Crizotinib
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Author: Maria Elena Boggio Merlo
Date: 06/07/2013

Description

Maria Elena Boggio, Aurelia Mondino, Biotecnologie Mediche a.a. 2012/2013

DESCRIPTION

Crizotinib (PF-02341066,trade name Xalkori, Pfizer) is an oral tyrosine kinase inhibitor targeting Anaplastic Lymphoma Kinase (ALK), Met proto-oncogene, and c-ros oncogene 1 (ROS1).
Initial development of the drug was aimed at utilizing its c-Met inhibitory activity as mutations in this pathway are implicated in the progression of many human cancers.
Crizotinib was developed using structure-based drug design as an orally available and clinically useful alternative to another compound, PHA-665752, which was not feasible for clinical use due to its pharmacological properties.

Crizotinib in the treatment of non-small-cell lung cancer, 2013

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Alk and Cancer
ALK belongs to the leukocyte tyrosine kinase receptor superfamily. ALK is a single-chain transmembrane receptor. The extracellular domain contains an N-terminal signal peptide sequence and is the ligand-binding site for the activating ligands of ALK, pleiotrophin, and midkine. This is followed by the transmembrane and juxtamembrane region which contains a binding site for phosphotyrosine-dependent interaction with insulin receptor substrate-1. The final section has an intracellular tyrosine kinase domain with three phosphorylation sites, followed by the C-terminal domain with interaction sites for phospholipase C-gamma and Src homology 2 domain-containing SHC.
In 1994, fusion of the ALK on chromosome 2p23 with the nucleophosmin (NPM) gene on chromosome 5q35 was described in non-Hodgkin lymphoma. In NSCLC, ALK rearrangements were identified in 2007 by 2 independent groups. Soda et al found that the echinoderm microtubule associated protein-like 4 (EML4)- ALK fusion transcript, had transforming activity in vitro and in a mouse model, and that inhibition of EML4-ALK activity in vivo led to the reduction of cancer growth. Contemporaneously, Rikova et al characterized the phosphotyrosine profile in 191 NSCLC cell lines and primary tumors, and identified a high level of ALK phosphorylation in several NSCLC tumor samples and in the H2228 cell line.
Consistent with the role of ALK in neurogenesis, activating mutations in ALK lead to both familial and sporadic neuroblastoma which provided a rationale for therapeutic ALK inhibition in the treatment of neuroblastoma.
The abnormal EML4-ALK fusion gene occurs in the 4% of patients with NSCLC and leads to ligand-independent dimerization of the ALK kinase domain, and consequently, uncontrolled cellular proliferation and inhibition of apoptosis.
Patients with this gene fusion are typically younger non-smokers who do not have mutations in either the epidermal growth factor receptor gene (EGFR) or in the K-Ras gene

Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond, 2011

CLASSIFICATION

Crizotinib is an adenosine triphosphate-competitive small molecule oral inhibitor of ALK, c-Met/hepatocyte growth factor receptor (HGFR), Recepteur d’Origine Nantais, and ROS receptor tyrosine kinases.

Was evaluated against a panel of more than 120 kinases in biochemical assays and twelve cell-based phosphorylation assays, and was determined to be nearly 20-fold more selective for ALK and MET compared with other kinases evaluated.

Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond, 2011

Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma

As a lot of currently used inibitors, there are several opinions about crizotinib selectivity: as reported before was initially developed as a MET inhibitor, but recent studies have demonstrate, in vitro, that crizotinib is a potential ROS inhibitor.

ROS1 rearrangements define a unique class of lung cancers, 2012

INDICATIONS

After the EGFR mutations, ALK fusion is the second most frequent oncogenic driver in NSCLC for which a targeted therapy is available based on regulatory approval. In fact, it was approved by FDA for first or subsequent- line treatment of patients with ALK-rearranged NSCLC (locally advanced, metastatic). Approval required a companion molecular test for the EML4-ALK fusion.
Patients with significant and symptomatic progression during crizotinib therapy need an immediate change of therapy.
Crizotinib is undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.

National Cancer Institute

MOLECULAR MECHANISM

Crizotinib has an aminopyridine structure, and functions as a protein kinase inhibitor by competitive binding within the ATP-binding pocket of target kinases. In this way blocks the phosphorylation of c-Met/HGFR and selected ALK and ROS fusion variants in tumor cells in vitro and in vivo.
Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.

