World J Oncol

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 000, Number 000, April 2025, pages 000-000

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

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.

**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 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

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

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

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

0.8 - 1.25

0.75

0.59 - 0.96

PROLUNG [32]

Arrieta et al

2020

NSCLC

Later line

PD-1

Pembrolizumab + docetaxel

Docetaxel

0.41

0.16 - 1.95

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

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

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
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 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

95% CI

P-value

95% CI

P-value

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.

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

0.8 - 1.26

1.06

0.78 - 1.43

0.70

**Table 3.** Association Between Histological Subtype and Outcomes
Histological subtype	Squamous	Non-squamous
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

Table 3. Association Between Histological Subtype and Outcomes

Histological subtype

Squamous

Non-squamous

95% CI

P-value

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