Review Consolidates Evidence for Targeted Therapies in ALK, ROS1, RET, NTRK, NRG1 Fusion-Driven Lung Cancers

Oncogenic gene fusions define a critical subset of non-small cell lung carcinoma (NSCLC), where specific genetic alterations drive cancer growth. Historically, outcomes for advanced NSCLC were poor, but targeted therapies have revolutionized treatment for these fusion-positive patients. Current standard-of-care often involves broad chemotherapy, which lacks specificity. Understanding the mechanisms of action, resistance patterns, and toxicity profiles of targeted agents against specific fusions like ALK, ROS1, RET, NTRK, and NRG1 is crucial for optimizing precision oncology approaches and improving patient survival.

This comprehensive review consolidates current evidence for FDA-approved therapies specifically targeting ALK, ROS1, RET, NTRK, and NRG1 fusions in lung cancer. The authors analyzed existing literature to highlight the mechanisms of action for these targeted agents, summarize pivotal clinical trials, detail common resistance patterns, and outline their toxicity profiles. The review also discussed advancements in molecular diagnostics, including the increasing role of RNA-based sequencing, and explored emerging strategies for treatment in the adjuvant and perioperative settings.

The review highlights that successive generations of tyrosine kinase inhibitors (TKIs) and, more recently, monoclonal antibodies have delivered substantial improvements in response rates, progression-free survival, and central nervous system control across multiple fusion-defined populations in NSCLC. It systematically details the specific mechanisms of action, key clinical trial data, and characteristic resistance patterns for therapies targeting ALK, ROS1, RET, NTRK, and NRG1 fusions. The authors also outline the toxicity profiles associated with these targeted agents. > The consolidated evidence underscores the transformative impact of precision oncology, driven by targeted therapies, on patient outcomes in fusion-driven non-small cell lung carcinoma, while also identifying ongoing challenges like resistance and the need for expanded approaches for rare fusions.