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.
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%).
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.
• 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.