Immunotherapy for locally advanced non-small cell lung cancer: current evidence and future perspectives

Non-small cell lung cancer (NSCLC) is the most common type of lung tumors, and one of the leading causes of cancer deaths worldwide. Disease stage at diagnosis significantly impacts on survival, with overall 5-year survival rates ranging from 60% for localized disease, 33% for loco-regional disease, and 5.5% for subjects with distant metastases. Locally advanced NSCLC is a disease characterized by high tumor burden, frequently not amenable of surgical intervention. Overall, only 30% of patients present with potentially resectable disease at diagnosis, and usually undergo neoadjuvant chemotherapy (CT) before surgery. The majority of patients with locally advanced NSCLC (~70%) have unresectable disease at diagnosis. In such cases, multimodal treatment approach with the association of platinum-based CT and radiotherapy (RT), has demonstrated to be superior to sequential therapy or RT alone. Maintenance with immunotherapy after combined CT/RT has further improved the progression-free survival and overall survival. Evidence have suggested that concomitant CT/RT with immunotherapy (IT) enhance disease response, mainly due to its synergized effect on the immune system. Immune checkpoint inhibitors (ICI) have gained an unprecedented success in the treatment of metastatic NSCLC, and represent a promising treatment strategy also in locally advanced disease. There is a strong biologic rationale supporting the use of ICI as a part of multimodal treatment combination of NSCLC. Several clinical trials are ongoing in locally advanced NSCLC, with the aim to explore the role of IT in earlier phases of treatment, combined with RT in place of CT, but also as a trimodal treatment. Considering non-resectable disease, ongoing efforts will help to clarify whether the association of RT with either CT and IT, alone or in combination, is feasible and effectively improve survival outcomes compared with maintenance IT alone. Results from ongoing trials will help to understand the way to improve the efficacy of IT, providing further changes in our standard of care for the treatment of locally advanced NSCLC.