Brigatinib

Approved Uses

Brigatinib is used to treat adults with a type of lung cancer called non-small cell lung cancer (NSCLC). It is specifically indicated for cancer that is:

• Metastatic: The cancer has spread from the lungs to other parts of the body.
• ALK-positive: The cancer cells have a specific genetic change involving the anaplastic lymphoma kinase (ALK) gene.

Before starting treatment, a healthcare provider will perform a specific test to confirm that the cancer is ALK-positive. This medication is designed to target and block the abnormal proteins produced by this gene change, which helps slow or stop the growth of cancer cells.

Mechanism of Action

Brigatinib belongs to a class of drugs called tyrosine kinase inhibitors. It is designed to target and block the activity of certain abnormal proteins in the body, most notably the anaplastic lymphoma kinase (ALK) protein.

In some types of non-small cell lung cancer, the ALK gene becomes altered, causing the body to produce an overactive ALK protein. This abnormal protein sends constant signals to cancer cells, telling them to divide and multiply rapidly. Brigatinib works by:

• Binding to the ALK protein: By attaching to the protein, the drug prevents it from sending growth signals.
• Inhibiting other targets: It also blocks other proteins, such as ROS1, which can contribute to cancer progression.
• Slowing tumor growth: By cutting off these signaling pathways, the medication helps slow down or stop the spread of the cancer.

Because brigatinib targets specific proteins found primarily on or in cancer cells, it is considered a targeted therapy. This approach aims to interfere with the specific molecules involved in tumor growth rather than affecting all rapidly dividing cells in the body.

Common Side Effects

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

• Nausea, vomiting, diarrhea, or constipation
• Fatigue or feeling weak
• Headache
• Cough
• Muscle, joint, or back pain
• Decreased appetite
• Rash, dry skin, or itching
• Dizziness
• Numbness or tingling in the hands or feet

Serious Side Effects

Some side effects can be severe and require immediate medical attention. Contact a healthcare provider right away if you experience:

• Lung problems: New or worsening shortness of breath, chest pain, or cough, especially during the first week of treatment.
• High blood pressure: Headaches, dizziness, or blurred vision.
• Heart rate changes: A very slow heartbeat or feeling lightheaded.
• Vision changes: Blurred vision, double vision, or increased sensitivity to light.
• Muscle damage: Unexplained muscle pain, tenderness, or weakness.
• High blood sugar: Increased thirst, frequent urination, or feeling very hungry.
• Pancreatitis: Severe pain in the upper stomach that may spread to the back, often with nausea and vomiting.
• Liver problems: Yellowing of the skin or eyes (jaundice), dark urine, or pain on the right side of the stomach.

Lung Problems

Brigatinib may cause severe, life-threatening, or fatal inflammation of the lungs, known as interstitial lung disease or pneumonitis. These symptoms often occur within the first week of treatment. Healthcare providers monitor for new or worsening respiratory symptoms, such as shortness of breath, cough, or fever.

Heart and Blood Pressure Changes

• High Blood Pressure: Hypertension is a common side effect. Blood pressure is typically monitored before starting treatment and regularly thereafter.
• Slow Heart Rate: This medication can cause bradycardia (a slow heart rate). Monitoring of heart rate and blood pressure is necessary, especially for those taking other medications that lower heart rate.

Vision Disturbances

Visual changes, including blurred vision, double vision, or seeing flashes of light, may occur. Any changes in vision require medical evaluation.

Laboratory Abnormalities

• Muscle Enzymes: Increased levels of creatine phosphokinase (CPK) may occur, which can indicate muscle damage. Symptoms include unexplained muscle pain or weakness.
• Pancreatic Enzymes: Elevations in amylase and lipase levels may occur during treatment.
• Blood Sugar: Brigatinib can cause high blood sugar (hyperglycemia). Monitoring is especially important for individuals with diabetes or glucose intolerance.

Sun Sensitivity

This medication can increase sensitivity to sunlight. Protective measures, such as sunscreen and protective clothing, are recommended during treatment and for several days after the last dose.

Pregnancy Risks

Brigatinib can cause fetal harm when administered to pregnant individuals. Effective contraception is recommended for both females and males with female partners of reproductive potential during treatment and for a period following the final dose.

Pregnancy and Contraception

Brigatinib may cause birth defects or the death of an unborn baby. Healthcare providers typically require a pregnancy test before starting treatment to confirm that a patient is not pregnant. If you are pregnant or planning to become pregnant, it is important to discuss the potential risks with your healthcare team.

Effective birth control is required for patients of reproductive potential during and after treatment:

• Females: Use effective birth control during treatment and for at least 4 months after the final dose. Brigatinib may interact with hormonal contraceptives (such as pills, patches, or injections), making them less effective. Non-hormonal birth control methods are generally recommended.
• Males: Men with female partners who are able to become pregnant should use effective birth control during treatment and for at least 3 months after the final dose.

Breastfeeding

It is not known whether brigatinib passes into breast milk. Because of the potential for serious adverse reactions in a nursing infant, breastfeeding is not recommended during treatment and for at least 1 week after the last dose of the medication.

Dosage Forms

Brigatinib is available as a tablet to be taken by mouth. It is typically administered once daily, with or without food.

The tablets are intended to be swallowed whole. They should not be crushed, chewed, or broken before swallowing.

FDA Approval History

Brigatinib received its initial FDA approval in April 2017 under the accelerated approval pathway. This original indication was for patients with metastatic ALK-positive non-small cell lung cancer (NSCLC) who had progressed on or were intolerant to crizotinib.

In May 2020, the FDA granted full approval for brigatinib as a first-line treatment for adult patients with metastatic ALK-positive NSCLC. This expanded the drug's use to include patients who have not previously received treatment for their metastatic disease.

Regulatory Status and Availability

• Biomarker Requirement: FDA-approved labeling requires the confirmation of an ALK-positive tumor status using a validated test before beginning therapy.
• Generic Availability: There is currently no generic version of brigatinib available in the United States. It is only available under the brand name Alunbrig.
• Safety Oversight: There are no boxed warnings or Risk Evaluation and Mitigation Strategy (REMS) requirements for this medication.

Initial FDA Approval

Brigatinib was first approved by the U.S. Food and Drug Administration (FDA) in April 2017. This initial accelerated approval was specifically for patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who had previously taken crizotinib but saw their condition worsen or were unable to tolerate the medication.

Expanded Approval for First-Line Treatment

In May 2020, the FDA expanded the approved use of brigatinib. It is now indicated for the first-line treatment of adult patients with ALK-positive metastatic NSCLC. This expansion allows healthcare providers to prescribe the medication to patients who have not yet received other systemic therapies for their metastatic disease.

Regulatory Designations

The FDA granted brigatinib several special statuses during its clinical development to help bring the therapy to patients more quickly. These included:

• Breakthrough Therapy: A designation intended to expedite the development and review of drugs for serious or life-threatening conditions.
• Orphan Drug: A status given to drugs developed for rare diseases or conditions.
• Priority Review: A designation for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions.