Visceral crisis in a patient with non-small cell lung cancer and ROS1::SDC4 fusion: intrinsic resistance to entrectinib via L2026M mutation-a case report.

Abstract

Background: ROS1 rearrangements are identified in approximately 1-2% of non-small cell lung cancer (NSCLC) cases, predominantly in younger, non-smoking patients. Targeted therapies such as entrectinib, a second-generation ROS1 tyrosine kinase inhibitor (TKI), have demonstrated efficacy, particularly in managing brain metastases. However, intrinsic and acquired resistance mechanisms remain poorly understood, limiting long-term treatment success.

Case description: We report a unique case of early entrectinib resistance due to a gatekeeper mutation in the ROS1 kinase domain, underscoring the importance of molecular profiling in optimizing therapeutic strategies. We report a case of a 50-year-old male, a non-smoker, who was diagnosed with ROS1-rearranged NSCLC harboring an ROS1::SDC4 fusion. First-line treatment with entrectinib was initiated, resulting in an initial partial response. However, rapid disease progression was observed within a few months. Retrospective molecular analysis identified the L2026M mutation in the ROS1 kinase domain, a known gatekeeper mutation that reduces TKI binding affinity and enhances tumor cell survival. This case highlights the clinical impact of resistance mutations in ROS1-positive NSCLC and underscores the critical role of comprehensive molecular profiling in guiding treatment decisions.

Conclusions: The emergence of the L2026M mutation suggests a need for next-generation TKIs and combination strategies to overcome resistance. Future studies should explore novel inhibitors targeting ROS1 resistance pathways to improve outcomes in this subset of NSCLC patients.