Neoadjuvant chemoimmunotherapy or chemoradiotherapy in stage III non-small cell lung cancer: crossing the Rubicon?

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) represents 80-85% of cases, with 20-35% diagnosed at stage III. Stage III NSCLC is highly heterogeneous, encompassing both resectable and unresectable disease. The aim of this article is to review current evidence on the treatment of stage III NSCLC, with a focus on neoadjuvant chemoimmunotherapy (CT-IO) vs. the standard of chemoradiotherapy (CT/RT) followed by consolidation immunotherapy.

The narrative review was conducted and carried out using clinical trials and studies included were found through searching several databases: PubMed, Cochrane, Science Direct, EMBASE, and the clinical trial registry (www.clinicaltrials.gov).

Historically, concurrent CT/RT followed by 1 year of durvalumab has been the standard for unresectable stage III disease, as demonstrated in the PACIFIC trial. The introduction of CT-IO neoadjuvant regimens has shown improved outcomes in stage IIIA and IIIB disease, particularly in terms of pathological complete response (pCR), event-free survival (EFS), and overall survival (OS). Clinical trial heterogeneity regarding tumor-node-metastasis (TNM) staging, patient selection, and adjuvant therapy duration limits direct comparisons. However, emerging data suggest that CT-IO could become a new standard for stage IIIA and selected IIIB/IIIC patients. Neoadjuvant CT-IO represents a significant shift in the treatment paradigm of stage III NSCLC, offering personalized and potentially more effective therapeutic options.

While CT/RT remains essential for certain subsets, particularly T4 or unresectable tumors, CT-IO should be strongly considered for most patients with stage IIIA and IIIB NSCLC.