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PD-(L)1 Inhibitor Monotherapy vs Chemoimmunotherapy for Advanced NSCLC With High PD-L1 Expression: A Systematic
Alessandro Di Federico1,2, Samuele Compagno1,2, Francesco Mantuano1,2
1Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Importance:
For patients with advanced non-small cell lung cancer (NSCLC) and programmed cell death 1 ligand 1 (PD-L1) expression of 50% or higher, programmed cell death 1 protein or PD-L1 (PD-[L]1) inhibitor monotherapy is commonly used as first-line therapy; however, whether adding chemotherapy improves outcomes in this population remains unknown.
Objective:
To compare overall survival (OS) and progression-free survival (PFS) associated with PD-(L)1 inhibitor monotherapy vs chemoimmunotherapy in treatment-naive patients with advanced NSCLC and high PD-L1 expression.
Data Sources:
PubMed, Embase, and major oncology conference proceedings were searched for phase 3 randomized clinical trials (RCTs) published before August 3, 2025.
Study Selection:
Eligible studies were phase 3 RCTs that enrolled patients with untreated advanced NSCLC, evaluated PD-(L)1 inhibitor monotherapy or chemoimmunotherapy vs chemotherapy alone, and reported outcomes in patients with high PD-L1 expression.
Data Extraction And Synthesis:
Hazard ratios (HRs) for OS and PFS were extracted from published studies and synthesized using inverse variance methods. Additional analyses included meta-regression, network meta-analysis, and reconstructed individual patient data from published Kaplan-Meier curves.
Main Outcomes And Measures:
Primary outcome was OS; secondary outcome was PFS.
Results:
Among 24 trials including 5546 patients with PD-L1-high NSCLC, 16 evaluated chemoimmunotherapy and 8 PD-(L)1 inhibitor monotherapy. Compared with chemotherapy, survival was improved by both chemoimmunotherapy (OS: HR, 0.63 [95% CI, 0.56-0.72]; P < .001; PFS: HR, 0.44 [95% CI, 0.39-0.49]; P < .001) and PD-(L)1 inhibitor monotherapy (OS: HR, 0.74 [95% CI, 0.69-0.80]; P < .001; PFS: HR, 0.70 [95% CI, 0.65-0.76]; P < .001). Tests for subgroup differences suggested improved benefit with chemoimmunotherapy compared to PD-(L)1 inhibitor monotherapy (OS: χ21 = 4.1; P = .04; I2 = 75.8%; PFS: χ21 = 48.1; P < .001; I2 = 97.9%), consistent with meta-regression analyses (OS: HR, 0.85 [95% CI, 0.72-1.00]; P = .048; PFS: HR, 0.61 [95% CI, 0.50-0.75]; P < .001) and network meta-analyses (OS: HR, 0.85 [95% CI, 0.73-0.99]; PFS: HR, 0.61 [95% CI, 0.50-0.75]). In the reconstructed individual patient data analysis, median OS was longer with chemoimmunotherapy (n = 704 patients) compared to PD-(L)1 inhibitor monotherapy (n = 1706 patients) (29.2 months [95% CI, 25.2-35.4] vs 19.8 months [95% CI, 18.3-21.7]; HR, 0.74 [95% CI, 0.66-0.82]; P < .001). Similarly, median PFS was significantly longer with chemoimmunotherapy (n = 701 patients) compared to PD-(L)1 inhibitor monotherapy (n = 1706 patients) (11.3 months [95% CI, 10.3-13.5] vs 6.8 months [95% CI, 6.2-7.1]; HR, 0.67 [95% CI, 0.60-0.75]; P < .001).
Conclusions And Relevance:
In this meta-analysis of phase 3 RCTs, chemoimmunotherapy was associated with significantly improved OS and PFS compared with PD-(L)1 inhibitor monotherapy in patients with advanced NSCLC and high PD-L1 expression. Prospective trials are needed to confirm these findings.
