Targeting Oncogenic Gene Fusions in Lung Cancer

Oncogenic gene fusions define a clinically important subset of non-small cell lung carcinoma (NSCLC) for which targeted therapies have transformed outcomes. Over the past 15 years, successive generations of tyrosine kinase inhibitors (and more recently, monoclonal antibodies) have demonstrated substantial improvements in response rates, progression-free survival, and central nervous system control across multiple fusion-defined populations. This review consolidates current evidence for FDA-approved therapies targeting ALK, ROS1, RET, NTRK, and NRG1 fusions in lung cancer, highlighting mechanisms of action, pivotal clinical trials, resistance patterns, and toxicity profiles. We also discuss advances in molecular diagnostics (including the growing role of RNA-based sequencing) and emerging strategies in the adjuvant and perioperative settings. Finally, we outline ongoing clinical trials and future directions aimed at overcoming resistance and expanding precision oncology approaches for patients with rare fusion-driven lung cancers.