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Response to crizotinib in a squamous cell lung carcinoma patient harbouring echinoderm microtubule-associated protein-like 4-anaplastic lymphoma translocation: A case report.

ABSTRACT: Squamous cell lung cancer (SCC) presenting with anaplastic lymphoma kinase (ALK) translocation is rare. We present a case of ALK gene translocation-SCC in which a remarkable tumor response to crizotinib was achieved after the failure of prior chemoradiotherapy. Considering this remarkable response, we conclude that ALK testing in female non-smokers or in any patient unresponsive to the initial regimen of chemotherapy, is recommended for SCC patients.

SUBMITTER: Wang W

PROVIDER: S-EPMC4846625 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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Successful oral desensitization with crizotinib after crizotinib-induced hepatitis in an anaplastic lymphoma kinase-rearranged non-small-cell lung cancer patient: A case report.

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Crizotinib in Combination with Everolimus Synergistically Inhibits Proliferation of Anaplastic Lymphoma Kinase?Positive Anaplastic Large Cell Lymphoma.

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Project description:Leptomeningeal carcinomatosis (LM) is an infrequent yet morbid and often fatal complication of non-small cell lung cancer (NSCLC). Management of LM is multimodal, often involving systemic chemotherapy, radiotherapy, and a variety of symptom management maneuvers to address elevated intracranial pressure, pain, and mood changes that can accompany the disease. It is increasingly recognized that tumors with actionable mutations in NSCLC, including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations, respond well to systemic therapy with tyrosine kinase inhibitors yet often progress in the central nervous system. More information is needed regarding the natural history and optimal management of LM in specific molecular subtypes of NSCLC. This case report summarizes the management of a patient with ALK-positive NSCLC who developed LM while on targeted treatment with crizotinib within the context of current NCCN Clinical Practice Guidelines in Oncology and recently published studies.

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

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

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An Anaplastic Lymphoma Kinase Immunohistochemistry-Negative but Fluorescence In Situ Hybridization-Positive Lung Adenocarcinoma Is Resistant to Crizotinib.

Project description:Oncogenic fusion of anaplastic lymphoma kinase (ALK) with echinoderm microtubule associated protein like 4 protein or other partner genes occurs in 3% to 6% of lung adenocarcinomas. Although fluorescence in situ hybridization (FISH) is the accepted standard for detecting anaplastic lymphoma receptor tyrosine kinase gene (ALK) gene rearrangement that gives rise to new fusion genes, not all ALK FISH-positive patients respond to ALK inhibitor therapies. We report here an ALK FISH-positive patient-derived xenograft (PDX) that was nonresponsive to crizotinib therapy.The PDX patient human lung cancer (PHLC402) was established in NOD/SCID mice from a patient with resected pT4N1M0 lung adenocarcinoma. ALK gene status was investigated using the standard FISH break-apart assay, reverse-transcriptase quantitative polymerase chain reaction, RNA sequencing and immunohistochemical assay using the 5A4 antibody. PHLC402 was treated with crizotinib (50 mg/kg) by daily oral gavage.ALK FISH assay was positive in both the primary patient tumor and PDX, which were negative for ALK protein expression by immunohistochemical analysis. ALK fusion product was not detected by RNA sequencing and reverse-transcriptase quantitative polymerase chain reaction comparing the 5' and 3' ALK transcript levels. Crizotinib treatment of PHLC402 grown in mice resulted in no tumor response.ALK protein expression may be necessary for ALK FISH-positive lung cancer to be responsive to ALK inhibitor therapy.

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Exposure-Response Analyses of Anaplastic Lymphoma Kinase Inhibitors Crizotinib and Alectinib in Non-Small Cell Lung Cancer Patients.

Project description:Crizotinib and alectinib are anaplastic lymphoma kinase (ALK)-inhibitors indicated for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). At the currently used fixed doses, interindividual variability in exposure is high. The aim of this study was to investigate whether minimum plasma concentrations (Cmin ) of crizotinib and alectinib are related to efficacy and toxicity. An observational study was performed, in which ALK-positive NSCLC patients who were treated with crizotinib and alectinib and from whom pharmacokinetic samples were collected in routine care, were included in the study. Exposure-response analyses were explored using previously proposed Cmin thresholds of 235 ng/mL for crizotinib and 435 ng/mL for alectinib. Forty-eight crizotinib and 52 alectinib patients were included. For crizotinib, median progression-free survival (mPFS) was 5.7 vs. 17.4 months for patients with Cmin < 235 ng/mL (48%) and ≥ 235 ng/mL, respectively (P = 0.08). In multivariable analysis, Cmin < 235 ng/mL resulted in a hazard ratio (HR) of 1.79 (95% confidence interval (CI), 0.90-3.59, P = 0.100). In a pooled analysis of all crizotinib patients (not only ALK-positive, n = 79), the HR was 2.15 (95% CI, 1.21-3.84, P = 0.009). For alectinib, mPFS was 12.6 months vs. not estimable (95% CI, 19.8-not estimable) for patients with Cmin < 435 ng/mL (37%) and ≥ 435 ng/mL, respectively (P = 0.04). Multivariable analysis resulted in an HR of 4.29 (95% CI, 1.33-13.90, P = 0.015). In conclusion, PFS of crizotinib and alectinib treated NSCLC patients is prolonged in patients with Cmin ≥ 235 ng/mL and 435 ng/mL, respectively. Therefore, therapeutic drug monitoring should be part of routine clinical management for these agents.

| S-EPMC7891593 | biostudies-literature

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