Introduction
Xalkori (crizotinib) is an oral, small molecule tyrosine kinase inhibitor developed by Pfizer for the treatment of certain types of advanced non-small cell lung cancer (NSCLC). It represents a landmark in precision medicine as one of the first targeted therapies approved concurrently with a companion diagnostic test. Xalkori received initial FDA approval in 2011 for ALK-positive NSCLC and has since expanded to include ROS1-positive NSCLC.
Mechanism of Action
Crizotinib is a selective inhibitor of receptor tyrosine kinases including ALK (anaplastic lymphoma kinase), hepatocyte growth factor receptor (c-MET), and ROS1 (c-ros oncogene 1). In ALK-positive NSCLC, chromosomal rearrangements create fusion genes that encode constitutively active ALK tyrosine kinases, which drive oncogenic signaling pathways. Xalkori competitively binds to the ATP-binding site of these kinases, inhibiting their phosphorylation and subsequent activation of downstream signaling pathways involved in cell proliferation, survival, and metastasis.
Indications
- Treatment of metastatic non-small cell lung cancer (NSCLC) positive for ALK rearrangement (as detected by an FDA-approved test)
- Treatment of metastatic NSCLC positive for ROS1 rearrangement
Dosage and Administration
Standard dosing: 250 mg orally twice daily with or without food Dose modifications:- Hepatic impairment (Child-Pugh Class B or C): Reduce dose to 200 mg twice daily
- Hepatic impairment (Child-Pugh Class C with severe impairment): Reduce dose to 250 mg once daily
- Renal impairment (CrCl <30 mL/min): 250 mg once daily
- Capsules should be swallowed whole with water
- If a dose is missed, take it as soon as remembered unless less than 6 hours until next dose
- Do not take an extra dose to make up for a missed dose
Pharmacokinetics
Absorption: Median time to peak plasma concentration (Tmax) is 4-6 hours. High-fat meal reduces AUC by approximately 14%. Distribution: Mean apparent volume of distribution is 1772 L. Protein binding is approximately 91%, primarily to albumin and alpha-1 acid glycoprotein. Metabolism: Primarily metabolized by CYP3A4/5 enzymes. Major metabolic pathways include oxidation of the piperidine ring to form crizotinib lactam and O-dealkylation. Elimination: Mean elimination half-life is 42 hours. Approximately 85% of the dose is eliminated in feces (53% as unchanged drug) and 22% in urine (2.3% as unchanged drug).Contraindications
- Hypersensitivity to crizotinib or any component of the formulation
- Concurrent use with strong CYP3A inhibitors (unless benefits outweigh risks and appropriate dose reduction implemented)
- Concurrent use with strong CYP3A inducers
Warnings and Precautions
Hepatotoxicity: Severe and sometimes fatal hepatotoxicity has occurred. Monitor liver function tests every 2 weeks during first 2 months, then monthly and as clinically indicated. Pneumonitis: Interstitial lung disease (ILD)/pneumonitis has occurred in approximately 2.9% of patients. Permanently discontinue for treatment-related ILD/pneumonitis of any severity. QT interval prolongation: QT interval prolongation may occur. Monitor ECG and electrolytes in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those taking medications known to prolong QT interval. Bradycardia: Symptomatic bradycardia can occur. Monitor heart rate and blood pressure regularly. Vision disorders: Visual impairment including blurred vision, photopsia, photophobia, and vitreous floaters occurs in approximately 70% of patients. Ophthalmic evaluation recommended if symptoms persist or worsen. Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for at least 45 days after final dose.Drug Interactions
Strong CYP3A inhibitors (e.g., ketoconazole, ritonavir, clarithromycin): Increase crizotinib exposure. Avoid concurrent use or reduce crizotinib dose. Strong CYP3A inducers (e.g., rifampin, carbamazepine, St. John's wort): Decrease crizotinib exposure. Avoid concurrent use. CYP3A substrates: Crizotinib may increase concentrations of sensitive CYP3A substrates. Use caution with narrow therapeutic index drugs. Drugs that prolong QT interval: Increased risk of QT prolongation with concomitant use.Adverse Effects
Most common (≥25%): Vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, dizziness, neuropathy Serious adverse effects:- Hepatotoxicity (11% Grade 3-4)
- Pneumonitis/ILD (2.9%)
- QT interval prolongation (2.1% Grade 3)
- Bradycardia (5.5%)
- Severe visual loss (0.2%)
Monitoring Parameters
- Liver function tests (ALT, AST, total bilirubin) every 2 weeks for first 2 months, then monthly
- ECG and electrolytes at baseline and periodically during treatment
- Heart rate and blood pressure regularly
- Visual symptoms assessment at each visit
- Renal function at baseline and periodically
- Complete blood count regularly
- Response assessment with CT scans every 6-8 weeks initially
Patient Education
- Take Xalkori exactly as prescribed; do not change dose or stop without discussing with healthcare provider
- Report any new or worsening symptoms immediately, especially:
- Yellowing of skin/eyes, dark urine, abdominal pain (liver problems) - Shortness of breath, cough, fever (lung problems) - Dizziness, lightheadedness, palpitations (heart problems) - Vision changes or disturbances
- Use effective contraception during treatment and for at least 45 days after final dose
- Inform all healthcare providers about Xalkori use before starting any new medications
- Do not consume grapefruit or grapefruit juice during treatment
- Store at room temperature in original container
References
1. FDA Prescribing Information: XALKORI® (crizotinib). Revised 2022. 2. Kwak EL, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703. 3. Shaw AT, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371(21):1963-1971. 4. Kim DW, et al. Long-term efficacy and safety of crizotinib in patients with advanced ALK-positive non-small-cell lung cancer: final 5-year results from the PROFILE 1001 study. J Clin Oncol. 2022;40(16_suppl):9018. 5. National Comprehensive Cancer Network (NCCN) Guidelines: Non-Small Cell Lung Cancer. Version 3.2023. 6. Solomon BJ, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167-2177.