In conclusion, we have determined the molecular basis of the novel EGFR TKI lazertinib bound to EGFR in X-ray co-crystal structures showcasing that the lazertinib pyrazole ring binds facilitates H-bonds and van der Waals interactions consistent with drug efficacy and T790M selectivity. Structural and functional correlation to osimertinib and LN2057 demonstrate the importance of productive intermolecular interactions with T790M. Additionally, we find that lazertinib does not H-bond with K745, which likely contributes to lower potency for WT EGFR. Another important feature to lazertinib is the lack of potency on HER2 that is often associated with dose-limiting adverse events, as confirmed here in biochemical and cell-based studies. Our present structural analysis, however, does not reveal a discrete molecular origin for the preference of lazertinib for EGFR when compared to HER2. We speculate that differences in the sequence and dynamics of the HER2 kinase domain, as evident from reported crystal structures, negatively impacts lazertinib reversible binding to HER2 and not osimertinib and LN2057