Crizotinib

Non-Small Cell Lung Cancer

Crizotinib is used to treat non-small cell lung cancer (NSCLC) that has spread to other parts of the body (metastatic). It is specifically indicated for patients whose tumors test positive for an abnormal anaplastic lymphoma kinase (ALK) gene or a ROS1 gene.

Anaplastic Large Cell Lymphoma

This medication is also used for children and young adults with a type of blood cancer known as systemic anaplastic large cell lymphoma (ALCL). It is prescribed when the cancer is ALK-positive and has either returned after previous treatment or did not respond to initial therapies.

Inflammatory Myofibroblastic Tumor

Crizotinib is used to treat adults and children with a rare condition called inflammatory myofibroblastic tumor (IMT). It is used when the tumor is ALK-positive and cannot be removed by surgery, has come back after treatment, or is resistant to other treatments.

Genetic Testing

Because crizotinib targets specific genetic mutations, a healthcare provider must confirm the presence of the ALK or ROS1 markers using a specialized laboratory test before treatment begins. The medication is only intended for patients whose tumors have these specific genetic characteristics.

Mechanism of Action

Crizotinib belongs to a class of medications called kinase inhibitors. It is designed to target and block the activity of specific proteins found on the surface or inside of cancer cells. These proteins include anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), and hepatocyte growth factor receptor (HGFR).

In some types of cancer, such as certain forms of non-small cell lung cancer, the genes responsible for these proteins become abnormal or fused with other genes. This genetic change causes the proteins to be constantly active, sending continuous signals that tell the cancer cells to grow, multiply, and spread throughout the body.

How It Affects Cancer Cells

Crizotinib works by binding to these overactive proteins and blocking their signaling pathways. When these signals are interrupted, the following may occur:

• The growth and division of cancer cells are slowed or stopped.
• The tumor may shrink in size.
• The spread of the cancer to other parts of the body may be delayed.

Because crizotinib specifically targets these abnormal proteins, it is considered a targeted therapy. It is typically used only in patients whose tumors have been tested and confirmed to have specific genetic markers, such as an ALK-positive or ROS1-positive status.

Common Side Effects

Many people taking crizotinib experience mild to moderate side effects. These may include:

• Vision changes, such as seeing flashes of light, blurred vision, or floaters
• Nausea, vomiting, diarrhea, or constipation
• Swelling in the hands, feet, or legs
• Fatigue or feeling very tired
• Decreased appetite
• Dizziness
• Numbness or tingling in the hands or feet

Serious Side Effects

Some side effects can be severe and require immediate medical attention. Seek help right away for:

• Liver issues: Symptoms include yellowing of the skin or eyes, dark urine, or pain in the upper right side of the stomach.
• Lung inflammation: New or worsening shortness of breath, cough, or fever.
• Heart rhythm problems: Feeling lightheaded, fainting, or experiencing a very slow or irregular heartbeat.
• Severe vision changes: Sudden loss of vision or severe blurring.

Liver Toxicity

Severe, life-threatening, or fatal liver toxicity has occurred in patients taking crizotinib. Monitoring of liver function tests, including ALT, AST, and total bilirubin, is typically performed every two weeks for the first two months of treatment and monthly thereafter. Treatment may need to be suspended or discontinued if liver enzymes reach certain levels.

Interstitial Lung Disease

Severe or fatal lung inflammation, known as interstitial lung disease (ILD) or pneumonitis, can occur. Patients should be monitored for pulmonary symptoms such as shortness of breath, cough, or fever. If ILD is suspected, the medication is usually withheld and may be permanently discontinued if the condition is confirmed.

Heart Rhythm and Rate

• QT Interval Prolongation: Crizotinib can cause changes in the heart's electrical rhythm. Monitoring with electrocardiograms (ECGs) and electrolyte levels is recommended, especially for patients with a history of heart rhythm issues or those taking other medications that affect the QT interval.
• Bradycardia: A slow heart rate (bradycardia) has been reported. Heart rate and blood pressure should be monitored regularly. Dose adjustments or discontinuation may be necessary if symptomatic bradycardia occurs.

