Safety and antitumor activity of VRN110755, a brain-penetrant, selective EGFR inhibitor, in patients with EGFR-driven non–small cell lung cancer.

Abstract

8623 Background: Third-generation EGFR tyrosine kinase inhibitors (TKIs) have improved outcomes in EGFR-mutant non–small cell lung cancer (NSCLC); however, acquired resistance, including EGFR C797S mutations, and central nervous system (CNS) progression remain major unmet medical needs. VRN110755 is an orally available, highly selective EGFR inhibitor designed to target a broad spectrum of EGFR mutations, including C797S, and has demonstrated robust brain penetration in preclinical models. Methods: This ongoing, open-label, multicenter Phase I/II study evaluates the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of VRN110755 in patients with EGFR-mutant NSCLC who progressed on prior third-generation EGFR TKIs and had no remaining standard treatment options. A dose-escalation phase (10–480 mg once daily) followed by protocol-defined backfill cohorts (80–400 mg) was conducted. Patients with stable, asymptomatic brain metastases and/or leptomeningeal metastases were eligible. This abstract reports data available at the time of analysis to characterize emerging safety, PK, and antitumor activity and to inform ongoing dose optimization and cohort expansion under protocol-defined safety monitoring. Early reporting was undertaken due to emerging systemic and intracranial activity in a population with high unmet medical need; enrollment and follow-up are ongoing. Results: As of January 18, 2026, 63 patients were enrolled. VRN110755 demonstrated dose-proportional PK. At 320 mg, target engagement (C trough /IC 50 ) against common EGFR mutations exceeded that of osimertinib 80 mg by approximately four-fold. Treatment-related adverse events were predominantly low grade (grade 1: 37%; grade 2: 20%; grade 3: 2%), with no dose-limiting toxicities observed; the most common event was grade 1 rash (16%). Low rates of diarrhea were reported, with no interstitial lung disease or clinically meaningful QTc prolongation observed to date. Among 38 response-evaluable patients treated at doses ≥160 mg following progression on prior EGFR TKIs, 7 (18.4%) achieved partial responses and 28 (73.7%) achieved stable disease, yielding a disease control rate of 92.1%; approximately half remained on treatment beyond 7.5 months, suggesting durable disease control. In patients with baseline EGFR C797S mutations (n=7), the overall response rate was 85.7% (6/7), with ctDNA clearance of C797S observed in 83.3% (5/6) of responders. Complete intracranial responses were observed in two patients, and a K p,uu,CSF of 2.0 was documented at the 160 mg dose. Conclusions: VRN110755 demonstrated favorable PK, a manageable safety profile, and encouraging systemic and CNS antitumor activity in heavily pretreated EGFR-mutant NSCLC, including C797S-positive disease, supporting continued clinical development. Clinical trial information: VRN110755_01.