases refractory and resistant to ALK inhibitors occur at a certain incidence, and how to treat such cases is a current issue. Following crizotinib and alectinib, ceritinib(Zykadia® capsules)is the third ALK inhibitor approved in Japan, and it is expected to be useful for patients who have developed crizotinib resistance. However, ceritinib has been pointed out to have a high incidence of gastrointestinal adverse events that impact patients' quality of life. Accordingly, in this paper, we report the clinical results and incidence of gastrointestinal adverse reactions with ceritinib in treatment of ALK-positive NSCLC patients. We also present management methods of the adverse events.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited. Herein, we deployed a shRNA screen of 1,000 genes in multiple ALK-inhibitor-resistant patient-derived cells (PDCs) to discover those that confer sensitivity to ALK inhibition. This approach identified SHP2, a nonreceptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. Treatment with SHP099, the recently discovered small-molecule inhibitor of SHP2, in combination with the ALK tyrosine kinase inhibitor (TKI) ceritinib halted the growth of resistant PDCs through preventing compensatory RAS and ERK1 and ERK2 (ERK1/2) reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK-independent mechanisms underlying resistance.

Topics: Anaplastic Lymphoma Kinase; Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Female; Gene Rearrangement; Humans; Lung Neoplasms; Mice, Nude; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyrimidines; RNA, Small Interfering; Sulfones

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) are usually effective in lung adenocarcinoma patients with anaplastic lymphoma kinase (ALK) rearrangement. However, even after a good response to ALK-TKI therapy, most patients acquire resistance to these agents. Histological transformation is one of several suggested mechanisms of acquired resistance to ALK-TKIs. The clinicopathologic features of four patients with ALK-expressing adenocarcinoma and neuroendocrine features were analyzed.. We selected combined neuroendocrine differentiation in pulmonary adenocarcinoma cases with positive ALK immunostaining. Neuroendocrine differentiation was confirmed by CD56 immunohistochemical stain. Additional ALK fluorescence in situ hybridization (FISH) study and epidermal growth factor receptor (EGFR) mutation tests were also performed.. All four cases were positive for ALK immunohistochemistry and no EGFR mutations were detected. Interestingly, the results of ALK FISH assays showed rearrangement in only two cases. Three cases showed combined adenocarcinoma and neuroendocrine component without history of ALK-TKI administration; one of them was treated with crizotinib and experienced partial tumor regression. The remaining case had an adenocarcinoma at initial biopsy and she showed a partial response to crizotinib, and neuroendocrine changes were visible on second biopsy. Then she was treated with ceritinib and achieved a partial response.. We suggest that ALK-rearranged adenocarcinoma with combined neuroendocrine component is responsive to ALK-TKIs. Moreover, even after neuroendocrine transformation as a result of resistance to ALK-TKIs, the tumor may have partial response to second generation ALK-TKIs.

Topics: Adenocarcinoma; Adult; Aged; Anaplastic Lymphoma Kinase; CD56 Antigen; ErbB Receptors; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Anaplastic lymphoma kinase (ALK) inhibitors are highly effective in patients with

Topics: Acetylation; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Enhancer Elements, Genetic; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histones; Humans; Lung; Lung Neoplasms; Mice; Mice, SCID; Mice, Transgenic; MicroRNAs; Oncogene Proteins, Fusion; Panobinostat; Protein Kinase Inhibitors; Pyrimidines; Sulfones; Xenograft Model Antitumor Assays

Intradural extramedullary spinal cord metastases in lung cancer are rarely reported, but are a disastrous event because of severe clinical symptoms and poor prognosis. Herein, we report a case of a lung cancer patient with ALK rearrangement who experienced brain, leptomeningeal, and intradural extramedullary spinal cord metastases after developing resistance to crizotinib. After ceritinib therapy, his clinical symptoms improved and magnetic resonance imaging revealed that the intradural extramedullary lesions had reduced.

Topics: Anaplastic Lymphoma Kinase; China; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Pyrimidines; Spinal Cord Neoplasms; Sulfones; Translocation, Genetic; 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

Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), a distinct molecular entity, is highly sensitive to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib or ceritinib. Interstitial lung disease is a rare (1.2%) pulmonary toxicity that can result from ALK TKIs, however, organizing pneumonia has not been reported to date.. A 45-year-old Korean female with ALK-rearranged metastatic lung adenocarcinoma underwent ceritinib treatment and exhibited a partial response, until she developed organizing pneumonia resembling disease progression.. Multiple rebiopsies confirmed the involvement of organizing pneumonia in the pathology.. Ceritinib was stopped and the patient was treated with intravenous antibiotics followed by oral antibiotics for two weeks.. After recovering from organizing pneumonia, ceritinib was successfully rechallenged and the patient attained a complete response.. When a new mass-like lesion develops in the lungs of responding patients, benign lung conditions, including organizing pneumonia should be considered in differential diagnoses.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cryptogenic Organizing Pneumonia; Diagnosis, Differential; Disease Progression; Female; Humans; Lung Neoplasms; Middle Aged; Pyrimidines; Sulfones

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

In this study, a series of novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety was described for ALK inhibitor. The pyrazole, imidazole, 1,2,4-triazole, piperazine and phenanthridine moieties were employed at the 2-position of pyrimidine. Among the compounds synthesized, 28, 29, 36, and 42 showed promising anti-ALK activities in enzymatic- and cell-based assays. In vivo H3122 xenograft model study showed that compound 29 effectively suppressed ALK-driven tumor growth, similar to the extent of ceritinib, suggesting that it could be used for a novel ALK inhibitor development.

