Dacomitinib is an irreversible, second-generation pan-HER tyrosine kinase inhibitor that selectively targets EGFR, HER2, and HER4. It is approved for the first-line oral treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletion or exon 21 L858R substitution mutations, as detected by an FDA-approved test. By covalently binding to the kinase domain, dacomitinib blocks downstream signaling pathways that drive cancer cell proliferation, survival, and metastasis, leading to tumor growth inhibition. It demonstrated superior progression-free survival compared to first-generation EGFR TKIs like gefitinib in clinical trials. Research is ongoing for its potential in other EGFR-driven cancers, including head and neck squamous cell carcinoma, either as monotherapy or in combination therapies.