Immunotherapy for resectable NSCLC: neoadjuvant/perioperative followed by surgery over surgery followed by adjuvant. Systematic review and meta-analysis with subgroup analyses

Background: Immunotherapy has rapidly changed the treatment of early-stage non-small-cell lung cancer (NSCLC) in recent years. We aimed to summarize available evidence on the use of immunotherapy in neoadjuvant/perioperative and adjuvant settings for resectable NSCLC and explore some controversial subgroups. Materials and methods: Systematic literature research was carried out for randomized controlled trials of neoadjuvant/perioperative chemo-immunotherapy or adjuvant immunotherapy for resectable NSCLC. Separate meta-analyses for neoadjuvant/perioperative or adjuvant immunotherapy were carried out. Subgroup analyses were also carried out to estimate the effect of immunotherapy according to tumor histology, stage, programmed death-ligand 1 (PD-L1), age, sex and smoking status. Results: Out of 6005 records screened, a total of 11 trials met the inclusion criteria. This pooled analysis showed that patients receiving neoadjuvant or perioperative chemo-immunotherapy had significantly better event-free survival (EFS) compared with those treated with neoadjuvant chemotherapy alone [hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.51-0.66]. Similarly, adjuvant immunotherapy also led to improved outcomes (HR 0.85, 95% CI 0.77-0.94). However, among patients with stage II NSCLC, neoadjuvant/perioperative chemo-immunotherapy demonstrated EFS benefit (HR 0.69, 95% CI 0.54-0.88), while no significant EFS benefit was observed with adjuvant immunotherapy (HR 0.81, 95% CI 0.63-1.05). Similarly, there was an improvement in EFS for patients with squamous-cell carcinoma who received neoadjuvant/perioperative chemo-immunotherapy versus neoadjuvant chemotherapy (HR 0.56, 95% CI 0.45-0.68) and for PD-L1 < 1% (HR 0.77, 95% CI 0.65-0.93), whereas such improvement was not evident with adjuvant immunotherapy (HR 0.93, 95% CI 0.76-1.13 and HR 0.85, 95% CI 0.71-1.01, respectively). Overall survival analysis demonstrated a significant benefit from neoadjuvant/perioperative immunotherapy (HR 0.65, 95% CI 0.53-0.81), but not with adjuvant immunotherapy (HR 0.91, 95% CI 0.76-1.10). Conclusions: Our results indicate that neoadjuvant/perioperative immunotherapy should be considered the standard. This should be preferred over upfront surgery, also in stage II, PD-L1-negative and squamous histology.