Abstract A093: VRN110755 Shows Promise with Improved Efficacy in EGFR mutation NSCLC: Highlighting CNS activity, Potency Against Resistant EGFR Mutations, and a Favorable Safety Profile

Abstract Purpose: This study aims to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anticancer activity of VRN110755 in patients with non-small cell lung cancer (NSCLC) harboring epithelial growth factor receptor (EGFR) mutants, including common driver and intrinsic/acquired resistant mutations. Methods (VRN110755_01, Phase I/II, Korea and Taiwan): This is an open-label, multicenter, phase I/II study. It's evaluating the safety, tolerability, PK, PD, and anti-tumor efficacy of VRN110755 in NSCLC patients with EGFR mutations who have undergone prior systemic treatments, including EGFR tyrosine kinase inhibitors (TKI). The primary endpoint of the phase I study is to determine the maximal tolerable dose (MTD) and the recommended dose for phase II (RP2D). Patients receive VRN110755 (10 mg to 400 mg, once daily) on a 28-day cycle. Results (as of July 10, 2025): Thirty-seven patients have received VRN110755 at doses up to 240 mg from the dose-limiting toxicity (DLT) assessment cohorts (10, 20, 40, 80, 160, and 240 mg) and backfill cohorts (80, 160, and 240 mg). The median number of prior systemic treatments was 3, ranging from 1 to 15. Notably, across all cohorts from 10 mg to 240 mg, no DLTs and no Grade 2/3/4 treatment-related adverse events (TRAE) were observed. All reported treatment-related adverse events (TRAEs) were G1: skin rash (8.1%), pruritus (5.4%), dry skin (5.4%), and diarrhea (5.4%). PK analysis revealed that plasma drug concentrations at doses above 40 mg consistently remained higher than the IC50 values of various EGFR mutants, including Del19, L858R, Del19-C797S, L858R-C797S, G719X, and L861Q. This suggests that clinical benefit is expected from doses of 40 mg or higher. Encouragingly, a patient who had progressed with a C797S mutation after osimertinib treatment showed a 51% tumor reduction with 40 mg of VRN110755. This finding highlights VRN110755 as a novel therapeutic option for C797S resistance following third-generation EGFR TKI treatment. For 15 tumor-assessment-evaluable patients treated with 80 mg and higher doses, the disease control rate (DCR) was 75%, regardless of resistance mechanisms to prior treatment (including TP53 mutations at 53%, T790M at 33%, EGFR amplification at 20%, and C797S at 7%). Within 10 patients in the subgroup with brain metastases (BM), the DCR was an impressive 80%. Conclusion: VRN110755 demonstrated clinically meaningful antitumor activity and was well-tolerated in patients, even with heavily pre-treated NSCLC harboring EGFR mutations. VRN110755 is anticipated to offer significant advantages over first-, second-, and third-generation EGFR TKIs due to its potential for improved efficacy through high CNS activity, potency against intrinsic/acquired resistant EGFR mutations, and a more favorable safety profile. Citation Format: Myung-Ju Ahn, Ki Hyeong Lee, Chia-Chi Lin, Byoung-Yong Shim, Min Hee Hong, Hye Ryun Kim, Yu Jung Kim, Jen-Yu Hung, Sunghwan Kim, Shuang Yin. Zhang. VRN110755 Shows Promise with Improved Efficacy in EGFR mutation NSCLC: Highlighting CNS activity, Potency Against Resistant EGFR Mutations, and a Favorable Safety Profile [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A093.