State-of-the-Art Advances and Management of Unresectable Locally Advanced (stage III) Non-Small Cell Lung Cancer

Unresectable stage III non-small cell lung cancer (NSCLC) represents a biologically and clinically heterogeneous group of tumors. Concurrent chemoradiotherapy (cCRT) has long been the cornerstone of treatment for patients who are medically inoperable or have unresectable disease because of extensive nodal involvement or local invasion. Despite the curative intent of this approach, only about 30% of patients survive 5 years. Recently, advances have been made in both radiation oncology and medical oncology to incorporate precision medicine techniques and individualize treatment for each patient. Advances in radiation delivery techniques, including intensity-modulated radiotherapy, image-guided radiotherapy, motion management strategies, and adaptive radiotherapy, have improved the precision of treatment to the tumor and lymph nodes while minimizing toxicity to surrounding normal tissues. The introduction of consolidation immunotherapy following CRT has fundamentally changed the treatment paradigm. The phase III PACIFIC trial established consolidation durvalumab as the standard of care, demonstrating significant improvements in progression-free survival (PFS) and overall survival (OS). Similarly, biomarker-driven strategies have begun to reshape management for oncogene-driven tumors. The phase III LAURA trial demonstrated a substantial PFS benefit with consolidation osimertinib in patients with EGFR-mutated stage III NSCLC after definitive CRT. Ongoing research is focused on optimizing treatment sequencing, including induction chemoimmunotherapy approaches, radiation dose intensification strategies such as stereotactic boosts, and integration of targeted therapies for actionable genomic alterations. In this review, we summarize the current evidence guiding the management of unresectable stage III NSCLC, highlight advances in radiation and systemic therapies, and discuss emerging strategies aimed at improving locoregional control and long-term survival.