A landmark meta-analysis published in Frontiers in Immunology provides compelling evidence for the superiority of perioperative immunotherapy combined with chemotherapy over chemotherapy alone in treating resectable non-small cell lung cancer (NSCLC). The comprehensive analysis of five phase III randomized controlled trials involving 2,855 patients represents the most robust evaluation to date of this emerging treatment paradigm.
Significant Survival Benefits Demonstrated
The meta-analysis revealed substantial improvements across multiple clinical endpoints. Overall survival analysis from three studies encompassing 1,652 patients showed that perioperative immunotherapy plus chemotherapy reduced the risk of death by 32% (HR=0.68; 95% CI: 0.56-0.83; P=0.0002) with no heterogeneity between studies.
Event-free survival data from all five trials demonstrated even more pronounced benefits, with patients receiving combination therapy achieving significantly longer EFS (HR=0.58; 95% CI: 0.51-0.65; P<0.00001). The pathological complete response rate was dramatically higher in the combination group, with a 7.54-fold increase (OR=7.54; 95% CI: 4.63-12.26; P<0.00001) compared to chemotherapy alone.
Enhanced Surgical Outcomes
The analysis confirmed that perioperative immunotherapy does not compromise surgical feasibility. All patients achieved successful R0 resection rates of 100%, with the combination therapy group showing superior R0 resection rates compared to chemotherapy alone (OR=1.58; 95% CI: 1.15-2.18; P=0.005). The surgical resection rate was also higher in the combination group (OR=1.25; 95% CI: 1.04-1.49; P=0.02).
Patient Selection Insights
Subgroup analyses revealed important insights for patient selection. The treatment showed particular efficacy in current smokers (HR=0.52; 95% CI: 0.38-0.70) and former smokers (HR=0.63; 95% CI: 0.52-0.76), while never-smokers showed no statistically significant benefit (HR=0.76; 95% CI: 0.52-1.12). Patients with EGFR-mutation negative tumors demonstrated clear benefits (HR=0.55; 95% CI: 0.45-0.66), whereas those with EGFR mutations showed no significant improvement.
Both stage II (HR=0.66; 95% CI: 0.51-0.86) and stage III (HR=0.54; 95% CI: 0.43-0.63) patients benefited from the combination therapy, with further stratification showing significant benefits in stage IIIA (HR=0.55; 95% CI: 0.47-0.66) and stage IIIB (HR=0.54; 95% CI: 0.32-0.92) disease.
Safety Profile and Tolerability
While the combination therapy demonstrated superior efficacy, it was associated with increased toxicity. The analysis showed higher rates of grade 3+ treatment-related adverse events (OR=1.25; 95% CI: 1.06-1.49; P=0.010), severe adverse events (OR=1.46; 95% CI: 1.19-1.78; P=0.0002), and immune-related adverse events (OR=2.78; 95% CI: 2.18-3.55; P<0.00001).
Importantly, there was no statistically significant difference in treatment-related deaths between groups (OR=1.12; 95% CI: 0.64-1.97; P=0.69), indicating that while toxicity increased, the safety profile remained manageable.
Clinical Trial Evidence Base
The meta-analysis included five major phase III trials: AEGEAN, CheckMate-77T, KEYNOTE-671, Neotorch, and RATIONALE-315. These studies evaluated different immune checkpoint inhibitors including durvalumab, nivolumab, pembrolizumab, toripalimab, and tislelizumab, all combined with platinum-based chemotherapy regimens.
The KEYNOTE-671 study was particularly notable as the first to demonstrate statistically significant overall survival benefits with perioperative pembrolizumab, while the Neotorch trial introduced an innovative "3+1+13" treatment model combining neoadjuvant, adjuvant, and maintenance immunotherapy phases.
Implications for Clinical Practice
These findings support the integration of perioperative immunotherapy into standard care for resectable NSCLC, particularly for patients with smoking history and EGFR-mutation negative tumors. The results suggest that the combination of neoadjuvant and adjuvant immunotherapy may provide optimal benefits compared to either approach alone.
The analysis also highlights the importance of biomarker-driven patient selection, with PD-L1 expression levels showing correlation with treatment response. Patients with higher PD-L1 expression demonstrated greater benefits, with hazard ratios for event-free survival of 0.74, 0.51, and 0.45 for PD-L1 TPS <1%, 1-49%, and ≥50%, respectively.
Future Research Directions
The authors emphasize the need for additional research to identify optimal patient populations for adjuvant immunotherapy continuation and to establish the role of minimal residual disease (MRD) detection in treatment decisions. Circulating tumor DNA (ctDNA) clearance emerged as a potential biomarker, with higher clearance rates observed in the combination therapy group (56% vs. 35%).
The meta-analysis represents a significant milestone in establishing perioperative immunotherapy as a new standard of care for resectable NSCLC, while highlighting the importance of careful patient selection and toxicity monitoring in clinical implementation.