Topics: Administration, Oral; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Humans; Inhibitory Concentration 50; Lung Neoplasms; Mice; Mice, SCID; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Transplantation, Heterologous

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Drug Discovery; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Mice; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proteomics; Xenograft Model Antitumor Assays

This study aimed to provide the first real-world description of the characteristics, treatments, dosing patterns, and early outcomes of patients with ALK-positive non-small cell lung cancer (NSCLC) who received ceritinib in US clinical practice.. US oncologists provided data from medical charts of adult patients diagnosed with locally advanced or metastatic ALK-positive NSCLC who received ceritinib following crizotinib. Patient characteristics, treatment patterns, ceritinib dosing, early outcomes, and occurrence of gastrointestinal adverse events (AEs) by dose and instructions on food intake were assessed, and Kaplan-Meier analysis was used to describe clinician-defined progression-free survival (PFS) on ceritinib.. Medical charts of 58 ALK-positive NSCLC patients treated with ceritinib were reviewed (median age 63 years; 41% male; 21% with prior chemotherapy experience). At ceritinib initiation, 44 patients had multiple distant metastases, most commonly in the liver (60%), bone (53%), and brain (38%). Initial ceritinib dose varied: 71% received 750 mg, 19% 600 mg, and 10% 450 mg. Although median follow-up after ceritinib initiation was short (3.8 months), most patients achieved either a complete or partial response (69%) on ceritinib, regardless of metastatic sites present at initiation or initial dose. Median PFS on ceritinib was 12.9 months. 17% of patients had a gastrointestinal AE reported during follow-up. The majority of events occurred in patients instructed to fast; no patients instructed to take a lower dose of ceritinib with food reported gastrointestinal AEs.. These early findings of ceritinib use in clinical practice suggest that ceritinib is effective at treating crizotinib-experienced ALK-positive NSCLC patients, regardless of metastatic sites or initial dose, and dosing ceritinib with food may lead to fewer gastrointestinal AEs. Future studies with larger sample size and longer follow-up are warranted, including an ongoing randomized trial to assess the gastrointestinal tolerability of ceritinib 450 and 600 mg with low-fat meals.. Novartis Pharmaceutical Corporation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; United States

Pancreatic metastasis from non-small cell lung cancer (NSCLC) is usually asymptomatic or presents with abdominal pain, acute pancreatitis, or jaundice. A lung primary is associated with worse survival compared to pancreatic metastases from other organs. Surgical treatment of solitary metastasis to the pancreas from NSCLC has been reviewed in several studies, one of which had a notable disease-free interval. To our knowledge, there are no prior reports of targeted therapy of pancreatic metastasis of NSCLC followed by a significant response. Herein we report the case of a 31-year-old female with a solitary pancreatic metastasis from ALK-rearranged lung adenocarcinoma despite treatment with chemotherapy and crizotinib; she presented with symptoms of hyperglycemia. Targeted therapy with ceritinib (LDK378) led to symptomatic improvement and a significant radiologic response in the lung and pancreas, but not in the brain.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Humans; Hyperglycemia; Lung Neoplasms; Magnetic Resonance Imaging; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Neoplasm Staging; Protein Kinase Inhibitors; Pyrimidines; Radiotherapy, Adjuvant; Receptor Protein-Tyrosine Kinases; Sulfones; Tomography, X-Ray Computed; Translocation, Genetic; Treatment Outcome

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrimidines; Sulfones

Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) derive significant clinic benefit from treatment with ALK inhibitors. Crizotinib was the first approved tyrosine kinase inhibitor (TKI) for this distinct molecular subset of NSCLC. Disease progression on TKI inevitably arises secondary to diverse resistance mechanisms among which emergence of secondary ALK mutations is one of many ways in which tumor cells have adapted to survive. Therefore there is a clinical imperative to identify acquired ALK mutations via repeat tissue biopsy if clinically feasible. If such is present, switching to a different TKI with known clinical activities against the emergent resistance mutation (s) may pose a viable treatment option. Here we report for the first time a novel ALK T1151K mutation in a patient with metastatic ALK-rearranged NSCLC who progressed on crizotinib and then ceritinib. The co-crystal structure of ceritinib/ALK demonstrates a strong interaction between ceritinib and the P-loop which is facilitated by T1151 on the β3 sheet, a feature not present in the alectinib/ALK or lorlatinib/ALK co-crystal structure. It is predicated that the T1151K mutation weakens these interactions leading to drug resistance, or causes conformational changes of the ALK catalytic domain resulting in higher affinity for ATP and therefore diminished inhibitor binding. We conclude that the T1151K ALK mutation confers resistance to ceritinib, which may be rescued by alectinib or lorlatinib as evidenced by this clinical narrative.

