Adenocarcinoma of the lung with miliary brain and pulmonary metastases with echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase translocation treated with crizotinib: A case report

Falk, Alexander Tuan; Poudenx, M.; Otto, Josiane; Ghalloussi, H.; Barrière, Jérôme

doi:10.1016/j.lungcan.2012.08.015

Cited by 31 publications

(16 citation statements)

References 5 publications

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“…Unfortunately, crizotinib has a poor BBB penetration, so its efficacy in BMF-NSCLC patients is doubtful [10, 13, 14, 46, 49–51]. The available literature provides poor corresponding data [12, 49, 50, 52].…”

Section: Crizotinibmentioning

confidence: 99%

Systemic treatment of non-small cell lung cancer brain metastases

Cedrych

Kruczała

Walasek

et al. 2016

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In the systemic treatment of brain metastases from non-small cell lung cancer (BMF-NSCLC) chemo- and targeted therapy are used. Response rates after platinum-based chemotherapy, range from 23% to 45%. Development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): gefitinib or erlotinib, was an improvement in treatment of advanced NSCLC patients. EGFR mutations are present in 10–25% of NSCLC (mostly adenocarcinoma), and up to 55% in never-smoking women of East Asian descent. In the non-selected group of patients with BMF-NSCLC, the overall response rates after gefitinib or erlotinib treatment range from 10% to 38%, and the duration of response ranges from 9 to 13.5 months. In the case of present activating EGFR mutation, the response rate after EGRF-TKIs is greater than 50%, and in selected groups (adenocarcinoma, patients of Asian descent, never-smokers, asymptomatic BMF-NSCLC) even 70%. Gefitinib or erlotinib treatment improves survival of BMF-NSCLC patients with EGFR mutation in comparison to cases without the presence of this mutation. There is no data on the activity of the anti-EML4-ALK agent crizotinib. Bevacizumab, recombinant humanised monoclonal antibody anti-VEGF, in the treatment of advanced non-squamous NSCLC patients is a subject of intense research. Data from a clinical trial enrolling patients with pretreated or occult BMF-NSCLC proved that the addition of bevacizumab to various chemotherapy agents or erlotinib is a safe and efficient treatment, associated with a low incidence of CSN haemorrhages. However, the efficacy and safety of bevacizumab used for therapeutic intent, regarding active brain metastases is unknown.

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Section: Crizotinibmentioning

confidence: 99%

Systemic treatment of non-small cell lung cancer brain metastases

Cedrych

Kruczała

Walasek

et al. 2016

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“…Indeed, some Authors have reported a higher tendency to develop BMs among ALK-rearranged NSCLCs [19], which in some instances might be associated with specific radiological patterns, such as miliary distribution [20] or cystic lesions [21, 22]. Moreover, others have reported specific radiographic features [23–25] and bronchoscopic findings in EGFR mutated NSCLCs [26].…”

Section: Introductionmentioning

confidence: 99%

Influence of EGFR mutational status on metastatic behavior in non squamous non small cell lung cancer

et al. 2017

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Epidermal Growth Factor Receptor (EGFR) mutated Non Small Cell Lung Cancers (NSCLCs) are a molecularly subgroup of patients with peculiar clinic-pathological characteristics. Previous studies have suggested a possible interaction between oncogene status and metastatic behavior in non squamous NSCLCs with conflicting results. The aim of this study was to compare the different metastatic patterns, at baseline and during the course of the disease, in a cohort of 137 Caucasian patients with non-squamous NSCLC according to the EGFR mutational status and survival differences according to the different metastatic behavior. We observed unique metastatic distributions between EGFR-mutated and EGFR wild type non-squamous NSCLCs. These data support the hypothesis that tumor bio-molecular characteristics and genotype may influence the metastatic process in NSCLC and might help the development of enrichment strategies for tumor genotyping in these tumors, especially in the presence of limited tissue availability.

