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Crizotinib, an ALK/MET Tyrosine Kinase Inhibitor for ALK-Positive NSCLC

Crizotinib, an ALK/MET Tyrosine Kinase Inhibitor for ALK-Positive NSCLC

Approved Drug

Crizotinib (Xalkori)

Indications

Treatment of patients with locally advanced or metastatic non–small-cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Mechanism of Action

Crizotinib is a receptor tyrosine kinase inhibitor that blocks cell signaling by tyrosine kinases ALK, hepatocyte growth factor receptor (HGFR, c-Met) and Recepteur d'Origine Nantais (RON). Patients with EML4-ALK fusion gene–positive NSCLC have constant ALK signaling without any normal stimulation (ligand-independent dimerization with resulting constitutive kinase activity). Tumor growth appears addicted to stimulation by the fusion gene, and blocking it stops cell signaling.

Metabolism

Following oral administration, absolute bioavailability is 43%, and median peak concentration is reached in 4 to 6 hours. A high-fat meal reduced AUC and peak concentration by 14%, but drug can be administered with or without food. With twice-daily dosing, steady state is reached in 15 days. Drug is 91% bound to plasma proteins, and appears to be a substrate for P-glycoprotein (P-gp). Drug is extensively tissue-bound after leaving the plasma. Crizotinib has a terminal plasma half-life of 42 hours. It is metabolized by the liver microenzymes, principally CYP3A4/5, and excreted in the feces (63%, unchanged drug 53%) and urine (22%, unchanged drug 2%).

Drug Administration

Oral, 250 mg taken twice daily with or without food, for as long as patient derives clinical benefit. Swallow whole. If a dose is forgotten, it can be taken late as long as it is more than 6 hours to the next dose.

• Available in 200-mg and 250-mg capsules.

• Monitor CBC/differential at baseline, then monthly and as clinically indicated; increase testing frequency if grade 3 or 4 abnormalities arise, or if fever or infection occurs.

• Monitor LFTs at baseline, then monthly and as clinically indicated, with increased testing frequency if grade 2, 3, or 4 abnormalities occur.

Dose Modifications

Grade 3 hematologic toxicity, including lymphopenia with associated opportunistic infections: hold until recovery to grade < 2, then resume at same dose and schedule; if recurrence, hold until recovery to grade < 2, then resume at 250 mg once daily.

Grade 4 hematologic toxicity: hold until recovery to grade < 2, then resume at 200 mg PO twice daily; if grade 4 recurrence, discontinue drug.

Grade 3 or 4 ALT or AST elevation with elevated grade < 1 total bilirubin: hold until recovery to grade < 1 or baseline, then resume at 200 mg twice daily; if recurrence recovery to grade < 1, then resume at 250 mg once daily. Permanently discontinue in case of further grade 3 or 4 recurrence.

Grades 2, 3, or 4 ALT or AST elevation with concurrent grade 2, 3, or 4 total bilirubin elevation: permanently discontinue drug.

Any grade pneumonitis: permanently discontinue drug.

Grade 3 QTc prolongation: hold drug until recovery to grade < 1, then resume at 200 mg twice daily.

Grade 4 QTc prolongation: permanently discontinue drug.

Inhibiting the EML4-ALK Fusion Protein in NSCLC

Tumors of about 7% of patients with non–small-cell lung cancer (NSCLC) are stimulated by the EML4-ALK fusion oncogene. This fusion oncogene is formed by a genetic inversion in chromosome 2 whereby one end of the gene EML4 (echinoderm microtubule-associated protein-like 4) is fused with one end of the ALK (anaplastic lymphoma kinase) gene. The newly formed EML4-ALK fusion gene is highly oncogenic, driving constant signaling to the lung cancer cell nucleus, telling the cell to divide. It appears that the NSCLC tumors formed by this fusion oncogene are “addicted” to stimulation by the EML4-ALK fusion protein. Therefore, if EML4-ALK can be inhibited, then the tumors will stop dividing.[1] Patients with this fusion oncogene are generally younger (median age 54 years, compared with a median age of 64 years in lung cancer patients who do not have the EML4-ALK fusion gene), have history of never or light smoking, and have an adenocarcinoma histology with signet rings (suggesting aggressive tumor behavior).

Two single-arm studies presented at 2011 meeting of the American Society of Clinical Oncology reported on clinical outcomes of crizotinib (Xalkori) for treatment of NSCLC patients with the EML4-ALK fusion gene. Crino et al showed that crizotinib resulted in dramatic regression or disappearance of tumor in 57% of patients, 33% had stable disease, progression-free survival (PFS) at 6 months was 72%, and median PFS was 10 months.[2] Shaw performed a retrospective study and presented 18-month follow-up data showing 1-year survival in 74%, and 2-year survival in 54% of patients treated with crizotinib. In contrast, patients with the EML4-ALK fusion gene who were not treated with crizotinib had a 1-year survival of 44% and a 2-year survival of 12%.[3] Crizotinib was approved by the US Food and Drug Administration (FDA) as part of their Priority Review Program, an expedited 6-month review of a drug that offers either major clinical advances or apparent benefit to patients with a disease for which there is no adequate therapy.[4]

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