Dynamic therapeutic response to osimertinib and immunotherapy in an EGFR L747S and L858R co-mutant NSCLC

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are recommended as the first-line standard treatment for advanced lung adenocarcinoma with common EGFR sensitive mutations (exon 19 E746-A750 deletion and exon 21 L858R). However, the optimal management for rare or compound EGFR mutations remains undefined.

We report a case of advanced lung adenocarcinoma with a rare compound EGFR L747S/L858R mutation. The patient underwent four lines of therapy, showing significant responses to alternating cycles of Osimertinib and Pembrolizumab-chemotherapy, despite intervening disease progression. The clinical course culminated in fatal treatment-induced myelosuppression, with an overall survival exceeding 43 months.

This case underscores dynamic clonal evolution in advanced NSCLC: the initial L747S/L858R clone showed Osimertinib sensitivity, while subsequent resistance revealed a distinct profile (distinct TP53 mutation, MET amplification, high PD-L1/TMB) that explained the durable response to Pembrolizumab. These findings provide crucial evidence for sequential therapy strategies in compound EGFR mutations. Our findings also highlight the utility of Next Generation Sequencing (NGS) in identifying targetable resistance mechanisms, enabling prolonged survival in patients with compound EGFR mutations and offering valuable insights for clinical decision-making.