No Overall Survival Benefit with Adding Chemotherapy to Immunotherapy in PD-L1 TPS >= 50% NSCLC: An Agent-Stratified Reassessment
- 1The First Hospital of Jilin University
Abstract
IMPORTANCEA recent meta-analysis showed that chemoimmunotherapy was associated with improved overall survival (OS) compared with immune checkpoint inhibitor (ICI) monotherapy for programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) [≥] 50% advanced non-small-cell lung cancer (NSCLC). However, whether this benefit reflects chemotherapy effect or ICI heterogeneity remains unclear.
OBJECTIVETo reassess the survival benefit of adding chemotherapy to ICI monotherapy using agent-stratified comparisons anchored to chemotherapy.
DATA SOURCESThe 24 phase 3 randomized clinical trials included in the original meta-analysis (search date, August 3, 2025).
DATA EXTRACTION AND SYNTHESISHazard ratios (HRs) for OS and progression-free survival (PFS) were extracted from each trial in the original meta-analysis. Two analytic frameworks were used: within-agent comparisons (same ICI in both chemoimmunotherapy and monotherapy) and across-agent comparisons (ICI in one treatment strategy only). For within-agent comparisons, a two-stage random-effects meta-analysis was conducted. In stage 1, ICI-specific HRs for chemoimmunotherapy and ICI monotherapy versus chemotherapy were pooled and their ratio was calculated (RHR = HRchemoimmuno/HRmono; RHR < 1 favors chemoimmunotherapy). The RHRs were pooled in stage 2. For across-agent comparisons, RHR was derived from pooled HRs by treatment strategy.
MAIN OUTCOMES AND MEASURESEndpoints were OS and PFS.
RESULTSIn within-agent comparisons (4 ICIs; 13 trials; N = 3252), pooled RHR was 0.94 (95% CI, 0.78-1.13; P = .48; I{superscript 2} = 0.0%) for OS and 0.85 (95% CI, 0.68-1.06; P = .14; I{superscript 2} = 0.0%) for PFS. In across-agent comparisons (7 ICIs; 11 trials; N = 2231), RHR favored chemoimmunotherapy for OS (0.68; 95% CI, 0.50-0.92; P = .01) and PFS (0.46; 95% CI, 0.37-0.58; P < .001). In a sensitivity analysis restricted to trials of NCCN-recommended regimens, pooled RHR was 1.02 (95% CI, 0.81-1.28; P = .87) for OS.
CONCLUSIONS AND RELEVANCEIn the within-agent comparisons, adding chemotherapy to ICI monotherapy did not improve OS or PFS in patients with PD-L1 TPS [≥] 50% advanced NSCLC. The benefit in the original meta-analysis appears driven by across-ICI heterogeneity. These findings are consistent with ICI monotherapy as a standard first-line option and underscore the need for agent-level stratification in across-trial comparisons.
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BibTeX
@misc{han2026overall,
title = {{No Overall Survival Benefit with Adding Chemotherapy to Immunotherapy in PD-L1 TPS >= 50% NSCLC: An Agent-Stratified Reassessment}},
author = {F. Han and J. Wang and S. Shi and M. Jin and C. Ren},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.26361919},
url = {https://www.medrxiv.org/content/10.64898/2026.09.01.26361919v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - No Overall Survival Benefit with Adding Chemotherapy to Immunotherapy in PD-L1 TPS >= 50% NSCLC: An Agent-Stratified Reassessment
AU - F. Han
AU - J. Wang
AU - S. Shi
AU - M. Jin
AU - C. Ren
PY - 2026
DA - 2026/09/01
PB - medRxiv
DO - 10.64898/2026.09.01.26361919
UR - https://www.medrxiv.org/content/10.64898/2026.09.01.26361919v1
AB - IMPORTANCEA recent meta-analysis showed that chemoimmunotherapy was associated with improved overall survival (OS) compared with immune checkpoint inhibitor (ICI) monotherapy for programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) [≥] 50% advanced non-small-cell lung cancer (NSCLC). However, whether this benefit reflects chemotherapy effect or ICI heterogeneity remains unclear. OBJECTIVETo reassess the survival benefit of adding chemotherapy to ICI monotherapy using agent-stratified comparisons anchored to chemotherapy. DATA SOURCESThe 24 phase 3 randomized clinical trials included in the original meta-analysis (search date, August 3, 2025). DATA EXTRACTION AND SYNTHESISHazard ratios (HRs) for OS and progression-free survival (PFS) were extracted from each trial in the original meta-analysis. Two analytic frameworks were used: within-agent comparisons (same ICI in both chemoimmunotherapy and monotherapy) and across-agent comparisons (ICI in one treatment strategy only). For within-agent comparisons, a two-stage random-effects meta-analysis was conducted. In stage 1, ICI-specific HRs for chemoimmunotherapy and ICI monotherapy versus chemotherapy were pooled and their ratio was calculated (RHR = HRchemoimmuno/HRmono; RHR < 1 favors chemoimmunotherapy). The RHRs were pooled in stage 2. For across-agent comparisons, RHR was derived from pooled HRs by treatment strategy. MAIN OUTCOMES AND MEASURESEndpoints were OS and PFS. RESULTSIn within-agent comparisons (4 ICIs; 13 trials; N = 3252), pooled RHR was 0.94 (95% CI, 0.78-1.13; P = .48; I{superscript 2} = 0.0%) for OS and 0.85 (95% CI, 0.68-1.06; P = .14; I{superscript 2} = 0.0%) for PFS. In across-agent comparisons (7 ICIs; 11 trials; N = 2231), RHR favored chemoimmunotherapy for OS (0.68; 95% CI, 0.50-0.92; P = .01) and PFS (0.46; 95% CI, 0.37-0.58; P < .001). In a sensitivity analysis restricted to trials of NCCN-recommended regimens, pooled RHR was 1.02 (95% CI, 0.81-1.28; P = .87) for OS. CONCLUSIONS AND RELEVANCEIn the within-agent comparisons, adding chemotherapy to ICI monotherapy did not improve OS or PFS in patients with PD-L1 TPS [≥] 50% advanced NSCLC. The benefit in the original meta-analysis appears driven by across-ICI heterogeneity. These findings are consistent with ICI monotherapy as a standard first-line option and underscore the need for agent-level stratification in across-trial comparisons.
ER -