Topics: Adult; Alleles; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Crizotinib; DNA Mutational Analysis; Humans; Lung Neoplasms; Male; Models, Molecular; Molecular Conformation; Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Translocation, Genetic

BACKGROUND ALK gene rearrangements as oncogenic drivers have been described in many cancers, including inflammatory myofibroblastic sarcoma (IMS). The first-generation ALK inhibitor was limited in its ability to cross the blood-brain-barrier to treat brain metastasis. Drug-resistance invariably develops over time in ALK-rearranged tumors, which leads to disease progression. The newer generations of ALK inhibitors are designed to have higher potency in ALK inhibition and improved CNS penetration. CASE REPORT We report a rare case of pulmonary IMS with ALK-1 gene rearrangement and multiple brain metastases as initial presentation. After the primary lung tumor and the larger brain metastases were resected, control of residual CNS disease and subsequent progression and CNS spread was achieved with favorable clinical response by all three generations of ALK inhibitors. CONCLUSIONS ALK inhibitors may be an effective therapy for this rare and unusual form of ALK-1-rearranged cancer, even in the presence of multifocal CNS metastases with leptomeningeal involvement.

Topics: Adolescent; Aminopyridines; Anaplastic Lymphoma Kinase; Brain Neoplasms; Crizotinib; Female; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Meningeal Neoplasms; Myofibroblasts; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sarcoma; Sulfones

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Targeted drugs are effective when they directly inhibit strong disease drivers, but only a small fraction of diseases feature defined actionable drivers. Alternatively, network-based approaches can uncover new therapeutic opportunities. Applying an integrated phenotypic screening, chemical and phosphoproteomics strategy, here we describe the anaplastic lymphoma kinase (ALK) inhibitor ceritinib as having activity across several ALK-negative lung cancer cell lines and identify new targets and network-wide signaling effects. Combining pharmacological inhibitors and RNA interference revealed a polypharmacology mechanism involving the noncanonical targets IGF1R, FAK1, RSK1 and RSK2. Mutating the downstream signaling hub YB1 protected cells from ceritinib. Consistent with YB1 signaling being known to cause taxol resistance, combination of ceritinib with paclitaxel displayed strong synergy, particularly in cells expressing high FAK autophosphorylation, which we show to be prevalent in lung cancer. Together, we present a systems chemical biology platform for elucidating multikinase inhibitor polypharmacology mechanisms, subsequent design of synergistic drug combinations, and identification of mechanistic biomarker candidates.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Microtubules; Molecular Structure; Polypharmacology; Protein Kinase Inhibitors; Proteomics; Pyrimidines; Receptor Protein-Tyrosine Kinases; RNA Interference; Structure-Activity Relationship; Sulfones

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

The treatment of non-small cell lung cancer (NSCLC) has now changed dramatically in recent years and anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitors are developing rapidly.. Here we reported a 57-year-old ALK-positive NSCLC man with brain metastases.. A case of lung adenocarcinoma with brain metastases.. Crizotinib was administered orally at a dose of 250mg twice a day until the brain metastases were found. Treatment with orally administered ceritinib at a dose of 450mg/d was initiated after crizotinib treatment.. The patient is currently receiving maintenance ceritinib treatment, with no evidence of extracranial or intracranial tumor progression for 25 months.. Ceritinib may be a good choice for ALK-positive NSCLC patients with brain metastases who acquire resistance to crizotinib.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Middle Aged; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

We report an ALK-rearranged adenocarcinoma of the lung presenting as a pituitary metastasis, clinically simulating a pituitary adenoma. The patient, a 50 year-old, former-smoking woman was admitted with a Parinaud's syndrome characterized by progressive oculomotor impairment of visual verticality, bitemporal hemianopsia and nystagmus. Imaging studies showed a sellar tumor and the biopsy revealed a TTF-1 and napsin positive lung adenocarcinoma strongly expressing synaptophysin and CD56, also harboring ALK rearrangement. A subsequent CT scan disclosed the primary lung mass of the left upper lobe. The patient progressed after 4 cycles of cisplatin/pemetrexed as first line treatment, but showed a partial response and a significant clinical benefit from the combination of ceritinib and nivolumab in a phase Ib trial. Despite its central nervous system tropism, ALK-rearranged adenocarcinoma manifesting with pituitary gland involvement was never reported. Second generation ALK inhibitors seem the best therapeutic strategy.

