Unveiling the Uncommon: Targeting Rare MET Fusions in NSCLC: A Comprehensive Review

Background/Objectives: Advancements in molecular diagnostics and targeted therapies have significantly transformed the management of non-small cell lung cancer (NSCLC). Rare MET rearrangements, including novel fusions such as HLA-DRB1-MET and HLA-DQB2-MET, represent actionable genetic alterations with critical therapeutic implications. This review synthesizes findings from multiple case reports to highlight the efficacy of MET tyrosine kinase inhibitors (TKIs) in MET-driven oncogenesis. Methods: A systematic review of published case reports and studies on MET rearrangements in NSCLC was conducted. Data were analyzed to assess the clinical outcomes of patients treated with MET TKIs, such as crizotinib and tepotinib. Additionally, our case report demonstrates the utility of comprehensive next-generation sequencing (NGS) in identifying rare MET fusions and guiding personalized treatment strategies.Results: Our case illustrates the potential of NGS in detecting rare MET fusions and achieving durable disease control with crizotinib. Comparative analyses indicate the necessity of individualized treatment approaches, particularly in cases involving central nervous system (CNS) involvement and prior treatment history. The review further emphasizes that MET alterations are more frequently identified in never-smoking female patients, where driver mutation detection rates exceed 60%. Conclusions: Precision oncology plays a pivotal role in addressing rare MET rearrangements in NSCLC. Despite advancements, challenges persist in early identification, therapeutic sequencing, and access to advanced diagnostics. Collaborative efforts among researchers, clinicians, and policymakers are crucial to refining treatment strategies and improving patient outcomes.