2024 World Conference on Lung Cancer (WCLC) - Posters-P3.03I.08 Efficacy of Novel Third-Generation Tyrosine Kinase Inhibitors for Uncommon EGFR Mutations- Anin Vitrostudy

P3.03I.08 Efficacy of Novel Third-Generation Tyrosine Kinase Inhibitors for Uncommon EGFR Mutations- Anin Vitrostudy

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This study assessed the efficacy of novel third-generation tyrosine kinase inhibitors (3G-TKIs) on uncommon EGFR mutations in non-small cell lung cancer (NSCLC), using Ba/F3 model cells. Current treatment guidelines recommend afatinib or osimertinib, but they show limited effectiveness for these mutations. This research explores whether novel 3G-TKIs are more effective.<br /><br />The study tested several 3G-TKIs, including almonertinib (also known as aumolertinib), lazertinib, alfultinib (furmonertinib), rezivertinib, and befotertinib, along with osimertinib. Five specific EGFR mutations—Del18, E709K, G719A, S768I, and L861Q—were evaluated due to their frequency among patients with uncommon EGFR mutations. The Ba/F3 cells used in the study were specifically driven by these EGFR mutations.<br /><br />Results showed that afatinib had the greatest inhibitory effect across all these uncommon mutations. While 3G-TKIs generally showed drug-specific rather than generation-specific activity, befotertinib displayed broad efficacy. However, specific 3G-TKIs, such as lazertinib, effectively counteracted resistance emerging from T790M and T725M secondary mutations which appeared after treatment with afatinib and osimertinib.<br /><br />The study also highlighted various secondary mutations that can act as resistance mechanisms against current 3G-TKIs. In particular, the T725M mutation was identified as a novel secondary mutation in cells with the G719A mutation, remaining sensitive to afatinib and lazertinib, suggesting a potential pathway to overcome some drug resistances. Furthermore, lazertinib’s flat molecular structure possibly aids its binding efficacy compared to other TKIs like osimertinib, which struggles due to its molecular protrusions.<br /><br />This research underscores the need for continued exploration of next-generation TKIs, especially those like befotertinib and lazertinib, to counteract resistance in uncommon EGFR mutations effectively.

Asset Subtitle

Hana Oiki

Meta Tag

Speaker Hana Oiki

Topic Tumor Biology – Translational Biology

Keywords

third-generation tyrosine kinase inhibitors

EGFR mutations

non-small cell lung cancer

Ba/F3 model cells

afatinib

osimertinib

lazertinib

befotertinib

drug resistance

secondary mutations