Molecular Alterations in Lung Cancer – Beyond EGFR, ALK and ROS1

Lung cancer is a leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) comprising nearly 85% of cases and showing a rising incidence globally, including in India. Over the last two decades, the identification of actionable oncogenic driver alterations has transformed NSCLC therapy. Early discoveries such as EGFR mutations, as well as ALK and ROS1 rearrangements, detected in ~25–50% of lung adenocarcinomas, ushered in targeted therapies, improving survival in advanced disease. Advances in molecular profiling, especially next-generation sequencing, have further broadened the list of clinically relevant and targetable genomic alterations, including mutations in KRAS, BRAF, ERBB2 (HER2), and MET, as well as gene fusions involving RET, NTRK1/2/3, and NRG1. Many of these can now be matched with approved targeted therapies, while others are emerging as promising biomarkers in trials. Select molecular alterations also influence decisions regarding immune checkpoint inhibitor therapy, highlighting the importance of comprehensive genomic characterisation at diagnosis. The diversity of actionable NSCLC alterations requires strategic testing approaches, from single-gene assays to multiplexed platforms, tailored to clinical and resource contexts. Precision oncology, defined by the integration of tumor-specific molecular alterations into treatment planning, has thus become central to contemporary NSCLC management. This review provides a comprehensive overview of established and emerging oncogenic drivers in NSCLC, their biological and clinical significance, and their therapeutic implications, with an emphasis on practical considerations for molecular testing and personalized treatment selection.