Background: Despite the availability of multiple EGFR tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC), durable disease control remains limited by the emergence of resistance mutations. Covalent third-generation EGFR TKIs lose inhibitory activity in the presence of the C797S mutation, representing a major unmet clinical need. VRN110755 is a novel, long-resident non-covalent EGFR TKI designed to retain high potency across common and uncommon activating EGFR mutations while maintaining activity against resistance mutations. Methods: This ongoing Phase 1a dose-escalation study evaluated the safety, pharmacokinetics (PK), and preliminary antitumor activity of VRN110755 administered orally at doses up to 480 mg. For exploratory subgroup analysis, patients with EGFR C797S-positive tumors were identified by local molecular testing performed within three months prior to Cycle 1 Day 1 or by central circulating tumor DNA (ctDNA) analysis. Molecular responses were assessed longitudinally using plasma ctDNA. Results: At the data cutoff, no dose-limiting toxicities were observed at doses up to 480 mg. VRN110755 demonstrated a favorable safety profile relative to the established safety profile of approved-dose osimertinib. Among seven patients with confirmed EGFR mutations including C797S, six achieved a partial response (PR), corresponding to a confirmed objective response rate of 85.7%. Molecular response assessment demonstrated ctDNA reduction in all five evaluable patients, with complete ctDNA clearance observed in four. PK analysis showed dose-proportional systemic exposure, with plasma concentration exceeding the IC 90 for relevant EGFR mutations beginning at 160 mg, supporting a robust pharmacokinetic-pharmacodynamic relationship consistent with observed clinical activity. Conclusion: VRN110755 demonstrates promising clinical activity and a favorable safety profile in patients with EGFR-mutated NSCLC, including those harboring resistance-associated EGFR alterations. By targeting key resistance mechanisms while maintaining high potency against activating EGFR mutations, VRN110755 represents a promising next-generation EGFR inhibitor. These findings support further clinical evaluation of VRN110755 both following failure of third-generation EGFR TKIs and in earlier lines of therapy.