Non-Small Cell Lung Cancer in 2026: A Narrative Review of Clinical Advances and Systemic Challenges

Non-small cell lung cancer management has undergone a fundamental transformation, driven by the simultaneous maturation of targeted therapy, antibody-drug conjugates, and immune checkpoint inhibition across all disease stages. Comprehensive molecular profiling via next-generation sequencing now guides treatment selection for the majority of patients with adenocarcinoma, with actionable alterations identified in over 60% of cases. Key advances include the perioperative extension of osimertinib and alectinib into resected EGFR-mutated and ALK-positive disease, respectively, and the establishment of osimertinib consolidation following chemoradiotherapy in unresectable stage III EGFR-mutated NSCLC. Zongertinib received accelerated FDA approval for HER2-mutant disease, offering a selective oral option with meaningful CNS activity. Datopotamab deruxtecan and telisotuzumab vedotin further established antibody-drug conjugates as a validated treatment pillar. Perioperative immunotherapy with pembrolizumab, durvalumab, and nivolumab-based regimens now carries NCCN category 1 recommendations for resectable, driver-negative disease. Despite these advances, acquired resistance, sequencing complexity, and inequitable access to molecular diagnostics and novel therapeutics remain consequential challenges. Realising the full population-level benefit of this therapeutic progress requires concurrent investment in diagnostic infrastructure, health equity frameworks, and streamlined reimbursement pathways.