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]

Patient Education

• Take crizotinib twice daily with or without food, at about the same time each day. If you miss a dose, you can still take it as long as there are at least 6 hours until the next dose. Otherwise, skip the dose. Do not drink grapefruit juice or eat grapefruit while taking crizotinib, as grapefruit can increase the drug levels in your blood.

• This drug can cause the following side effects: vision problems, nausea, vomiting, diarrhea, swelling of your hands or feet, constipation. Tell your doctor or nurse if you have side effects that bother you or do not go away.

• If you experience these side effects, it is important to tell your doctor about them right away:

– Vision problems that usually occur the first 2 weeks of therapy: Report any flashes of light, blurred vision, light hurting your eyes, new or increased floaters (floating specs).

– Swelling in lungs (pneumonitis): Report new or worsened trouble breathing, shortness of breath, cough, fever.

– Liver problems: You will have blood tests every month to check on this; tell your doctor right away if you get yellow skin or yellowing of the whites of your eyes, nausea or vomiting, decreased appetite, pain on the right side of your stomach, or if you feel very tired, your urine turns dark or brown, or you bleed or bruise more easily than usual.

– Irregular heartbeats, feeling dizzy or faint.

• Crizotinib can interact with many other drugs. Tell your doctor all the medicines you are taking, including herbal supplements and vitamins. Do not take St. John's Wort (Hypericum perforatum), as this interacts with your medicine. Crizotinib interacts with medications taken for depression, infections due to bacteria or fungus, tuberculosis, HIV-AIDS, heart conditions, and seizures.

Drug Interactions

• Strong CYP3A4 inhibitors (eg, atazanavir [Reyataz], clarithromycin, indinavir [Crixivan], itraconazole, ketoconazole, nefazodone, nelfinavir [Viracept], ritonavir [Norvir], saquinavir, voriconazole [Vfend], grapefruit/grapefruit juice): increase crizotinib plasma concentrations. Use caution when moderate CYP3A4 inhibitors are used with crizotinib.

• Strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's Wort). Avoid coadministration as drug will decrease crizotinib plasma concentrations.

• Drugs metabolized by CYP3A4 (CYP3A substrates with narrow therapeutic index), eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus. Avoid coadministration, or metabolized drug (substrate) dose will need to be decreased.

Special Considerations

• FDA approval was based on response rate, and there are no data available at this time showing improvement in patient-reported outcomes or survival.

• Visual changes may occur commonly, including visual impairment, blurred vision, photophobia, and diplopia.

• Patients may develop increased LFTs (ALT, total bilirubin). Monitor LFTs monthly, and more frequently in patients who develop grade 2–4 elevations.

• QT interval prolongation may occur, especially in patients who have a history of QTc prolongation or are taking medicines that prolong the QT interval. ECG and serum electrolytes should be monitored at baseline and during treatment for individuals at risk.

• ALK testing to establish ALK positivity is mandatory.

• Drug has the same safety and efficacy in geriatric patients as in younger patients.

Adverse Reactions to Crizotinib by Body System

(

boldface type

indicates more common events, with 25% or higher incidence)

Cardiovascular: Edema, QT prolongation, bradycardia

CNS: Visual disturbances when going from dark to light environments, dizziness, headache, dysgeusia, insomnia

GI:Nausea, diarrhea, vomiting, constipation, stomatitis, esophagitis, abdominal pain, decreased appetite

Musculoskeletal: Arthralgia, back pain

Neurological: Neuropathy

Pulmonary:URI, dyspnea, cough

Renal: Renal cysts

Reproductive: Drug presumed to be harmful to fetus

Skin: Rash

Laboratory: Elevated serum transaminases, neutropenia, thrombocytopenia, lymphopenia

Contraindications/Precautions

• Visual changes are common. Evaluation by an ophthalmologist is recommended if patients develop photopsia (seeing sparks or flashes of color) or new or worsened vitreous floaters, as these may be signs of a retinal hole or pending retinal detachment. Caution patients not to drive or operate machinery if visual changes occur.

• Pneumonitis may occur, and can be severe. Monitor patient for signs and symptoms of pneumonitis (shortness of breath, cough, fatigue, loss of appetite, unintentional weight loss).

• Crizotinib can cause fetal harm when given to a pregnant woman. Teach female patients of childbearing potential to use effective contraception. Mothers should not nurse while receiving the drug.

• Safety and efficacy in children has not been studied; however, decreased bone formation was seen in rat long bones.

• Drug has not been studied in patients with hepatic dysfunction. Drug is extensively metabolized by the liver, so administration will probably increase plasma crizotinib levels.

• Use drug cautiously in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase; LFTs: liver function tests; ms = millisecond

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Shaw AT: Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res 17(8):2081–2086, 2011.

2. Crino L, Kim D, Riely GH, et al: Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005 (abstract 7514). J Clin Oncol 29:479s, 2011.

3. Shaw AT, Yeap BY, Solomon BJ, et al: Impact of crizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls (abstract 7507). J Clin Oncol 29:477s, 2011.

4. United States Food and Drug Administration: Fast Track, Accelerated Approval and Priority Review: Accelerating Availability of New Drugs for Patients with Serious Diseases. Available at:http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm