2023 World Conference on Lung Cancer (Posters)-P2.09. VRN110755, A New Therapeutic Option for EGFR Mutation-Driven NSCLC with Brain Metastasis or 1st-line Osimertinib-Resistant EGFR Mutations

P2.09. VRN110755, A New Therapeutic Option for EGFR Mutation-Driven NSCLC with Brain Metastasis or 1st-line Osimertinib-Resistant EGFR Mutations - PDF(Abstract)

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This abstract discusses a new therapeutic option for patients with metastatic non-small cell lung cancer (NSCLC) who have EGFR mutations and brain metastasis or are resistant to the drug osimertinib. Currently, osimertinib is recommended as a first-line therapy for NSCLC patients with EGFR mutations, but there are still unmet medical needs in this area. The authors highlight three main limitations of current EGFR therapies: acquired resistant EGFR mutations, rare EGFR mutations, and brain metastases in patients with osimertinib-resistant EGFR mutations. They introduce VRN110755, a brain permeable and EGFR mutant selective inhibitor that can overcome these limitations.<br /><br />The authors present nonclinical data on VRN110755, including its kinase selectivity and in vitro and in vivo efficacy. VRN110755 was found to be a potent and highly selective inhibitor of EGFR mutants that spares wild-type EGFR. It showed sub-nanomolar inhibition of a subset of EGFR mutations in kinase catalytic inhibition assays and had higher cellular potency against EGFR mutant-dependent cells compared to wild-type EGFR-dependent cells. In vivo studies demonstrated that VRN110755 had comparable or superior efficacy to approved EGFR tyrosine kinase inhibitors (TKIs), including osimertinib, against osimertinib-resistant EGFR mutants and uncommon EGFR mutants. In particular, VRN110755 showed superior efficacy to other TKIs in intracranial in vivo models, suggesting it could be more beneficial for NSCLC patients with brain metastases.<br /><br />The pharmacokinetic studies showed that VRN110755 has higher brain permeability than approved EGFR TKIs, including osimertinib. Animal models also indicated that target engagement was maintained for 48 hours after a single oral administration of VRN110755, suggesting a long half-life and residency in the tumor. GLP toxicological studies suggested that VRN110755 has an excellent safety profile for future clinical trials.<br /><br />Based on these nonclinical data, the authors conclude that VRN110755 could be a potential treatment option for patients with EGFR mutation-driven NSCLC who have brain metastasis or are resistant to first-line osimertinib. The first-in-human study for VRN110755 is planned for 2023.

Asset Subtitle

Sunghwan Kim

Meta Tag

Speaker Sunghwan Kim

Topic Metastatic NSCLC: Targeted Therapy - EGFR/HER2

Keywords

metastatic non-small cell lung cancer

NSCLC

EGFR mutations

brain metastasis

osimertinib resistance

therapeutic option

EGFR therapies

VRN110755

kinase selectivity

in vivo efficacy