Wikipedia:crizotinib

PHARMACOKINETICS

Crizotinib has almost equivalent IC50 values against both C-Met and the NPM-ALK fusion gene present in ALKpositive lymphoma cell lines (values are 5 to 50 nmol/L). The IC50 of crizotinib in NSCLC cell lines carrying an EML4-ALK fusion is significantly smaller, ranging from 250 to 340 nmol/L
After a single crizotinib dose of 250 mg, the peak plasma concentration was achieved 4 to 6 hours later. Age, sex, or body weight did not affect crizotinib pharmacokinetic properties, nor did food intake. Pharmacokinetics were linear from a 100 mg once daily dose to a 300 mg twice daily dose. At the dose of 250 mg twice per day orally, steady-state concentration was reached within 15 days of repeated administration, with a half-life of approximately 43 to 51 hours.
Crizotinib is mainly excreted in the feces, and to a lesser extent, in urine.
Crizotinib is predominantly metabolized by the CYP3A isozymes in human microsomes. The total clearance of crizotinib from plasma was lower after 250 mg twice a day than after a single 250 mg dose (100 L/hour), likely due to the autoinhibition of CYP3A.

Crizotinib in the treatment of non-small-cell lung cancer, 2013

DOSAGE AND ADMINISTRATION

The recommended dose and schedule of crizotinib is 250 mg taken orally twice daily. Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose
reduction is necessary, then reduce the dose of crizotinib to 200 mg taken orally twice daily. If further dose
reduction is necessary, then reduce the dosage to 250 mg taken orally once daily

Crizotinib in the treatment of non-small-cell lung cancer, 2013

SIDE EFFECTS & TOXICITY

Crizotinib is well tolerated by most patients, with the most common toxicities being grade 2 or less, primarily gastrointestinal disturbances (nausea, vomiting, diarrhea) and visual effects (delayed light adaptation). About visual disturbances, never this side effect led to reduction, interruption or discontinuation of the drug, and most patients can adapt.
Other toxicities reported at frequencies >20% included peripheral edema, dizziness, fatigue, and decreased appetite.
Dose-limiting toxicities of crizotinib in the initial phase I study included liver toxicity (increase in alanine aminotransaminase) and fatigue.
Discontinuations because of treatment-related adverse events were rare and included lung toxicity(pneumonitis) and increasing ALT.
Other notable toxicities include development of complex renal cysts and cardiac toxicity, in particular QT interval prolongation (it's better not to use crizotinib in patients with congenital long QT syndrome and in general periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, etc, are to be considered)

Crizotinib in the treatment of non-small-cell lung cancer, 2013

Xalkori, data sheet

RESISTANCE

As with other targeted agents, acquired resistance to crizotinib after treatment with this drug is a relevant problem. Resistance develops on average within the first year. However, there is marked heterogeneity in the duration of benefit from crizotinib.
The target gene itself can be altered either by mutation or by amplification, and tumor cells might lose their dependency from the inhibited signaling pathway by activating alternative signaling pathways.
In up to one-third of relapsing patients, crizotinib resistance is mediated by secondary resistance mutations located in the ALK tyrosine kinase domain. The most commonly identified resistance mutation is the gatekeeper mutation L1196M. Tumors are still addicted to ALK signaling and for these patients, second generation ALK inhibitors might represent a promising treatment approach.
In a small number of patients, amplification of the ALK fusion gene with or without concurrent ALK mutation leads to drug resistance.
The activation of several alternative signaling pathways in ALK-positive lung cancer patients resistant to crizotinib has been reported. One is the coactivation of EGFR signaling. Concurrent inhibition of ALK and EGFR was effective in this setting. The precise mechanism by which EGFR is activated is unknown, although in vitro studies suggest that EGFR and some of its ligands might be upregulated. It is noteworthy that EGFR mutations have not been identified in any crizotinib-resistant tumor specimens. Activation of the protooncogene kinase is a another bypass signaling pathway which might mediate crizotinib resistance. Finally, also activation of KRAS might represent a resistance mechanism in ALK-positive tumors because new KRAS mutations have been detected in ALK-positive NSCLC resistant to crizotinib.

Cause of the limited durability of treatment with crizotinib strategies to overcome mechanism of resistance are urgently needed and represent the greatest part of new studies about ALK and cancer. Moreover many “second-generation” ALK inhibitors are now or soon to be entered into early clinical development to try to overcome crizotinib resistance.

Crizotinib in the treatment of non-small-cell lung cancer, 2013

DEPENDENCE AND WITHDRAW

Must be avoided comedication with:
*inhibitors or inducers of CYP3A must be avoided
*bradycardic agents

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Comments
2013-07-22T00:19:41 - Maria Elena Boggio Merlo
2013-07-22T00:05:41 - Maria Elena Boggio Merlo
2013-07-22T00:05:40 - Maria Elena Boggio Merlo
Attachments
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crizo.GIFMEBM11/07/2013
mechanism.GIFMEBM17/07/2013
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