BLU-945, a highly potent and selective oral EGFR inhibitor, was generally well tolerated at clinically active doses in heavily pre-treated patients with EGFRm NSCLC, with few AEs characteristic of wildtype EGFR toxicity observed at doses up to 400 mg QD. Despite presence of EGFR mutations conferring resistance to osimertinib, treatment with BLU-945 resulted in rapid dose-dependent reduction in ctDNA, consistent with preclinical data. Increasing BLU-945 doses were associated with increasing antitumor activity, with tumor shrinkage noted at doses of 200 mg QD and above, including an unconfirmed partial response at 400 mg QD. The clonal evolution and resulting mutational complexity of EGFR driven NSCLC tumor cells demonstrates the need for precision medicine combinations to improve clinical outcomes. Initial safety and clinical activity results from the phase 1 SYMPHONY trial support expanded clinical development of BLU-945 in combination with osimertinib and other complementary agents. Dose escalation continues to determine the MTD and RP2D of BLU-945 as a monotherapy and in combination with Osimertinib.