Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, most prevalently L858R and exon19del, are common causes of non-small cell lung cancer (NSCLC) and often serve as predictive markers for the selection of EGFR tyrosine kinase inhibitors (TKIs) as effective targeted therapies. Prolonged efficacy of first-generation TKIs (gefitinib and erlotinib) is eventually made limited due to drug resistance as a result of patients acquiring a second T790M "gatekeeper" mutation. To produce a viable treatment option for T790M-positive NSCLC tumors, drug development efforts have yielded the clinically-approved drug AZD9291 (osimertinib), which is selective for T790M-containing EGFR and made potent by forming an irreversible covalent bond to C797. Despite promising indications, drug resistance to osimertinib is inevitable and caused in part by the acquisition of a third kinase domain mutation C797S that prevents formation of the potency-enabling covalent bond. More recently, osimertinib has been shown effective, and clinically-approved, as a front-line therapy in untreated patients harboring EGFR L858R and exon19del activating mutations. 6 As osimertinib is the only approved third-generation EGFR TKI for L858R and exon19del EGFR mutant tumors, development efforts from Yuhan and Janssen biotech sought to produce a drug with improved medicinal chemistry properties. These efforts resulted in YH25448 (lazertinib), which is structurally related to osimertinib comprising an aminopyrimidine core and acrylamide warhead but is distinct with respect to the substituted pyrazole as well as morpholine groups (Figure ). Preclinical head-to-head or in combination with the antibody Amivantamab (NCT04077463), and is currently approved to treat T790M-containing NSCLC in the Republic of Korea. Regardless of these improvements, drug resistance to lazertinib has been shown to be due to the acquisition of C797S mutation. 9-10 Despite the improved properties and positive clinical outlook, no crystal structures have been reported detailing the molecular basis for lazertinib inhibition of mutant EGFR.