Evolution from KRAS G12C-mutant to ALK fusion-positive stage IV lung adenocarcinoma following immune checkpoint inhibitor therapy: a case report

Background: Immune checkpoint inhibitors (ICIs) have become standard treatment for KRAS-mutant lung adenocarcinoma, but acquired resistance inevitably develops. Tumor clonal evolution under therapeutic pressure is a key resistance mechanism. The emergence of a new oncogenic driver mutually exclusive with the original one is rare. Case report: We report a 51-year-old female with stage IV lung adenocarcinoma harboring a KRAS G12C mutation along with TP53 and RB1 alterations. She received first-line therapy including the ICI tislelizumab in combination with chemotherapy and bevacizumab, achieving a partial response (PR) that was maintained for approximately 12 months (from April 2024 to April 2025), before subsequent disease progression was documented 26 months after treatment initiation. Upon disease progression, a repeat biopsy of the lung lesion revealed persistent adenocarcinoma histology without small-cell or squamous transformation. Remarkably, next-generation sequencing demonstrated the loss of the original KRAS G12C mutation and the emergence of a novel EML4-ALK fusion. The patient was switched to the ALK inhibitor ensartinib, achieving a second PR. Conclusion: This case provides supporting evidence consistent with the selection of a pre-existing ALK fusion clone in a KRAS-mutant lung adenocarcinoma under chemo-immunotherapy pressure. It also highlights the clinical value of re-biopsy at progression to guide subsequent targeted therapy.