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Brigatinib – Mechanism, Dosage & Side Effects

Brigatinib is a targeted cancer therapy used to treat ALK-positive non-small cell lung cancer. It blocks specific signaling pathways that drive tumor growth.

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Things worth knowing about "Brigatinib"

Brigatinib is a targeted cancer therapy used to treat ALK-positive non-small cell lung cancer. It blocks specific signaling pathways that drive tumor growth.

What is Brigatinib?

Brigatinib is a second-generation tyrosine kinase inhibitor (TKI) used in the treatment of ALK-positive non-small cell lung cancer (NSCLC). It belongs to the class of targeted therapies and is marketed under the brand name Alunbrig. The drug has been approved by both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA).

Indication

Brigatinib is indicated for adults with advanced ALK-positive non-small cell lung cancer. It is approved both as a first-line treatment for patients who have not previously received ALK-directed therapy and as a second-line option for patients who have progressed on or are intolerant to the first-generation ALK inhibitor crizotinib.

Mechanism of Action

Brigatinib works by selectively targeting and inhibiting the anaplastic lymphoma kinase (ALK), an enzyme that becomes permanently activated in certain lung cancers due to a chromosomal rearrangement known as the EML4-ALK fusion. This overactive kinase drives uncontrolled cell proliferation and tumor spread. By blocking ALK activity, brigatinib suppresses tumor growth and induces cancer cell death.

In addition to ALK, brigatinib also inhibits several other kinases, including:

ROS1: another kinase implicated in NSCLC
EGFR (Epidermal Growth Factor Receptor): a key growth signaling receptor
IGF-1R: Insulin-like Growth Factor 1 Receptor
FLT3: a kinase involved in certain leukemias

A key advantage of brigatinib is its potency against a broad spectrum of ALK resistance mutations that develop after treatment with first-generation inhibitors such as crizotinib, making it effective in resistant disease settings.

Dosage and Administration

Brigatinib is taken orally as a tablet once daily, following a two-step dosing schedule:

Days 1 to 7: 90 mg once daily (lead-in dose to assess tolerability)
From Day 8 onwards: 180 mg once daily (therapeutic dose), provided no significant pulmonary symptoms occur during the lead-in period

Tablets can be taken with or without food. Dose reductions or interruptions may be required based on the severity of side effects.

Side Effects

Like all cancer medications, brigatinib can cause side effects. Commonly reported adverse effects include:

Pulmonary toxicity: Early-onset pneumonitis (lung inflammation), particularly within the first week of treatment – a rare but serious complication
Hypertension (high blood pressure)
Bradycardia (slow heart rate)
Elevated liver enzymes (AST, ALT)
Elevated creatine kinase levels (a marker of muscle damage)
Nausea, diarrhea, and vomiting
Fatigue and weakness
Visual disturbances
Peripheral neuropathy (tingling or numbness in the hands and feet)

Early-onset pulmonary events, including interstitial lung disease and pneumonitis, occur in a small proportion of patients and are most likely to develop during the first week of therapy, requiring close monitoring.

Drug Interactions

Brigatinib is primarily metabolized by the liver enzyme CYP3A4. Therefore, substances that inhibit or induce this enzyme can significantly affect brigatinib blood levels:

Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) increase brigatinib plasma concentrations and may enhance the risk of adverse effects.
Strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, St. John's Wort) lower brigatinib levels and may reduce its therapeutic efficacy.

Clinical Evidence

The efficacy and safety of brigatinib were comprehensively demonstrated in the pivotal ALTA-1L trial (Phase 3 study). In this trial, brigatinib showed a significantly higher progression-free survival rate compared to crizotinib in treatment-naive ALK-positive NSCLC patients. Intracranial activity – meaning the ability to control brain metastases – was also significantly superior with brigatinib, which is clinically important given the tendency of ALK-positive NSCLC to spread to the brain.

References

European Medicines Agency (EMA): Alunbrig (Brigatinib) - Summary of Product Characteristics and Assessment Report. Available at: https://www.ema.europa.eu
Camidge DR et al. - Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. New England Journal of Medicine, 2018; 379:2027-2039.
National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology - Non-Small Cell Lung Cancer. Available at: https://www.nccn.org

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