dacomitinib

Dacomitinib is an oral, irreversible tyrosine kinase inhibitor that targets members of the epidermal growth factor receptor (EGFR) family, also known as the ErbB receptors. It binds covalently to the kinase domains of EGFR (HER1), HER2, and HER4, producing durable inhibition of signaling pathways involved in tumor cell proliferation and survival.

Indications and mechanism of action: It is approved for the first-line treatment of adults with metastatic non-small cell lung cancer whose tumors harbor activating mutations in EGFR (such as exon 19 deletions or L858R point mutations). It is not indicated for EGFR-wild-type NSCLC. By inhibiting multiple HER family receptors, dacomitinib aims to suppress signaling pathways that drive tumor growth.

Clinical efficacy: In the ARCHER 1050 trial, dacomitinib demonstrated superior progression-free survival compared with gefitinib in untreated EGFR-mutated NSCLC, with a notable increase in PFS but higher rates of treatment-related adverse events. Overall survival results were not clearly superior in that study; toxicity is a consideration in selecting therapy.

Administration and dosing: The usual starting dose is 45 mg taken orally once daily, with or without food. Dose reductions to 30 mg or 15 mg daily are used for intolerable or persistent adverse events. Treatment continues until disease progression or unacceptable toxicity.

Adverse effects and safety: The most common adverse events are diarrhea, rash or dermatitis acneiform, stomatitis, decreased appetite, and weight loss. Other risks include interstitial lung disease, keratitis, hypomagnesemia, and liver enzyme elevations. Patients require monitoring for pulmonary toxicity, skin toxicity, electrolyte disturbances, and liver function, with dose modification or discontinuation as needed. Dacomitinib is metabolized by hepatic cytochrome P450 enzymes and may interact with CYP inhibitors or inducers.