Efficacy of Conventional and Novel Tyrosine Kinase Inhibitors for Uncommon EGFR Mutations-An In Vitro Study

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Current treatments for non-small cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations, such as afatinib and osimertinib, have limited efficacy.
• Exploring novel therapeutic strategies is crucial for improving outcomes in these patients.

Purpose of the Study:

• To evaluate the efficacy of conventional and novel third-generation (3G) EGFR tyrosine kinase inhibitors (TKIs) against uncommon EGFR mutations in vitro.
• To identify TKIs that can overcome acquired resistance mutations to afatinib or osimertinib.

Main Methods:

• Utilized Ba/F3 cell lines engineered with five common uncommon EGFR mutations (Del18, E709K, G719A, S768I, L861Q).
• Assessed the growth inhibitory effects of afatinib, five 3G-TKIs (almonertinib, lazertinib, furmonertinib, rezivertinib, befotertinib), and other available TKIs.
• Investigated acquired resistance mutations and evaluated TKI efficacy against these resistant models.

Main Results:

• Afatinib demonstrated activity against all tested uncommon EGFR mutations.
• All tested 3G-TKIs were active against the L861Q mutation but inactive against S768I.
• Furmonertinib and befotertinib showed efficacy against exon 18 mutations (Del18, E709K, G719A).
• Lazertinib could overcome T790M and T725M resistance mutations found in afatinib- and osimertinib-resistant models, respectively.
• Some afatinib-resistant cells acquired V769L/M mutations, which were resistant to all tested EGFR-TKIs.

Conclusions:

• Afatinib exhibits broad activity, and certain 3G-TKIs show promise for front-line treatment of NSCLC with uncommon EGFR mutations.
• Lazertinib represents a potential second-line therapy option following the development of resistance to afatinib or osimertinib.