Targeted therapies in advanced non-small-cell lung cancer: new biomarkers and treatment strategies.
Precision oncology has changed the management of advanced non-small-cell lung cancer (NSCLC). Biomarker-matched therapies now improve outcomes in an increasing number of molecularly defined subgroups. In this second paper in a Series on therapeutics in lung cancer, we summarise recent advances in NSCLC with established alterations, including EGFR, ALK, ROS1, KRAS, BRAF, RET, HER2, MET, and NTRK, and discuss emerging targets, such as NRG1 fusions, MTAP loss, and SMARCA4 deficiency. Newer generations of tyrosine kinase inhibitors, the introduction of bispecific antibodies, and antibody-drug conjugates have improved response durability, intracranial disease control, and in some settings, overall survival. However, durable benefit can remain limited by acquired resistance, tumour heterogeneity, lineage plasticity, and off-target escape, supporting repeat tissue biopsy and circulating-tumour DNA profiling to guide subsequent treatment. With several options available such as monotherapy and combination approaches, individualised treatment selection is becoming increasingly complex. We discuss these choices, including the management of CNS disease and oligoprogression, and long-term tolerability. As drug development extends beyond canonical drivers to rarer alterations and adverse co-mutations, the range of targetable disease is increasing. Further progress will depend on more effective and adaptive treatment strategies together with equitable access to comprehensive molecular profiling, timely biomarker testing, and next-generation targeted therapies.