Background: Rearranged during transfection (RET) fusion–positive non-small cell lung cancer (NSCLC) represents a distinct molecular subset of lung cancer. Although selective RET inhibitors have demonstrated impressive efficacy in clinical trials, real-world data provide important insights into treatment outcomes and clinical management outside controlled settings.

Objective: To summarize real-world evidence on the clinical characteristics, treatment patterns, and outcomes of patients with RET fusion–positive NSCLC, and to highlight key considerations for optimizing care.

Methods: A narrative review of published real-world studies, registries, and multicenter cohorts reporting on RET+ NSCLC was performed. Data regarding patient demographics, diagnostic approaches, use of selective RET inhibitors (e.g., selpercatinib, pralsetinib), response rates, survival outcomes, and adverse event management were synthesized.

Results: Real-world studies confirm high response rates and durable disease control with selective RET inhibitors, comparable to pivotal trials. Challenges remain in timely molecular testing, managing brain metastases, and addressing resistance mechanisms. Safety profiles in practice settings are consistent with clinical trial data, with most adverse events manageable through dose adjustments and supportive care.

Conclusions: Real-world evidence reinforces the pivotal role of selective RET inhibitors in RET+ NSCLC and underscores the need for broad molecular testing and proactive management of resistance. Continued collection of real-world data will inform optimal sequencing strategies and long-term patient outcomes.

Keywords: RET fusion, non-small cell lung cancer, real-world evidence, targeted therapy, selpercatinib, pralsetinib.