Crizotinib

Crizotinib is an orally administered targeted anticancer medicine belonging to the tyrosine kinase inhibitor class. It primarily inhibits anaplastic lymphoma kinase, or ALK, and ROS1 receptor tyrosine kinases, as well as other kinase targets including MET. Genetic rearrangements involving ALK or ROS1 can produce abnormal signaling that promotes cancer-cell growth, survival, and proliferation. By inhibiting these kinase pathways, crizotinib can reduce signaling that supports the growth of tumors driven by these molecular alterations. Crizotinib is available as oral capsules and is generally administered twice daily. Its principal clinical role is the treatment of appropriately diagnosed advanced or metastatic non-small cell lung cancer with ALK or ROS1 alterations. The medicine became clinically important as one of the first targeted treatments for ALK-rearranged lung cancer and subsequently established a role in ROS1-positive disease. Clinical studies demonstrated activity in both previously treated and previously untreated ALK-positive non-small cell lung cancer. Crizotinib can also have activity against intracranial disease because it reaches the central nervous system, although central nervous system penetration and disease control can vary between patients. Treatment selection requires molecular confirmation of the relevant alteration rather than relying on clinical or histological characteristics alone.

Crizotinib was initially developed as a selective inhibitor of MET and subsequently became an important targeted therapy after its activity against ALK-rearranged non-small cell lung cancer was established. Early clinical development included studies of patients with ALK-positive advanced disease, followed by the PROFILE clinical trial program evaluating crizotinib in different treatment settings. The United States Food and Drug Administration approved crizotinib on August 26, 2011, for locally advanced or metastatic ALK-positive non-small cell lung cancer detected by an FDA-approved test. FDA subsequently expanded the indication on March 11, 2016, to include metastatic ROS1-positive non-small cell lung cancer. The FDA approval information was later consolidated to cover adult patients with metastatic non-small cell lung cancer whose tumors are ALK- or ROS1-positive as detected by an FDA-approved test. The European Medicines Agency granted marketing authorization for crizotinib on October 23, 2012, initially for ALK-positive advanced non-small cell lung cancer, with subsequent regulatory expansions. The European indication includes first-line and previously treated ALK-positive advanced disease and ROS1-positive advanced non-small cell lung cancer, as well as certain pediatric ALK-positive malignancies. Major clinical evidence came from the PROFILE 1005, PROFILE 1007, and PROFILE 1014 studies.

Crizotinib is used for adults with advanced or metastatic non-small cell lung cancer whose tumors are positive for an ALK or ROS1 alteration, depending on the applicable regulatory indication. Molecular testing should confirm the relevant biomarker before treatment. In the United States, crizotinib is indicated for metastatic ALK-positive or ROS1-positive non-small cell lung cancer in patients whose tumors meet the required molecular criteria. In the European Union, crizotinib is authorized as monotherapy for first-line treatment and treatment of previously treated ALK-positive advanced non-small cell lung cancer and for adults with ROS1-positive advanced non-small cell lung cancer. European authorization also includes certain pediatric patients with relapsed or refractory systemic ALK-positive anaplastic large cell lymphoma and recurrent or refractory ALK-positive unresectable inflammatory myofibroblastic tumor. For advanced lung cancer, crizotinib is generally administered as a targeted single-agent therapy rather than as part of conventional cytotoxic chemotherapy.

Crizotinib is administered orally, usually as 250 mg twice daily for adults with ALK-positive or ROS1-positive advanced non-small cell lung cancer, with or without food. Treatment is generally continued until disease progression or unacceptable toxicity. The capsules should be swallowed whole rather than crushed or opened. Dose interruption or reduction may be necessary for significant adverse reactions, with the specific adjustment depending on the type and severity of toxicity. Patients with significant renal impairment may require a reduced starting dose because crizotinib exposure can increase when kidney function is substantially reduced. Hepatic impairment may also require individualized consideration. Treatment should be administered consistently according to the prescribed schedule, and missed doses should be handled according to current prescribing instructions rather than by taking additional doses.

Common side effects of crizotinib include visual disturbances, nausea, diarrhea, vomiting, constipation, edema, fatigue, decreased appetite, dizziness, and changes in liver function tests. Visual effects may include blurred vision, flashes of light, floaters, or other changes in visual perception and are often reported during treatment. Gastrointestinal symptoms can affect appetite, hydration, and daily activities. Peripheral edema may present as swelling of the legs, ankles, feet, or hands. Laboratory abnormalities, particularly elevations in liver enzymes, can also occur. Patients should report persistent or worsening symptoms so that appropriate assessment, supportive treatment, or dose modification can be considered.

Important serious risks associated with crizotinib include severe hepatotoxicity, interstitial lung disease or pneumonitis, QT interval prolongation, bradycardia, severe visual disorders, renal cysts, and serious gastrointestinal or cardiac complications. Liver injury can occasionally be severe or life-threatening and requires regular monitoring of liver function. New or worsening cough, difficulty breathing, fever, or other respiratory symptoms require prompt evaluation for interstitial lung disease or pneumonitis. Crizotinib can prolong the QT interval and may cause clinically significant bradycardia, particularly in patients with cardiovascular risk factors or when combined with medicines affecting cardiac conduction. Visual disturbances should be assessed when persistent, severe, or associated with other concerning symptoms. Complex renal cysts have also been reported and may require imaging and clinical evaluation when suspected.

Before starting crizotinib, molecular testing should confirm the relevant ALK or ROS1 alteration, and baseline assessment should include liver function, renal function, cardiac history, concomitant medications, and visual symptoms where clinically appropriate. Liver function tests should be monitored regularly, particularly during the initial months of treatment and after dose adjustments. Electrocardiographic monitoring and electrolyte assessment may be appropriate for patients with cardiac risk factors or those receiving medicines that can prolong the QT interval. Crizotinib is metabolized mainly through CYP3A, and strong CYP3A inhibitors can increase crizotinib exposure, while strong CYP3A inducers can reduce exposure and may decrease therapeutic effect. Concomitant medicines that cause bradycardia or QT prolongation should be reviewed carefully. Patients with significant renal impairment may require dose adjustment. Pregnancy should also be considered because crizotinib may cause fetal harm, and appropriate reproductive counselling should be provided.

Prescribers should confirm the ALK or ROS1 molecular alteration before treatment and review previous targeted therapies, disease distribution, central nervous system involvement, liver and kidney function, cardiovascular risk, and concomitant medicines. Baseline and periodic liver function testing is important, while ECG and electrolyte monitoring should be considered in patients with relevant cardiac risk or interacting medicines. Pharmacists should screen for strong CYP3A inhibitors and inducers, QT-prolonging medicines, and drugs capable of causing clinically significant bradycardia. Patients should be counselled about possible visual disturbances and advised to report significant or persistent changes in vision. New respiratory symptoms, jaundice, severe fatigue, palpitations, fainting, marked swelling, or unexplained abdominal or flank symptoms should be evaluated promptly. Treatment interruptions and dose modifications should follow the severity-specific recommendations in the current prescribing information.