Topics: Adenocarcinoma of Lung; Adenoma; Anaplastic Lymphoma Kinase; Biomarkers, Tumor; Female; Gene Rearrangement; Humans; Immunohistochemistry; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Pituitary Gland; Pituitary Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Activation of the EGFR pathway is one of the mechanisms inducing acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib and alectinib. Ceritinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the ALK gene rearrangement. However, the precise mechanism underlying acquired resistance to ceritinib is not well-defined. This study set out to clarify the mechanism in ALK-translocated lung cancer and to find the preclinical rationale overcoming EGFR pathway-induced acquired resistance to ALK-TKIs. To this end, ceritinib-resistant cells (H3122-CER) were established from the H3122 NSCLC cell line harboring the ALK gene rearrangement via long-term exposure to ceritinib. H3122-CER cells acquired resistance to ceritinib through EGFR bypass pathway activation. Furthermore, H3122 cells that became resistant to ceritinib or alectinib through EGFR pathway activation showed cross-resistance to other ALK-TKIs. Ceritinib and afatinib combination treatment partially restored the sensitivity to ceritinib.. This study proposes a preclinical rationale to use ALK-TKIs and afatinib combination therapy for ALK-translocated lung cancers that have acquired resistance to ALK-TKIs through EGFR pathway activation. Mol Cancer Res; 15(1); 106-14. ©2016 AACR.

Topics: Afatinib; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Ligands; Lung Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; Receptor Protein-Tyrosine Kinases; Signal Transduction; Sulfones; Translocation, Genetic

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

A series of novel 2,4-diaminopyrimidines bearing tetrahydronaphthalenyl moiety were synthesized and evaluated for their anti-anaplastic lymphoma kinase (ALK) activities using enzymatic and cell-based assays. Among the compounds synthesized, compound 17b showed promising pharmacological results in in vitro, ex vivo, and pharmacokinetic studies. An in vivo efficacy study with compound 17b demonstrated highly potent inhibitory activity in H3122 tumor xenograft model mice. A series of kinase assays showed that compound 17b inhibited various kinases including FAK, ACK1, FGFR, RSK1, IGF-1R, among others, thus demonstrating its potential for synergistic anti-tumor activity and development as a multi-targeted non-small cell lung cancer (NSCLC) therapy.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Lung; Lung Neoplasms; Male; Mice; Mice, SCID; Naphthalenes; Protein Kinase Inhibitors; Pyrimidines; Rats; Receptor Protein-Tyrosine Kinases

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

Crizotinib achieves excellent systemic control in anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC); however, central nervous system (CNS) metastases frequently occur as an early event. Whole brain irradiation, the standard treatment, results in neurocognitive impairment. We present a case series of three ALK+ NSCLC patients with progressing CNS metastases who were treated with pulse-dose crizotinib followed by ceritinib. Three ALK+ NSCLC patients treated between 2011 and 2014 (two males, two never smokers, age range 20-54years, all echinoderm microtubule-associated protein-like 4/ALK rearrangement), were diagnosed with progressing cerebral disease while receiving crizotinib. Clinico-pathological characteristics, treatments, and outcomes were analyzed. In two patients the progression was limited to the CNS, and radiological evidence of leptomeningeal spread was present in one patient. Sequential use of crizotinib 500mg administered once daily (pulse-dose) followed by ceritinib on progression achieved control of the disease in the CNS for over 18 months and over 7 months in Patient 1 and Patient 2, respectively. This strategy provided durable CNS control after whole-brain radiotherapy failure in Patient 1, and allowed the whole-brain radiotherapy to be deferred in Patient 2. Limited CNS progression was documented in Patient 3 while he was on standard-dose/pulse-dose crizotinib for 15months; durable (over 7 months) complete remission was achieved with stereotactic radiotherapy and ceritinib. Manipulating the crizotinib schedule in ALK+ NSCLC patients with CNS metastases and using a novel ALK-inhibitor at the time of further progression may provide durable CNS control and allow brain radiotherapy to be deferred.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cranial Irradiation; Crizotinib; Disease Progression; Female; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Outcome; Young Adult

The emergence of acquired anaplastic lymphoma kinase (ALK) resistant mutations is a common molecular mechanism underpinning disease progression during crizotinib treatment of ALK-positive (ALK+) non-small cell lung cancer (NSCLC) patients. Identifying acquired resistance mutations in ALK is paramount for tailoring future therapy with second generation ALK inhibitors and beyond. Comprehensive genomic profiling using hybrid-capture next generation sequencing has been successful in identifying acquired ALK resistance mutations. Here we described the emergence of an ALK F1245C mutation in an advanced ALK+ NSCLC patient (EML4-ALK variant 3a/b) who developed slow disease progression after a durable response to crizotinib. The patient was eventually switched to ceritinib with on-going clinical response. This is the first patient report that ALK F1245C is an acquired resistance mutation to crizotinib that can be overcome by ceritinib.

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

We report two cases of acute hepatitis induced by crizotinib in patients with ALK-rearranged non-small cell lung cancer (NSCLC) who were treated after by a second generation of ALK inhibitor without any incident. These cases suggest that ceritinib could be used as an alternative agent when crizotinib is responsible for hepatitis.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Substitution; Female; Hepatitis; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Outcome

Topics: Anaplastic Lymphoma Kinase; Bone Neoplasms; Carcinoma, Non-Small-Cell Lung; Disease Progression; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Osteoblasts; Prognosis; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Tomography, X-Ray Computed

