Abstract CT136: First-in-human studies of VRN110755 in NSCLC patients with EGFR mutations: Safety, pharmacokinetics, and early efficacy assessment

Abstract Metastatic non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations, such as Del19 and L858R, has seen significant therapeutic advancements with the development of effective systemic treatments. However, acquired resistance mutations (e.g., C797S), rare EGFR mutations, and brain/leptomeningeal metastases (BM/LM) in patients with intrinsic or acquired resistance to current standard-of-care (SoC) therapies remain critical unmet medical needs. VRN110755 is a novel therapeutic inhibitor exhibiting potent activity against EGFR-driven signaling. Preclinical studies demonstrated its inhibitory potency across a broad spectrum of EGFR mutations and established a correlation between pharmacokinetic (PK) exposure and anti-tumor efficacy in mouse models. In-cell Western analysis using human serum confirmed the PK-PD relationship. Notably, VRN110755 shows excellent brain permeability across multiple animal species suggesting its potential for efficient target engagement in both primary tumor and brain regions in humans. Human PK modeling predicts that a once-daily dose of 40 mg can inhibit tumor growth in EGFR-driven NSCLC patients with classical mutations and osimertinib-resistant C797S mutation. Furthermore, a dose of 160 mg is expected to exceed the IC50 values for all tested EGFR mutants while avoiding significant inhibition of wild-type EGFR. The Phase 1 dose-escalation study is ongoing in South Korea and Taiwan. Early cohort results confirmed a dose-proportional PK profile consistent with preclinical predictions. Up to 80 mg, there is no dose-limiting toxicity or EGFR-related toxicity above grade 1 reported, so far. Tumor assessments showed >40% tumor shrinkage in a patient with a C797S mutation, who had progressed after dacomitinib and osimertinib, after 4 weeks of 40 mg treatment. Additionally, another patient with a Del19 mutation, who had progressed after afatinib and platimum chemotherapy, demonstrated >20 % tumor shrinkage after 3 weeks of 80 mg treatment. These findings strongly support the translation of preclinical data into early clinical outcomes for VRN110755. In conclusion, the preclinical and early clinical outcomes of VRN110755 highlight its potential as a promising therapeutic option that can address unmet medical needs in advanced EGFR mutated NSCLC, including resistance to current standard-of-care therapies and progression with BM/LM. Citation Format: Sunghwan Kim, Chia-Chi Lin, Myung-Ju Ahn, Hong-ryul Jung, Donghyuk Seo, Somi Lee, Yeonsil Kim, Byungwoo Park, Rutu Dabhi, Sangho Jeon, Jihye Yoo, Younho Lee, Daekwon Kim. First-in-human studies of VRN110755 in NSCLC patients with EGFR mutations: Safety, pharmacokinetics, and early efficacy assessment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT136.