World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access
Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc
Journal website https://wjon.elmerpub.com

Original Article

Volume 16, Number 3, June 2025, pages 299-310

Anti-Programmed Cell Death-1 Versus Anti-Programmed Death-Ligand 1 (PD-L1) in PD-L1-Negative Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Figures

↓  Figure 1. Study selection schema.
Figure 1.
↓  Figure 2. Funnel plot comparing the precision of individual studies in (a) anti-PD-1 and (b) anti-PD-L1. The y-axis represents the standard error. The x-axis displays the study estimated effect size (hazard ratio). Forrest plot comparing the heterogeneity of the included trials for the two subclasses (c) anti-PD-1 and (d) anti-PD-L1.PD-1: programmed cell death-1; PD-L1: programmed death-ligand 1.
Figure 2.

Tables

↓  Table 1. Characteristics of Included Clinical Trials
 
Reference Authors Year Histological subtype Line of therapy Class Experimental arm Control arm Sample size (PD-L1) negative ITT group Hazard ratio (PFS) 95% CI Hazard ratio (OS) 95% CI
CI: confidence interval; ITT: intension to treat; NSCLC: non-small cell lung cancer; OS: overall survival; PD-1: programmed cell death-1; PD-L1: programmed death-ligand 1; PFS: progression-free survival.
KEYNOTE-189 [23] Gandli et al 2018 Non-squamous NSCLC First line PD-1 Pembrolizumab + pemetrexed and a platinum-based drug Placebo + pemetrexed and a platinum-based drug 190 616 0.75 0.53 - 1.05 0.59 0.38 - 0.92
KEYNOTE-407 [24] Paz-Ares et al 2018 Squamous NSCLC First line PD-1 Pembrolizumab plus chemotherapy (carboplatin and either paclitaxel or nab-paclitaxel) Placebo + chemotherapy (carboplatin and either paclitaxel or nab-paclitaxel) 194 559 0.68 0.47 - 0.98 0.61 0.38 - 0.98
KEYNOTE-021 [20] Langer et al 2016 Non-squamous NSCLC First line PD-1 Pembrolizumab plus pemetrexed plus carboplatin Placebo + pemetrexed plus carboplatin 44 123 0.35 0.17 - 0.72 0.54 0.26 - 1.13
ARCTIC [25] Planchard et al 2020 NSCLC (study B) Later line PD-L1 Durvalumab with or without Tremelimumab Gemcitabine/vinorelbine and erlotinib 110 489 0.76 0.51 - 1.15 0.8 0.53 - 1.22
MYSTIC [26] Rizvi et al 2020 NSCLC First line PD-L1 Durvalumab Paclitaxel/gemcitabine + platinum (squamous) or pemetrexed + platinum for (non-squamous) 178 1,118 N/A N/A 1.2 0.86 - 1.6
POSEIDON [27] Johnson et al 2023 NSCLC First line PD-L1 Durvalumab + chemotherapy Chemotherapy 243 1,013 N/A N/A 0.99 0.76 - 1.3
CheckMate 017 [19] Brahmer et al 2015 Squamous NSCLC Later line PD-1 Nivolumab Chemotherapy (docetaxel) 106 272 0.66 0.43 - 1 0.58 0.37 - 0.92
CheckMate 057 [28] Borghaei et al 2015 Non-squamous NSCLC Later line PD-1 Nivolumab Chemotherapy (docetaxel) 109 582 1.19 0.88 - 1.61 0.9 0.66 - 1.24
CheckMate 227 [18] Hellmann et al 2019 NSCLC First line PD-1 Nivolumab + chemotherapy Chemotherapy 550 1,739 0.73 0.56 - 0.95 0.78 0.6 - 1.02
IMpower 131 [29] Jotte et al 2020 squamous NSCLC First line PD-L1 Atezolizumab + carboplatin + paclitaxel/nab-paclitaxel Carboplatin + paclitaxel/nab-paclitaxel 500 1,021 0.82 0.65 - 1.04 0.87 0.67 - 1.13
IMpower 150 [30] Socinski et al 2018 Non-squamous NSCLC First line PD-L1 Atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) Bevacizumab plus carboplatin plus paclitaxel (BCP) 338 800 0.77 0.61 - 0.99 0.81 0.61 - 1.07
OAK [31] Rittmeyer et al 2017 NSCLC Later line PD-L1 Atezolizumab Docetaxel 379 850 1 0.8 - 1.25 0.75 0.59 - 0.96
PROLUNG [32] Arrieta et al 2020 NSCLC Later line PD-1 Pembrolizumab + docetaxel Docetaxel 30 78 0.41 0.16 - 1.95 N/A N/A
CCTG BR34 [33] Leighl et al 2022 NSCLC First line PD-L1 Durvalumab + tremelimumab Durvalumab + tremelimumab + platinum doublet 116 301 1.61 1.08 - 2.5 1.06 0.7 - 1.6
ONO-4538-52/TASUKI-52 [21] Sugawara et al 2021 Non- squamous NSCLC First line PD-1 Nivolumab + chemotherapy Carboplatin + paclitaxel + bevacizumab 240 550 0.56 0.43 - 0.71 0.85 0.63 - 1.21
CheckMate 9LA [34] Paz-Ares et al 2021 NSCLC First line PD-1 Nivolumab + ipilimumab + chemotherapy Chemotherapy 264 719 0.69 0.52 - 0.91 0.67 0.51 - 0.87
IMpower 132 [35] Nishio et al 2021 NSCLC First line PD-L1 Atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) Carboplatin or cisplatin plus pemetrexed 163 578 0.45 0.31 - 0.64 0.67 0.46 - 0.96
CHOICE-01 [36] Wang et al 2023 NSCLC First line PD-1 Toripalimab Placebo + chemotherapy (nab-paclitaxel + carboplatin 139 465 0.47 0.32 - 0.71 0.79 0.49 - 1.31
EMPOWER-Lung 3 Part 2 [37] Makharadze et al 2023 NSCLC First line PD-1 Cemiplimab plus chemotherapy Placebo plus chemotherapy 139 466 0.76 0.51 - 1.15 1.01 0.63 - 1.6
RATIONALE 304 [38] Lu et al 2021 Non-squamous NSCLC First line PD-1 Chemotherapy Tislelizumab and chemotherapy 144 334 0.758 0.469 - 1.224
CameL [39] Xie et al 2022 Non-squamous NSCLC First line PD-1 Camrelizumab plus carboplatin and pemetrexed Carboplatin and pemetrexed 92 412 0.75 0.5 - 1.13 0.84 0.55 - 1.27
CameL-sq [40] Ren et al 2022 Squamous NSCLC First line PD-1 Carboplatin plus paclitaxel with camrelizumab Carboplatin plus paclitaxel with placebo 188 398 0.49 0.35 - 0.68 0.62 0.41 - 0.94
POPLAR [22] Fehrenbacher et al 2016 NSCLC Later line PD-L1 Atezolizumab Docetaxel 92 287 0.88 0.55 - 1.4

