Neoadjuvant Chemoimmunotherapy for NSCLC: A Systematic Review and Meta-Analysis

Abstract

Importance: To date, no meta-analyses have comprehensively assessed the association of neoadjuvant chemoimmunotherapy with clinical outcomes in non-small cell lung cancer (NSCLC) in randomized and nonrandomized settings. In addition, there exists controversy concerning the efficacy of neoadjuvant chemoimmunotherapy for patients with NSCLC with programmed cell death 1 ligand 1 (PD-L1) levels less than 1%.

Objective: To compare neoadjuvant chemoimmunotherapy with chemotherapy by adverse events and surgical, pathological, and efficacy outcomes using recently published randomized clinical trials and nonrandomized trials.

Data sources: MEDLINE and Embase were systematically searched from January 1, 2013, to October 25, 2023, for all clinical trials of neoadjuvant chemoimmunotherapy and chemotherapy that included at least 10 patients.

Study selection: Observational studies and trials reporting the use of neoadjuvant radiotherapy, including chemoradiotherapy, molecular targeted therapy, or immunotherapy monotherapy, were excluded.

Main outcomes and measures: Surgical, pathological, and efficacy end points and adverse events were pooled using a random-effects meta-analysis.

Results: Among 43 eligible trials comprising 5431 patients (4020 males [74.0%]; median age range, 55-70 years), there were 8 randomized clinical trials with 3387 patients. For randomized clinical trials, pooled overall survival (hazard ratio, 0.65; 95% CI, 0.54-0.79; I2 = 0%), event-free survival (hazard ratio, 0.59; 95% CI, 0.52-0.67; I2 = 14.9%), major pathological response (risk ratio, 3.42; 95% CI, 2.83-4.15; I2 = 31.2%), and complete pathological response (risk ratio, 5.52; 95% CI, 4.25-7.15; I2 = 27.4%) favored neoadjuvant chemoimmunotherapy over neoadjuvant chemotherapy. For patients with baseline tumor PD-L1 levels less than 1%, there was a significant benefit in event-free survival for neoadjuvant chemoimmunotherapy compared with chemotherapy (hazard ratio, 0.74; 95% CI, 0.62-0.89; I2 = 0%).

Conclusion and relevance: This study found that neoadjuvant chemoimmunotherapy was superior to neoadjuvant chemotherapy across surgical, pathological, and efficacy outcomes. These findings suggest that patients with resectable NSCLC with tumor PD-L1 levels less than 1% may have an event-free survival benefit with neoadjuvant chemoimmunotherapy.

Figure 1.. Pooled Hazard Ratios (HRs) of Overall Survival Across Randomized Clinical Trials

Pooled HRs comparing neoadjuvant chemoimmunotherapy with neoadjuvant chemotherapy are given for all patients, by programmed cell death 1 ligand 1 (PD-L1) status, and for patients with stage III disease. For Wakelee et al, Spicer et al, and Spicer et al, PD-L1 levels of 1% or greater and stage III were each split into 2 groups. Chemo-IO indicates chemoimmunotherapy. ^a PD-L1 group: 1% to 49%. ^b PD-L1 group 50% or greater. ^cStage IIIA. ^dStage IIIB.

Figure 2.. Pooled Hazard Ratios (HRs) of Event-Free Survival Across Randomized Clinical Trials

Pooled HRs comparing neoadjuvant chemoimmunotherapy with neoadjuvant chemotherapy are given for all patients, by stage, and by programmed cell death 1 ligand 1 (PD-L1) level. Additional references include Forde et al, Provencio Pulla et al, and Provencio Pulla et al for Forde et al; Spicer et al and Spicer et al for Wakelee et al; Lu et al for Lu et al ; and Cascone et al for Cascone et al. For Forde et al, 97.38% CIs were reported for overall event-free survival. For Heymach et al, a stratified HR was reported for overall event-free-survival. For Wakelee et al and Heymach et al, stage III was split into 2 groups. For Provencio, progression-free survival was used instead of event-free survival. Chemo-IO indicates chemoimmunotherapy. ^aStage IIIA. ^bStage IIIB.

Figure 3.. Pooled Risk Ratios (RRs) for Pathological Outcomes Across Randomized Clinical Trials

Pooled RRs comparing neoadjuvant chemoimmunotherapy with neoadjuvant chemotherapy are given for major pathological response (MPR) and complete pathological response (pCR). Chemo-IO indicates chemoimmunotherapy.

Figure 4.. Pooled Risk Ratios (RRs) for Surgical Outcomes Across Randomized Clinical Trials

Pooled RRs comparing neoadjuvant chemoimmunotherapy with neoadjuvant chemotherapy are given for surgical resection (A) and R0 resection (B). Chemo-IO indicates chemoimmunotherapy.