Ceritinib in patients with advanced anaplastic lymphoma kinase-rearranged anaplastic large-cell lymphoma.
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ABSTRACT:
SUBMITTER: Richly H
PROVIDER: S-EPMC4559938 | biostudies-literature | 2015 Sep
REPOSITORIES: biostudies-literature
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Project description:BackgroundMore than 80% of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients harbor the (nucleophosmin) NPM1-ALK fusion gene t(2;5) chromosomal translocation. We evaluated the preclinical and clinical efficacy of ceritinib treatment of this aggressive lymphoma.Materials and methodsWe studied the effects of ceritinib treatment in NPM1-ALK+ T-cell lymphoma cell lines in vitro and on tumor size and survival advantage in vivo utilizing tumor xenografts. We treated an NPM1-ALK+ ALCL patient with ceritinib. We reviewed all hematologic malignancies profiled by a large hybrid-capture next-generation sequencing (NGS)-based comprehensive genomic profiling assay for ALK alterations.ResultsIn our in vitro experiments, ceritinib inhibited constitutive activation of the fusion kinase NPM1-ALK and downstream effector molecules STAT3, AKT, and ERK1/2, and induced apoptosis of these lymphoma cell lines. Cell cycle analysis following ceritinib treatment showed G0/G1 arrest with a concomitant decrease in the percentage of cells in S and G2/M phases. Further, treatment with ceritinib in the NPM1-ALK+ ALCL xenograft model resulted in tumor regression and improved survival. Of 19 272 patients with hematopoietic diseases sequenced, 58 patients (0.30%) harbored ALK fusions that include histiocytic disorders, multiple myeloma, B-cell neoplasms, Castleman's disease, and juvenile xanthogranuloma. A multiple relapsed NPM1-ALK+ ALCL patient treated with ceritinib achieved complete remission with ongoing clinical benefit to date, 5 years after initiation of therapy.ConclusionsThis ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies.
| S-EPMC8271116 | biostudies-literature
Project description:The anaplastic lymphoma kinase (ALK) fusion oncogene is observed in 3%-5% of non-small cell lung cancer (NSCLC). Crizotinib and ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI) active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emergence of ALK-TKI resistance restricts the therapeutic effect. To date, various secondary mutations or bypass pathway activation-mediated resistance have been identified, but large parts of the resistance mechanism are yet to be identified. Here, we report the discovery of p-glycoprotein (P-gp/ABCB1) overexpression as a ceritinib resistance mechanism in ALK-rearranged NSCLC patients. P-gp exported ceritinib and its overexpression conferred ceritinib and crizotinib resistance, but not to PF-06463922 or alectinib, which are next-generation ALK inhibitors. Knockdown of ABCB1 or P-gp inhibitors sensitizes the patient-derived cancer cells to ceritinib, in vitro and in vivo. P-gp overexpression was identified in three out of 11 cases with in ALK-rearranged crizotinib or ceritinib resistant NSCLC patients. Our study suggests that alectinib, PF-06463922, or P-gp inhibitor with ceritinib could overcome the ceritinib or crizotinib resistance mediated by P-gp overexpression.
| S-EPMC4739423 | biostudies-literature
Project description:What is known and objectiveCeritinib 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.MethodsWe 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.Results and discussionFrom 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.What is new and conclusionCeritinib 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.
| S-EPMC7384129 | biostudies-literature
Project description: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).
