Perioperative immunotherapy for stage II-III non-small cell lung cancer: a meta-analysis base on randomized controlled trials

Abstract

Background: In recent years, we have observed the pivotal role of immunotherapy in improving survival for patients with non-small cell lung cancer (NSCLC). However, the effectiveness of immunotherapy in the perioperative (neoadjuvant + adjuvant) treatment of resectable NSCLC remains uncertain. We conducted a comprehensive analysis of its antitumor efficacy and adverse effects (AEs) by pooling data from the KEYNOTE-671, NADIM II, and AEGEAN clinical trials.

Methods: For eligible studies, we searched seven databases. The randomized controlled trials (RCTs) pertaining to the comparative analysis of combination neoadjuvant platinum-based chemotherapy plus perioperative immunotherapy (PIO) versus perioperative placebo (PP) were included. Primary endpoints were overall survival (OS) and event-free survival (EFS). Secondary endpoints encompassed drug responses, AEs, and surgical outcomes.

Results: Three RCTs (KEYNOTE-671, NADIM II, and AEGEAN) were included in the final analysis. PIO group (neoadjuvant platinum-based chemotherapy plus perioperative immunotherapy) exhibited superior efficacy in OS (hazard ratio [HR]: 0.63 [0.49-0.81]), EFS (HR: 0.61 [0.52, 0.72]), objective response rate (risk ratio [RR]: 2.21 [1.91, 2.54]), pathological complete response (RR: 4.36 [3.04, 6.25]), major pathological response (RR: 2.79 [2.25, 3.46]), R0 resection rate (RR: 1.13 [1.00, 1.26]) and rate of adjuvant treatment (RR: 1.08 [1.01, 1.15]) compared with PP group (neoadjuvant platinum-based chemotherapy plus perioperative placebo). In the subgroup analysis, EFS tended to favor the PIO group in almost all subgroups. BMI (>25), T stage (IV), N stage (N1-N2) and pathological response (with pathological complete response) were favorable factors in the PIO group. In the safety assessment, the PIO group exhibited higher rates of serious AEs (28.96% vs. 23.51%) and AEs leading to treatment discontinuation (12.84% vs. 5.81%). Meanwhile, although total adverse events, grade 3-5 adverse events, and fatal adverse events tended to favor the PP group, the differences were not statistically significant.

Conclusion: PIO appears to be superior to PP for resectable stage II-III NSCLC, demonstrating enhanced survival and pathological responses. However, its elevated adverse event (AE) rate warrants careful consideration.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier CRD42023487475.

Keywords: adjuvant; immunotherapy; meta-analysis; neoadjuvant; non-small cell lung cancer; surgery.

Figure 1

Study selection flow.

Figure 2

Forest plots of overall survival and event-free survival associated with perioperative immunotherapy versus perioperative placebo.

Figure 3

Comparisons of overall survival rate (6-48 months, A: trend of overall survival rate; C: trend of risk ratios) and event-free survival rate (6-48 months, B: trend of event-free survival rate; D: trend of risk ratios) associated with perioperative immunotherapy versus perioperative placebo according to survival time.

Figure 4

Subgroup analysis of event-free survival.

Figure 5

Forest plots of pathological responses (objective response rate, pathological complete response, and major pathological response) associated with perioperative immunotherapy versus perioperative placebo according to survival time.

Figure 6

Funnel plots of survival summary (A), pathological responses (B), adverse events’ summary during all treatment phase (C), adverse events’ summary during the neoadjuvant treatment phase (D), adverse events’ summary during the surgical treatment phase (E), adverse events’ summary during the adjuvant treatment phase (F) associated with perioperative immunotherapy versus perioperative placebo according to survival time.