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“…The response of ALK rearrangement‐positive brain lesions to crizotinib in various case reports is varied, perhaps related in part to different degrees of protection of individual tumors by the BBB. A lung adenocarcinoma patient with miliary brain metastases showed a 12‐month progression‐free survival after crizotinib introduction . Another case report found a pronounced and rapid regression of a brain metastasis in a patient with NSCLC, 3 weeks after initiation of crizotinib treatment .…”

Section: Discussionmentioning

confidence: 99%

Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P‐glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar

Tang

Nguyen

Sparidans

et al. 2013

Intl Journal of Cancer

129

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Crizotinib is an oral tyrosine kinase inhibitor approved for treating patients with non-small cell lung cancer (NSCLC) containing an anaplastic lymphoma kinase (ALK) rearrangement. We used knockout mice to study the roles of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) in plasma pharmacokinetics and brain accumulation of oral crizotinib, and the feasibility of improving crizotinib kinetics using coadministration of the dual ABCB1/ABCG2 inhibitor elacridar. In vitro, crizotinib was a good transport substrate of human ABCB1, but not of human ABCG2 or murine Abcg2. With low-dose oral crizotinib (5 mg/kg), Abcb1a/1b 2/2 and Abcb1a/1b;Abcg2 2/2 mice had an approximately twofold higher plasma AUC than wild-type mice, and a markedly (~40-fold) higher brain accumulation at 24 hr. Also at 4 hr, crizotinib brain concentrations were~25-fold, and brain-to-plasma ratios~14-fold higher in Abcb1a/1b 2/2 and Abcb1a/1b;Abcg2 2/2 mice than in wild-type mice. High-dose oral crizotinib (50 mg/kg) resulted in comparable plasma pharmacokinetics between wild-type and Abcb1a/1b 2/2 mice, suggesting saturation of intestinal Abcb1. Nonetheless, brain accumulation at 24 hr was still~70-fold higher in Abcb1a/1b 2/2 than in wild-type mice. Importantly, oral elacridar coadministration increased the plasma and brain concentrations and brain-toplasma ratios of crizotinib in wild-type mice, equaling the levels in Abcb1a/1b;Abcg2 2/2 mice. Our results indicate that crizotinib oral availability and brain accumulation were primarily restricted by Abcb1 at a non-saturating dose, and that coadministration of elacridar with crizotinib could substantially increase crizotinib oral availability and delivery to the brain. This principle might be used to enhance therapeutic efficacy of crizotinib against brain metastases in NSCLC patients.Lung cancer remains the leading cause of cancer deaths in western countries. 1 Patients with non-small cell lung cancer (NSCLC), accounting for approximately 80% of all lung cancer cases, 2 are often diagnosed at advanced stages of the disease. A subset of NSCLC was shown to have a small inversion within chromosome 2p, which results in the formation of a fusion gene comprising portions of the echinoderm microtubule associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene. 3 The EML4-ALK fusion results in constitutive activation of ALK kinase activity, which promotes cell proliferation, survival and cell cycling. 4 Since the identification of ALK rearrangements in 7% of NSCLC as a new and promising molecular target for treatment, 3 considerable effort has been focused on developing Key words: crizotinib, P-glycoprotein, ALK inhibitor, elacridar, brain accumulation Abbreviations: ABC: ATP-binding cassette; ABCB1: P-glycoprotein; ABCG2: breast cancer resistance protein; ALK: anaplastic lymphoma kinase; ANOVA: analysis of variance; AUC: area under plasma concentration-time curve; C brain : brain concentration; C max : maximum drug concentration in plasma; EML4: echinoderm mic...

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Adenocarcinoma of the lung with miliary brain and pulmonary metastases with echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase translocation treated with crizotinib: A case report

Cited by 31 publications

References 5 publications

Systemic treatment of non-small cell lung cancer brain metastases

Systemic treatment of non-small cell lung cancer brain metastases

Influence of EGFR mutational status on metastatic behavior in non squamous non small cell lung cancer

Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P‐glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar

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