Vision Disorders

Vision changes, such as light flashes, blurred vision, or sensitivity to light, are common. Severe visual loss has also been reported. Patients experiencing new or worsening vision symptoms should undergo an ophthalmological evaluation.

Gastrointestinal Effects

Severe nausea, vomiting, diarrhea, and constipation can occur. Supportive care or dose modifications may be required to manage these symptoms.

Embryo-Fetal Toxicity

Crizotinib can cause fetal harm when administered to pregnant individuals. Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during treatment and for a designated period after the last dose.

Pregnancy

Crizotinib may cause fetal harm when administered to a pregnant woman. Based on its mechanism of action and findings from animal studies, this medication can lead to birth defects or the loss of a pregnancy. It is important to discuss pregnancy status and family planning with a healthcare provider before starting this medication.

The following precautions are generally advised:

• Pregnancy Testing: Females who are able to become pregnant should have a pregnancy test to confirm they are not pregnant before beginning treatment.
• Contraception for Females: Effective birth control should be used during treatment and for at least 4 months after the last dose.
• Contraception for Males: Men with female partners of reproductive potential should use effective contraception (such as condoms) during treatment and for at least 90 days after the last dose.

Breastfeeding

There is no information on the presence of crizotinib in human milk or its effects on a breastfed child. Because of the potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for 45 days after the final dose.

Available Forms

Crizotinib is available in the following oral formulations:

• Capsules: These are hard-shell capsules intended to be swallowed whole. They should not be crushed, dissolved, or opened before administration.
• Oral Pellets: These consist of small pellets contained within a shell. The shell is designed to be opened so the pellets can be administered, which may be helpful for patients who have difficulty swallowing whole capsules.

FDA-Approved Indications

The U.S. Food and Drug Administration (FDA) has approved crizotinib for the treatment of several specific cancers:

• Non-Small Cell Lung Cancer (NSCLC): It is approved for adults with metastatic NSCLC whose tumors are positive for the anaplastic lymphoma kinase (ALK) or ROS1 gene alterations.
• Anaplastic Large Cell Lymphoma (ALCL): It is approved for pediatric patients (1 year of age and older) and young adults with systemic ALCL that is ALK-positive and has either returned or did not respond to previous treatments.
• Inflammatory Myofibroblastic Tumor (IMT): It is approved for adult and pediatric patients (1 year of age and older) with ALK-positive IMT that cannot be removed by surgery, has returned, or did not respond to other therapies.

Diagnostic Testing Requirements

FDA approval for these uses is contingent upon the presence of specific biomarkers. Patients must have their ALK or ROS1 status confirmed by an FDA-approved diagnostic test before starting treatment to ensure the medication is appropriate for their specific cancer type.

Safety and Regulatory Oversight

Crizotinib is not currently subject to any FDA Boxed Warnings or Risk Evaluation and Mitigation Strategy (REMS) programs. The FDA continues to monitor the safety and effectiveness of the drug through post-marketing surveillance and clinical data reviews.

Insurance and Out-of-Pocket Costs

Crizotinib is a high-cost specialty medication, and the final price for a patient is largely determined by their health insurance plan. Most insurance providers, including Medicare and private plans, cover the medication, but it is often placed in a high-cost specialty tier. This means patients may be responsible for a significant copayment or coinsurance amount. Some plans may also require prior authorization before the medication can be dispensed.

Specialty Pharmacy Services

Crizotinib is usually available only through specialty pharmacies rather than standard retail pharmacies. These pharmacies are equipped to handle high-cost medications and can often assist patients with the insurance approval process and coordinate delivery of the drug.

Financial Assistance Programs

Because of the high cost of treatment, several resources may be available to help reduce the financial burden:

• Manufacturer Assistance: Programs may be available to provide the medication at a lower cost or for free to patients who meet certain financial criteria or lack insurance.
• Copay Cards: Patients with commercial insurance may qualify for copay cards that reduce their monthly out-of-pocket expenses.
• Non-profit Organizations: Various charitable foundations offer grants to help patients cover the costs of cancer medications and related expenses.

Patients are encouraged to speak with their healthcare provider, pharmacist, or insurance company to understand the specific costs and assistance options available to them.