| S-EPMC6125456 | biostudies-literature
Project description: Not available
| S-EPMC8740884 | biostudies-literature
Project description:Patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma often present with B-symptoms or hemophagocytosis and generate an anti-tumor immune response. Specific serum cytokine levels or profiles may reflect the tumor burden, non-specific immune stimulation by the tumor or differences in the strength of the patients' anti-lymphoma immunity. We systematically correlated pretreatment concentrations of 25 cytokines with clinical and biological characteristics in a well-characterized cohort of 119 uniformly treated pediatric patients with anaplastic large cell lymphoma. Fifteen patients with anaplastic large cell lymphoma in remission and 11 patients with low-stage B-cell lymphoma served as controls. Concentrations of interleukin-9, interleukin-10, interleukin-17a, hepatocyte growth factor, soluble interleukin-2 receptor, and soluble CD30 were significantly higher in initial sera of patients than in the sera of subjects from both control groups, indicating an anaplastic large cell lymphoma-type cytokine signature. The levels of interleukin-6, interferon-γ, interferon γ-induced protein, and soluble interleukin-2 receptor correlated with the stage, initial general condition, minimal disseminated disease, anaplastic lymphoma kinase-antibody titers, and the risk of relapse among patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Only interleukin-6 showed an independent prognostic value in multivariate analyses. Pretreatment cytokine profiles in patients with anaplastic large cell lymphoma reflect a tumor signature as well as tumor burden and also differences in the strength of the patients' immune response.
| S-EPMC5830391 | biostudies-literature
Project description:Introduction: Survival of ALK-rearranged NSCLC patients has dramatically improved by the use of multiple ALK-tyrosine kinase inhibitors (ALK-TKI). However, still little is known about the impact of drug sequencing and clinical features on survival in a real-world setting. Methods: Patients with stage IV ALK-rearranged NSCLC treated at six centers in Switzerland and Italy were identified and standard clinical variables collected. OS curves were constructed using the Kaplan-Meier method and compared with the log-rank test. Multivariate Cox proportional hazard analysis was applied to determine the correlations between clinical features and OS. In four patients, biopsies were subjected to NGS. Results: One-hundred and twenty-one patients with stage IV ALK-rearranged NSCLC diagnosed between 2011 and 2016 were included. With a median follow-up time of 39.5 months, the median OS from diagnosis of stage IV disease was 48.0 months. First-line treatment consisted of an ALK-TKI in 24% of patients, with crizotinib in 83% of them. Chemotherapy as first-line treatment did not influence OS (p = 0.955). The use of more than one ALK-TKI line positively correlated with OS (p = 0.016), as well as the use of alectinib or lorlatinib in any treatment line, as compared to the use of crizotinib ± ceritinib (p = 0.022). A never smoking history was an independent prognostic factor for OS (p = 0.032). Moreover, treatment with alectinib significantly improved OS. Conclusions: Targeted treatment for ALK-positive NSCLC patients lead to prolonged OS. Smoking status was a negative independent prognostic factor in a multi-variate analysis. The use of alectinib or lorlatinib in any treatment line improved overall outcome.
| S-EPMC7472246 | biostudies-literature
Project description: Not available
| S-EPMC7679007 | biostudies-literature
Project description:Non-small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases and is the leading cause of cancer-related deaths. Most NSCLC patients are diagnosed with advanced disease and require systemic treatment. Despite emerging advances in chemotherapy and immunotherapy, the prognosis of stage IV patients remains poor. However, the discovery of oncogenic driver mutations including mutations in the epidermal growth factor receptor (EGFR), the anaplastic lymphoma kinase (ALK) and others, characterize a subset of patients with the opportunity of targeted therapies. Fusions between the ALK and echinoderm microtubule-associated protein-like 4 (EML4) are present in ∼ 3-5% of patients with NSCLC. Several first-, second-, and third-generation ALK tyrosine kinase inhibitors (TKIs) have been developed in the last decade and have tremendously changed treatment options and outcomes of ALK-positive NSCLC patients. With increasing treatment options, treatment sequence decisions have become more and more complex. ALK-mutations, fusion variants, or activation of by-pass pathways result in treatment resistance during the course of treatment in nearly all patients. Mutation-guided treatment sequencing can lead to better outcomes, and re-biopsy or liquid-biopsy should be performed whenever possible in case of disease progression in ALK-rearranged patients. In the future, combinational treatment of ALK TKIs with other pathway-inhibitors might further improve patients' treatment options and outcomes. Here, we review the data for currently available ALK TKIs, discuss approaches of treatment sequencing, and give an outlook on emerging developments.
| S-EPMC8154809 | biostudies-literature
Project description: Not available
| S-EPMC5465132 | biostudies-literature