Characterization of a rare EGFR resistance mutation in a lung cancer patient with a long response to osimertinib: case report.

INTRODUCTION

Osimertinib is the standard of care in first-line therapy for advanced EGFR-mutant NSCLC, but resistance invariably develops through EGFR-dependent or independent mechanisms.

CASE DESCRIPTION: Here, we report the case of a stage IVA adenocarcinoma patient with several metastases harboring an EGFR exon 19 deletion, which progressed locally after five years on osimertinib. Sequencing of the re-biopsy revealed the emergence of an acquired exon 20 mutation, p.(Cys797Ala), not previously characterized and absent from variant databases. Immunohistochemical analysis (IHC) showed phospho-EGFR positivity in the re-biopsy, indicating activation of the double mutant receptor and downstream pathways, while molecular modelling predicted resistance to osimertinib but sensitivity to fourth-generation TKIs. Based on these results, the patient was enrolled in a trial combining osimertinib with a SOS1 inhibitor, which targets a downstream effector of the EGFR pathway, deriving a clinical benefit.

DISCUSSION: This report of a patient with the rare p.(Cys797Ala) EGFR acquired mutation highlights the role of molecular modelling and IHC for phosphorylated proteins as tools to functionally characterize variants of unknown significance and help clinical decisions.