Osimertinib is a highly potent and selective third-generation epidermal growth factor receptor (EGFR) inhibitor, which provides excellent clinical benefits and is now a standard-of-care therapy for advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, AZ5104, a primary toxic metabolite of osimertinib, has caused unwanted toxicities. To address this unmet medical need, we initiated an iterative program focusing on structural optimizations of osimertinib and preclinical characterization, leading to the discovery of a highly potent, selective, and orally efficacious deuterated EGFR-targeting clinical candidate, dosimertinib. Preclinical studies revealed that dosimertinib demonstrated robust in vivo antitumor efficacy and favorable PK profiles, but with lower toxicity than osimertinib. These preclinical data support further clinical development of dosimertinib for the treatment of NSCLC. Dosimertinib has received official approval in China to initiate the phase I clinical trial (registration numbers: CXHL2000060 and CXHL2000061).