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

We report on the case of a patient affected by advanced non-small cell lung cancer (NSCLC) harboring an anaplastic lymphoma kinase (ALK) gene rearrangement who did not respond to crizotinib but subsequently benefited from treatment with ceritinib (LDK378). Although second-generation ALK inhibitors have shown activity in patients pretreated with crizotinib who experienced secondary resistance, this is the first report to date describing their efficacy in a case of primary resistance. Of note, none of the previously described molecular mechanisms explaining resistance to crizotinib was detected on either the initial or post-crizotinib biopsies. We hypothesize that crizotinib was powerless in controlling disease progression due to its inadequate inhibition of ALK signaling. Although we lack any molecular evidence elucidating the primary crizotinib resistance, we believe that ceritinib treatment led to tumor regression thanks to its superior biological potency.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; Drug Resistance, Neoplasm; Drug Substitution; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Tomography, X-Ray Computed; Translocation, Genetic; Treatment Outcome

Crizotinib and ceritinib have been developed to treat advanced or metastatic NSCLC by inhibiting anaplastic lymphoma receptor tyrosine kinase gene (ALK). No randomized trial has compared these treatments head-to-head. We compared efficacy outcomes between patients receiving ceritinib and an external control group receiving crizotinib, both as initial ALK-targeted therapies for previously treated advanced or metastatic ALK-positive NSCLC.. Individual patient data for the ceritinib-treated patients were drawn from two single-arm trials (ASCEND-1 and ASCEND-3); published summary data for the crizotinib-treated patients were extracted from three trials (PROFILE 1001, PROFILE 1005, and PROFILE 1007). To adjust for cross-trial differences, average baseline characteristics were matched using propensity score weighting. Overall survival (OS), progression-free survival (PFS), and overall response rate were then compared between treatment groups.. Before matching, the ceritinib-treated patients (n = 189) were significantly different from the crizotinib-treated patients (n = 557) in the distribution of race and number of prior regimens. After matching, all available baseline characteristics were balanced. Compared with crizotinib, ceritinib was associated with longer OS (hazard ratio = 0.59, 95% confidence interval: 0.46-0.75) and longer PFS (median 13.8 versus 8.3 months, hazard ratio = 0.52, 95% confidence interval: 0.44-0.62) in Cox proportional hazards models. The 12-month OS was 82.6% with ceritinib and 66.0% with crizotinib in a Kaplan-Meier analysis (log-rank p < 0.001). There was no significant difference in overall response rate between ceritinib and crizotinib.. In an adjusted comparison across separate clinical trials, ceritinib was associated with prolonged OS and PFS compared with crizotinib when used as initial ALK-targeted therapy for previously treated ALK-positive NSCLC.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALK. Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118-33. ©2016 AACRSee related commentary by Qiao and Lovly, p. 1084This article is highlighted in the In This Issue feature, p. 1069.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

We report the re-biopsied diagnosis of a patient with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive lung adenocarcinoma successfully treated with ceritinib 450 mg/day taken with food following disease progression and gastrointestinal intolerance to crizotinib.. A 74-year old female patient initially diagnosed with ALK-negative lung adenocarcinoma responded to initial standard chemotherapy. The patient was subsequently re-tested by next generation sequencing (NGS) and found to have ALK EIF2AK3-ALK fusion, and responded to crizotinib, but ultimately progressed and showed intolerance to this ALK inhibitor. She was then successfully treated with ceritinib 450 mg/day taken with food, has not suffered from any further gastrointestinal side-effects, and remains on ceritinib treatment after 12 months.. Second-line ceritinib treatment, when administered at 450 mg/day with food, is both well tolerated and efficacious in a patient with previously treated lung adenocarcinoma who had discontinued crizotinib due to disease progression and gastrointestinal adverse effects (AEs).

Topics: Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; eIF-2 Kinase; Female; Gene Fusion; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Outcome

Time to progression (TTP) is a surrogate marker of overall survival (OS). However, OS is also dependent on post-progression survival (PPS). This study evaluated the association between TTP and the duration of PPS among adult patients who received ceritinib (Zykadia. A pooled analysis was performed on 181 ASCEND-1 (phase I) and ASCEND-2 (phase II) patients who experienced disease progression while on ceritinib. TTP was assessed on its association with PPS in a Kaplan-Meier analysis and in Cox proportional hazard models, adjusted for clinical covariates.. Main outcomes measured include TTP, PPS, and OS.. Patients with TTP ≥6 months experienced significantly longer PPS compared to those with TTP <6 months (median: 9.8 vs. 6.5 months, log-rank p-value < .01). When TTP was assessed as a continuous variable, every 3 months of longer TTP was associated with a 21% lower hazard of death following progression (hazard ratio [HR]: 0.79, 95% confidence interval [CI]: 0.63-1.00; adjusted HR: 0.79, 95% CI: 0.64-0.99). This positive association translated into an OS benefit: each 3 months of longer TTP was associated with a lower hazard of death (adjusted HR: 0.46, 95% CI: 0.37-0.58). Median OS was 20.0 months for patients with TTP ≥6 months and was 10.9 months for patients with TTP <6 months.. A longer duration of TTP after treatment with ceritinib was significantly associated with a longer duration of both PPS and OS.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Disease Progression; Female; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLC) account for 3% to 7% of all NSCLC and require a standard treatment by crizotinib. However, crizotinib resistance is frequent within the first 12 months of treatment. Ceritinib is a novel tyrosine kinase inhibitor of ALK recently introduced in France for metastatic or locally advanced crizotinib-resistant ALK NSCLC. We report the first use of ceritinib in our institution with a spectacular tumoral response after only 3 months of treatment. This case demonstrates the major role of F-FDG PET/CT for monitoring the effectiveness of this new treatment.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Fluorodeoxyglucose F18; Humans; Lung Neoplasms; Neoplasm Metastasis; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Pyrimidines; Radiopharmaceuticals; Receptor Protein-Tyrosine Kinases; Sulfones

