Updates in Management of Unresectable Stage III Non Small Cell Lung Cancer: A Radiation Oncology Perspective

Unresectable stage III non-small-cell lung cancer (NSCLC) remains a clinical challenge, due to the need for optimal local and systemic control. The management of unresectable Stage III NSCLC has evolved with advancements in radiation therapy (RT), systemic therapies, and immunotherapy. For patients with locally advanced NSCLC who are not surgical candidates, concurrent chemoradiotherapy (CRT) has modest survival outcomes, due to both local progression and distant metastasis. Efforts to enhance outcomes have led to dose-escalation trials, advances in modern RT techniques such as intensity-modulated RT (IMRT) and proton beam therapy (PBT), and the integration of adaptive RT to optimize target coverage while sparing organs at risk. Concurrent and consolidative immunotherapy, particularly with PD-L1 inhibitors, has shown promise, as evidenced by the PACIFIC trial, which demonstrated improved progression-free survival (PFS) and overall survival (OS) with durvalumab following CRT. Ongoing trials are now investigating novel immunotherapy combinations and targeted therapies in this setting, including dual checkpoint inhibition, DNA repair inhibitors, and molecularly targeted agents like osimertinib for EGFR-mutated NSCLC. Emerging biomarkers, such as circulating tumor DNA and radiomics, offer potential for personalizing treatment and predicting outcomes. Additionally, PBT and MR-guided adaptive RT have shown the potential to reduce toxicities while maintaining efficacy. Integrating these novel approaches may offer opportunities for optimizing treatment responses and minimizing adverse effects in this challenging patient population. Further investigation into patient stratification, biomarker-driven therapy, and refined therapeutic combinations is essential to improve long-term outcomes in unresectable Stage III NSCLC. This narrative review explores the current management strategies for unresectable Stage III NSCLC, from a radiation oncology perspective.