Dacomitinib

Approved Indications:

• Non-Small Cell Lung Cancer (NSCLC):
• First-line treatment of patients with metastatic NSCLC harboring activating epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, confirmed by an FDA-approved test.
• Used in patients with locally advanced or metastatic disease.

Clinically Accepted Off-label Uses:

• Treatment of EGFR-mutated NSCLC in earlier or other lines of therapy (off-label, investigational).
• Potential use in other solid tumors expressing EGFR mutations (under clinical trial).

Adults:

• Recommended Dose: 45 mg orally once daily.
• Take at least 1 hour before or 2 hours after a meal to maximize absorption.
• Continue until disease progression or unacceptable toxicity.

Dose Modifications:

• For Adverse Reactions: Dose interruptions, reductions (to 30 mg, then 15 mg daily), or discontinuation may be required.
• No established dose adjustment for mild to moderate renal impairment; use with caution in severe renal impairment.
• Hepatic Impairment: Use caution in moderate or severe impairment; no formal dose recommendations.
• Elderly: No specific dose adjustment but monitor for toxicity.

Pediatrics:

• Safety and efficacy not established.

Dacomitinib is an oral, irreversible pan-HER (human epidermal growth factor receptor) tyrosine kinase inhibitor that covalently binds to and inhibits EGFR (HER1), HER2, and HER4 receptors. By irreversibly blocking the tyrosine kinase activity of these receptors, dacomitinib prevents autophosphorylation and downstream signaling pathways such as RAS-RAF-MEK-ERK and PI3K-AKT, which are responsible for tumor cell proliferation and survival. This leads to inhibition of tumor growth and induction of apoptosis in EGFR-mutant NSCLC cells.

Absorption:

• Peak plasma concentrations reached approximately 6 hours post-dose.
• Absolute bioavailability unknown; food may delay absorption but does not significantly affect extent.

Distribution:

• Highly protein bound (~98%).
• Volume of distribution approximately 2,200 L.

Metabolism:

• Metabolized primarily by CYP2D6 enzyme to inactive metabolites.

Elimination:

• Excreted mainly via feces (~79%) and urine (~3%).
• Half-life approximately 70 hours, supporting once-daily dosing.

• Pregnancy:
• No assigned FDA pregnancy category.
• Animal studies showed fetal toxicity and embryo-fetal lethality at clinically relevant exposures.
• Use during pregnancy only if potential benefit justifies potential risk.
• Lactation:
• Unknown if excreted in human milk.
• Breastfeeding not recommended during treatment.

• Primary Class: Antineoplastic agent
• Subclass: Tyrosine kinase inhibitor (TKI), irreversible pan-HER inhibitor

• Known hypersensitivity to dacomitinib or any excipients.
• Concomitant use with strong CYP2D6 inhibitors or inducers that may alter drug levels (unless closely monitored).
• Severe uncontrolled intercurrent illness (relative contraindication).

• Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening respiratory symptoms; discontinue if ILD suspected.
• Dermatologic Toxicity: Common rash and dry skin; severe cases require management or dose adjustment.
• Diarrhea: Monitor and treat promptly to prevent dehydration.
• Hepatotoxicity: Monitor liver function tests periodically.
• Cardiac Effects: QT prolongation risk unknown but caution advised in patients with cardiac risk factors.
• Ophthalmologic Effects: Rare reports of keratitis; monitor visual symptoms.
• Embryo-Fetal Toxicity: Counsel women of childbearing potential.

Common (≥20%):

• Diarrhea
• Rash/acneiform dermatitis
• Stomatitis/mucositis
• Paronychia
• Decreased appetite
• Fatigue
• Dry skin

Serious (≤5%):

• Interstitial lung disease/pneumonitis
• Severe dermatologic reactions (e.g., exfoliative dermatitis)
• Hepatotoxicity
• Cardiovascular events (rare)

Timing:

• Rash and diarrhea often begin within the first 1–2 weeks of therapy.
• ILD can occur anytime; vigilance needed.

• CYP2D6 Substrate: Inhibitors (e.g., fluoxetine) may increase dacomitinib levels; inducers (e.g., rifampin) may reduce efficacy.
• PPIs and H2 blockers: May reduce dacomitinib absorption; separate dosing timing recommended.
• P-glycoprotein: Minor involvement; interactions possible but less significant.
• Avoid St. John’s Wort (CYP inducer).
• Alcohol may increase risk of hepatotoxicity; limit consumption.

• 2024 oncology guidelines reinforce dacomitinib as a first-line option for EGFR-mutated metastatic NSCLC.
• Emphasis on managing adverse effects to improve tolerability and adherence.
• Ongoing trials evaluating combination therapies and resistance mechanisms.
• FDA updates on risk communication about ILD and dermatologic toxicities.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light; keep in original container.
• Do not freeze.
• Handle capsules with dry hands.