EGFR is considered a key therapeutic target in oncology because it is overexpressed in several types of cancer. For example, overactivity of EGFR drives the progression of NSCLC. 117 Erlotinib, gefitinib, and lapatinib are reversible non-covalent tyrosine kinase inhibitors (TKIs), which have been approved for the treatment of NSCLC and HER2 receptor positive breast cancer patients. 118-120 However, kinases have acquired resistance to the reversible TKIs over time. To circumvent resistance, second generation TKIscovalent inhibitors were strategically designed with acrylamide Michael acceptors to react with the cysteine residue (Cys797) in EGFR. These TKIs inhibit phosphorylation of EGFR irreversibly, providing prolonged suppression of EGFR signaling and showing greater efficacy than reversible first-generation inhibitors. Afatinib and dacomitinib are successful examples of such second generation irreversible covalent TKIs. Afatinib has been approved for clinical use in adult patients with advanced or metastatic NSCLC with the L858R mutation. The third generation of EGFR inhibitors that selectively target the T790M mutant over wild-type EGFR has been developed. They include WZ4002 122 , osimertinib , rociletinib (CO-1686) and the active clinical candidates nazartinib 126, 127 and avitinib. These agents generally bind to the ATP-binding site of mutant EGFR in a U-shaped conformation, positioning an acrylamide group to form a covalent bond with Cys797. Replacement of the quinazoline moiety in first-and second-generation compounds with a pyrimidine yielded compounds with high selectivity for mutant EGFR (T790M) over wildtype EGFR. The higher affinity of third-generation EGFR inhibitors for T790M over wildtype EGFR not only results in efficacy in cancers with the EGFR gatekeeper mutation but also contributes to an improved safety profile and enables a higher recommended dose for osimertinib than for afatinib. These novel EGFR and HER2 inhibitors may offer a novel therapeutic option for patients with mutant EGFR NSCLC.