Clinical outcomes of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer according to ALK fusion variants are not clear. We aimed to investigate the prevalence of ALK fusion variants and to compare clinical outcomes according to ALK fusion variants.. A retrospective analysis was conducted on patients with advanced ALK-rearranged adenocarcinoma treated with chemotherapy and ALK inhibitors. ALK rearrangement was identified by fluorescence in situ hybridization and confirmed by immunohistochemistry. Peptide nucleic acid-mediated quantitative polymerase chain reaction assays, designed to detect 28 types of echinoderm microtubule-associated protein-like 4 (EML)-ALK rearrangements, were performed. Clinicopathological analysis and treatment outcomes with platinum-based chemotherapy, pemetrexed therapy, and ALK inhibitors-including crizotinib and ceritinib-were evaluated.. A total of 52 patients with ALK-rearranged lung adenocarcinoma were enrolled. EML4-ALK variant 1 (v1) was the most common variant (38.5 %) followed by the non-EML4 variant (36.5 %), EML4-ALK variant 3a/b (19.2 %), and EML4-ALK variant 2 (5.8 %). No clinicopathological distinction was found between the different ALK fusion variants. Treatment response rates for each therapeutic agent did not differ according to ALK fusion variant. However, EML4 variants, especially v1, showed significantly longer progression-free survival (PFS) on pemetrexed treatment than did non-EML4 variants (median 31.1 months versus 5.7 months, P = 0.003). PFS with platinum-based chemotherapy and ALK inhibitors did not differ according to ALK fusion variant. Multivariate survival analysis using Cox's regression model revealed v1 as the only predictive factor for prolonged PFS on pemetrexed.. Among ALK fusion variants, v1 is the most common subtype. It showed superior progression-free survival on pemetrexed than did non-EML4 variants. No survival difference was demonstrated between variants treated with crizotinib or ceritinib.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aged; Anaplastic Lymphoma Kinase; Crizotinib; Disease-Free Survival; Female; Gene Rearrangement; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Mutation; Oncogene Proteins, Fusion; Pemetrexed; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Outcome

Anaplastic lymphoma kinase (ALK) has become as an important target for the treatment of various human cancers, especially non-small-cell lung cancer. A mutation, F1174C, suited in the C-terminal helix αC of ALK and distal from the small-molecule inhibitor ceritinib bound to the ATP-binding site, causes the emergence of drug resistance to ceritinib. However, the detailed mechanism for the allosteric effect of F1174C resistance mutation to ceritinib remains unclear. Here, molecular dynamics (MD) simulations and binding free energy calculations [Molecular Mechanics/Generalized Born Surface Area (MM/GBSA)] were carried out to explore the advent of drug resistance mutation in ALK. MD simulations observed that the exquisite aromatic-aromatic network formed by residues F1098, F1174, F1245, and F1271 in the wild-type ALK-ceritinib complex was disrupted by the F1174C mutation. The resulting mutation allosterically affected the conformational dynamic of P-loop and caused the upward movement of the P-loop from the ATP-binding site, thereby weakening the interaction between ceritinib and the P-loop. The subsequent MM/GBSA binding free energy calculations and decomposition analysis of binding free energy validated this prediction. This study provides mechanistic insight into the allosteric effect of F1174C resistance mutation to ceritinib in ALK and is expected to contribute to design the next-generation of ALK inhibitors.

Topics: Allosteric Regulation; Anaplastic Lymphoma Kinase; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Molecular Dynamics Simulation; Mutation; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Many oncologists have already adopted ceritinib as a second-line treatment for ALK-positive non-small cell lung cancer in patients who have developed resistance to crizotinib. The results of a randomized trial, presented at the European Society for Medical Oncology 2016 Congress, confirm that ceritinib is an effective option because it increases progression-free survival by 4 months over chemotherapy.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Disease-Free Survival; Docetaxel; Drug Therapy; Humans; Lung Neoplasms; Pemetrexed; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Taxoids; Treatment Outcome

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Docetaxel; Humans; Lung Neoplasms; Pemetrexed; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases; Sulfones; Taxoids