 

↓  Table 2. Results of the Differential Efficacy Between Anti-PD-1 Over Anti-PD-L1 in PD-L1-Negative Advanced NSCLC Patients
 
Agent subclass PD-L1 PD-1 Differential efficacy
HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value
CI: confidence interval; HR: hazard ratio; NSCLC: non-small cell lung cancer; OS: overall survival; PD-1: programmed cell death-1; PD-L1: programmed death-ligand 1; PFS: progression-free survival.
OS
  Overall 0.90 0.78 - 1.05 0.18 0.75 0.67 - 0.83 < 0.01 0.83 0.67 - 0.99 0.01
  First line 0.94 0.83 - 1.07 0.34 0.74 0.66 - 0.83 < 0.01 0.79 0.66 - 0.93 0.01
  Later lines 0.78 0.64 - 0.95 0.01 0.88 0.69 - 1.13 0.31 1.13 0.82 - 1.55 0.45
PFS
  Overall 0.83 0.64 - 1.08 0.16 0.73 0.6 - 0.88 < 0.01 0.88 0.64 - 1.2 0.42
  First line 0.76 0.64 - 0.91 < 0.01 0.64 0.58 - 0.71 < 0.01 0.84 0.68 - 1.03 0.09
  Later lines 0.94 0.77 - 1.14 0.53 1 0.8 - 1.26 1 1.06 0.78 - 1.43 0.70

 

↓  Table 3. Association Between Histological Subtype and Outcomes
 
Histological subtype Squamous Non-squamous
HR 95% CI P-value HR 95% CI P-value
CI: confidence interval; HR: hazard ratio; OS: overall survival; PD-1: programmed cell death-1; PD-L1: programmed death-ligand 1.
PD-1 (OS) 0.60 0.47 - 0.78 < 0.01 0.79 0.65 - 0.95 0.01
PD-L1 (OS) 0.87 0.67 - 1.13 0.29 0.81 0.61 - 1.07 0.14