Case Report: Longitudinal clonal evolution in EGFR-mutant lung adenocarcinoma with coexisting MET exon 14 skipping and EML4-ALK fusion and subsequent KRAS/BRAF bypass mutations

Acquired resistance to osimertinib in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer occurs through on-target mutations or bypass activation of alternative pathways. The longitudinal molecular evolution of a tumor across successive lines of therapy is rarely captured by repeat biopsy. We report a 68-year-old never-smoking woman with EGFR exon 19 deletion lung adenocarcinoma. First-line therapy achieved a partial response, with progression after 10.7 months; after 61 months of osimertinib, re-biopsy revealed concurrent EGFR T790M (9.3%), EML4-ALK fusion (E6:A20; 6.0%), and MET exon 14 skipping (c.3028G>T; 4.0%); aumolertinib plus ensartinib achieved stable disease for approximately 13 months. On further progression, a third biopsy showed molecular changes consistent with clonal evolution: the EML4-ALK fusion, MET exon 14 alteration, and EGFR T790M were no longer detected; the EGFR exon 19 deletion expanded to 47.71%; and KRAS G12R (10.17%), KRAS L19F (7.85%), BRAF D594N (8.13%), and BRAF E501K (6.38%) had emerged. Treatment with ivonescimab, a programmed cell death protein 1 and vascular endothelial growth factor bispecific antibody, plus pemetrexed and carboplatin, followed by pemetrexed plus ivonescimab, achieved stable disease; because chemotherapy was given concurrently, the contribution of ivonescimab cannot be isolated. PD-L1 (tumor proportion score <1%) was assessed on an earlier biopsy and blood tumor mutational burden was measured in 2019. This case is consistent with longitudinal clonal dynamics under sequential targeted therapy, namely regression of drug-sensitive clones and emergence of mitogen-activated protein kinase pathway bypass alterations, and the feasibility of an immunotherapy-containing regimen in a multi-driver tumor with unfavorable immune biomarkers.