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

Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation are considered mutually exclusive in nonsmall-cell lung cancer (NSCLC). However, sporadic cases having concomitant EGFR and ALK alterations have been reported. The present study aimed to assess the prevalence of NSCLCs with concomitant EGFR and ALK alterations using mutation detection methods with different sensitivity and to propose an effective diagnostic and therapeutic strategy.. A total of 1458 cases of lung cancer were screened for EGFR and ALK alterations by direct sequencing and flourescence in situ hybridization (FISH), respectively. For the 91 patients identified as having an ALK translocation, peptide nucleic acid (PNA)-clamping real-time PCR, targeted next-generation sequencing (NGS), and mutant-enriched NGS assays were carried out to detect EGFR mutation.. EGFR mutations and ALK translocations were observed in 42.4% (612/1445) and 6.3% (91/1445) of NSCLCs by direct sequencing and FISH, respectively. Concomitant EGFR and ALK alterations were detected in four cases, which accounted for 4.4% (4/91) of ALK-translocated NSCLCs. Additional analyses for EGFR using PNA real-time PCR and ultra-deep sequencing by NGS, mutant-enriched NGS increased the detection rate of concomitant EGFR and ALK alterations to 8.8% (8/91), 12.1% (11/91), and 15.4% (14/91) of ALK-translocated NSCLCs, respectively. Of the 14 patients, 3 who were treated with gefitinib showed poor response to gefitinib with stable disease in one and progressive disease in two patients. However, eight patients who received ALK inhibitor (crizotinib or ceritinib) showed good response, with response rate of 87.5% (7/8 with partial response) and durable progression-free survival.. A portion of NSCLC patients have concomitant EGFR and ALK alterations and the frequency of co-alteration detection increases when sensitive detection methods for EGFR mutation are applied. ALK inhibitors appear to be effective for patients with co-alterations.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; DNA Mutational Analysis; Female; Gefitinib; Genes, erbB-1; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Quinazolines; Real-Time Polymerase Chain Reaction; Receptor Protein-Tyrosine Kinases; Sensitivity and Specificity; Sulfones; Translocation, Genetic

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Crizotinib; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Genetic Testing; Genomics; Humans; Lung Neoplasms; Medical Oncology; Molecular Targeted Therapy; Mutation; Practice Guidelines as Topic; Precision Medicine; Pyrazoles; Pyridines; Pyrimidines; Quinazolines; Receptor Protein-Tyrosine Kinases; Societies, Medical; Sulfones; Translocation, Genetic

Anaplastic lymphoma kinase (ALK) rearrangements are important therapeutic targets in non-small cell lung cancer (NSCLC) that confer sensitivity to the ALK inhibitors crizotinib and ceritinib. To determine the outcome of sequential treatment with crizotinb and ceritinib, we retrospectively evaluated a cohort of ALK-positive patients treated with both agents.. We identified 73 ALK-positive NSCLC patients treated with crizotinib followed by ceritinib at four institutions. Medical records were reviewed to determine overall survival (OS) and progression-free survival (PFS) on crizotinib and ceritinib.. Among 73 ALK-positive patients, the median PFS (mPFS) on crizotinib was 8.2 months [95% confidence interval (CI), 7.4-10.6]. The median interval from crizotinib discontinuation to initiation of ceritinib was 25 days (range, 1-694). The mPFS on ceritinib was 7.8 months (6.5-9.1). Among 53 patients with no interval therapies between crizotinib and ceritinib, the mPFS on ceritinib was similar at 7.8 months (5.4-9.8). The median combined PFS for sequential treatment with crizotinib and ceritinib was 17.4 months (15.5-19.4). Among 23 patients who underwent post-crizotinib/pre-ceritinib biopsies, there was no difference in PFS on ceritinib between patients with or without ALK resistance mutations (mPFS 5.8 vs. 6.5 months, respectively; P = 0.510). In the overall study population, median OS was 49.4 months (35.5-63.1).. Ceritinib has significant antitumor activity in ALK-positive NSCLC-even when crizotinib immediately precedes treatment with ceritinib (median combined PFS 17.0 months). Additional studies are necessary to further define the impact of specific ALK resistance mutations on duration of response to ceritinib.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Biopsy; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Staging; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Survival Analysis; Treatment Outcome; Young Adult

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

With advanced non-small-cell lung cancer (NSCLC) harboring, the anaplastic lymphoma kinase (ALK) gene rearrangement often responds impressively to ALK inhibitors, such as crizotinib. Acquired tumor resistance to ALK inhibition develops after a median progression-free survival of 7.7 to 10.9 months, with several mechanisms of resistance already described. Second generation ALK inhibitors, such as ceritinib, may overcome some of these mechanisms and have known efficacy in brain metastases. Their effect on intramedullary spinal cord metastases, a rare form of central nervous system metastases, is unknown.

