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1 . Fallet V, Toper C, Antoine M, Cadranel J, Wislez M.[Management of crizotinib, a new individualized treatment].Bull Cancer. 2012 Jul-Aug;99(7-8):787-91.
Abstract
Crizotinib, an inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), achieves response rates of 57 % at eight weeks in patients with stage IV non-small cell lung cancer with ALK rearrangements. With such results, the crizotinib followed an accelerated procedure in the United States and obtained the Food and Drug Administration (FDA) approval based on the results of phase I studies. The results should be confirmed with one phase II study and two phase III studies in patients with ALK rearrangements. In France, the Commission of Authorization for Marketing has granted an Authorization of Temporary Use (ATU) for cohort on the 15 December 2011 to allow its administration in patients before marketing authorization.
2 . Okamoto W, Okamoto I, Arao T, Kuwata K, Hatashita E, Yamaguchi H, Sakai K, Yanagihara K, Nishio K, Nakagawa K.Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification.Mol Cancer Ther. 2012 Jul;11(7):1557-64. Epub 2012 Jun 22.
Abstract
Therapeutic strategies that target the tyrosine kinase MET hold promise for gastric cancer, but the mechanism underlying the antitumor activity of such strategies remains unclear. We examined the antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer cells positive or negative for MET amplification. Inhibition of MET signaling by crizotinib or RNA interference-mediated MET depletion resulted in induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in gastric cancer cells with MET amplification but not in those without it, suggesting that MET signaling is essential for the survival of MET amplification-positive cells. Crizotinib upregulated the expression of BIM, a proapoptotic member of the Bcl-2 family, as well as downregulated that of survivin, X-linked inhibitor of apoptosis protein (XIAP), and c-IAP1, members of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM inhibited crizotinib-induced apoptosis, suggesting that upregulation of BIM contributes to the proapoptotic effect of crizotinib. Crizotinib also exhibited a marked antitumor effect in gastric cancer xenografts positive for MET amplification, whereas it had little effect on those negative for this genetic change. Crizotinib thus shows a marked antitumor action both in vitro and in vivo specifically in gastric cancer cells positive for MET amplification.
3 . Crystal AS, Shaw AT.Variants on a Theme: A Biomarker of Crizotinib Response in ALK-Positive Non-Small Cell Lung Cancer?Clin Cancer Res. 2012 Sep 1;18(17):4479-81. Epub 2012 Aug 21.
Abstract
Anaplastic lymphoma kinase (ALK) gene rearrangements are found in approximately 5% of non-small cell lung carcinoma patients and confer sensitivity to ALK inhibitors such as crizotinib. The particular ALK fusion expressed may have an impact on protein stability and sensitivity to crizotinib, and this may underlie the heterogeneity in responses observed in the clinic.
4 . Sparidans RW, Tang SC, Nguyen LN, Schinkel AH, Schellens JH, Beijnen JH.Liquid chromatography-tandem mass spectrometric assay for the ALK inhibitor crizotinib in mouse plasma.J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Sep 15;905:150-4. Epub 2012 Aug 21.
Abstract
A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for the ALK inhibitor crizotinib was developed and validated. Plasma samples were pre-treated using protein precipitation with acetonitrile containing crizotinib-(13)C(2)-(2)H(5) as internal standard. The extract was directly injected into the chromatographic system after dilution with water. This system consisted of a sub-2μm particle, trifunctional bonded octadecyl silica column with a gradient using 0.1% (v/v) of ammonium hydroxide in water and methanol. The eluate was transferred into the electrospray interface with positive ionization and the analyte was detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was validated in a 10-10,000ng/ml calibration range with r(2)=0.99980±0.00014 for double logarithmic linear regression (n=5). Within day precisions (n=6) were 3.4-4.8%, between day (3 days; n=18) precisions 3.6-4.9%. Accuracies were between 107% and 112% for the whole calibration range. The drug was sufficiently stable under all relevant analytical conditions. Oxidative metabolites of crizotinib were monitored semi-quantitatively. Finally, the assay was successfully used to assess drug pharmacokinetics in mice.
5 . Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, Riely GJ, Solomon B, Ou SH, Kim DW, Salgia R, Fidias P, Engelman JA, Gandhi L, J?nne PA, Costa DB, Shapiro GI, Lorusso P, Ruffner K, Stephenson P, Tang Y, Wilner K, Clark JW, Shaw AT.Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.Lancet Oncol. 2012 Sep 3.
Abstract
BACKGROUND: ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. METHODS: In this phase 1 study, patients with ALK-positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov, number NCT00585195…
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