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

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Costs; Humans; Lung Neoplasms; Molecular Targeted Therapy; Nivolumab; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, ceritinib (LDK378), in the setting of crizotinib resistance. An interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of patients with crizotinib-resistant NSCLC, revealed that ceritinib potently overcomes crizotinib-resistant mutations. In particular, ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T, and S1206Y mutations, and a cocrystal structure of ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations was identified in 5 of 11 biopsies from patients with acquired resistance to ceritinib. Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease.. The second-generation ALK inhibitor ceritinib can overcome several crizotinib-resistant mutations and is potent against several in vitro and in vivo laboratory models of acquired resistance to crizotinib. These findings provide the molecular basis for the marked clinical activity of ceritinib in patients with ALK-positive NSCLC with crizotinib-resistant disease. Cancer Discov; 4(6); 662-73. ©2014 AACR. See related commentary by Ramalingam and Khuri, p. 634 This article is highlighted in the In This Issue feature, p. 621.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mice; Mice, SCID; Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Tumor Burden

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

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

In the past decade, the advent of targeted therapy led to a silent revolution in the war against lung cancer and a significant evolution on the concept of Phase I clinical trials design. Thanks to the specificity of their target, the new drugs have radically changed NSCLC treatment, leading to the development of personalized strategies. The accelerated approval of the first ALK-inhibitor, Crizotinib and more recently Ceritinib, without a Phase III randomized, clinical trial, has been an amazing success story in lung cancer research, marking the beginning of a new decade of targeted drugs development, characterized by modern, biomarker-driven, early clinical trial design and shorter times for clinical approval. Is Ceritinib a new panacea for the treatment of ALK-rearranged NSCLC? We aimed to discuss the reasons of such success, including the new emerging questions, regarding mechanisms of acquired resistance, and the best treatment algorithm for ALK-rearranged NSCLC patients.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Crizotinib; Drug Approval; Drug Design; Gene Rearrangement; Humans; Lung Neoplasms; Molecular Targeted Therapy; Precision Medicine; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Novartis's second-generation ALK inhibitor ceritinib has been approved by the FDA for patients with ALK-positive lung cancer who relapse after first-line therapy.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Humans; Lung Neoplasms; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Topics: Anaplastic Lymphoma Kinase; Drug Approval; Drug Industry; Humans; Lung Neoplasms; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; United States; United States Food and Drug Administration

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pyrimidines; Sulfones

The treatment of advanced non-small cell lung cancer (NSCLC) has dramatically changed over the last decade. It has developed from an unspecific approach based on platinum doublet chemotherapy to a personalized, molecularly targeted therapy. Crizotinib is a new tyrosine kinase inhibitor approved for the treatment of NSCLC with gene rearrangement of EML4 and ALK. Despite good initial responses, patients treated with crizotinib relapse after an average of 10 months. In this case report, we present a patient with acquired crizotinib resistance whose adenocarcinoma responded to a second course of crizotinib following a drug holiday and chemotherapy with pemetrexed. This is the second case report to suggest that retreatment with crizotinib is an option for patients with initial benefit from ALK inhibition.

Topics: Adenocarcinoma; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Crizotinib; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Compassionate Use Trials; Female; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

The echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was identified in patients with non-small cell lung cancer. To the best of our knowledge, there are only three cell lines harboring the EML4-ALK fusion gene, which have contributed to the development of therapeutic strategies. Therefore, we tried to establish a new lung cancer cell line harboring EML4-ALK.. A 61-year-old Japanese female presented with chest discomfort. She was diagnosed with left lung adenocarcinoma with T4N3M1 Stage IV. Although she was treated with chemotherapy, her disease progressed with massive pleural effusion. Because the EML4-ALK rearrangement was found in a biopsied specimen using fluorescence in situ hybridization, she was treated with crizotinib. She did well for 3 months.. Tumor cells were obtained from the malignant pleural effusion before treatment with crizotinib. Cells continued to proliferate substantially for several weeks. The cell line was designated ABC-11. The EML4-ALK fusion protein and genes were identified in ABC-11 cells using fluorescence in situ hybridization and immunohistochemistry, respectively. ABC-11 cells were sensitive to crizotinib and next-generation ALK inhibitors (ceritinib and AP26113), as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Phosphorylated ALK protein and its downstream signaling were suppressed by treatment with crizotinib in western blotting. Furthermore, we could transplant ABC-11 cells subcutaneously into BALB/c nu/nu mice.. We successfully established a new lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. This cell line could contribute to future research of EML4-ALK-positive lung cancer both in vivo and in vitro.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Crizotinib; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Microtubule-Associated Proteins; Middle Aged; Oncogene Proteins, Fusion; Pleural Effusion, Malignant; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Serine Endopeptidases; Signal Transduction; Sulfones

Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src) inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; DNA Mutational Analysis; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Enzyme Activation; ErbB Receptors; Humans; Lung Neoplasms; MAP Kinase Kinase 1; Molecular Targeted Therapy; Mutation; Patient-Specific Modeling; Protein Kinase Inhibitors; Proto-Oncogene Proteins pp60(c-src); Pyrimidines; Receptor Protein-Tyrosine Kinases; Receptor, Fibroblast Growth Factor, Type 3; Sulfones; Tumor Cells, Cultured

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Docetaxel; Erlotinib Hydrochloride; Female; Humans; Imidazoles; Indoles; Lung Neoplasms; Male; Medical Oncology; Multicenter Studies as Topic; Oximes; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinazolines; Randomized Controlled Trials as Topic; Small Cell Lung Carcinoma; Societies, Medical; Sulfones; Sunitinib; Taxoids; Treatment Outcome; Triazoles; United States