Clinical and Translational Oncology

https://doi.org/10.1007/s12094-020-02502-8

RESEARCH ARTICLE

The optimal immune checkpoint inhibitors combined

with chemotherapy for advanced non‑small‑cell lung cancer:
a systematic review and meta‑analysis
Y. Yang1 · H. Luo1 · X. L. Zheng1 · H. Ge1

Received: 11 May 2020 / Accepted: 15 September 2020

© Federación de Sociedades Españolas de Oncología (FESEO) 2020

Abstract
Background Immune checkpoint inhibitors (ICIs) plus chemotherapy (CT) have strikingly expanded the therapeutic land-
scape for advanced non-small cell lung cancer (NSCLC), but little is known about which is superior. We performed a meta-
analysis that compared the efficacy and safety of PD-1 inhibitor + CT with PD-L1 inhibitor + CT.
Methods PubMed, Embase, Web of Science, Cochrane Library, and major international scientific meetings were searched
for relevant randomized controlled trials (RCTs), and the indirect analysis was performed for PD-1 + CT vs PD-L1 + CT.
The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-
related adverse events (TRAEs).
Results 8 phase III RCTs with 4253 patients comparing PD-1/PD-L1 + CT in NSCLC were included. The PD-1 + CT led to
notably longer OS most in low/negative expression of PD-L1 for NSCLC patients compared with PD-L1 + CT. In terms of
Grade 3–5 TRAEs, the results showed that PD-1 + CT and PD-L1 + CT exclusively increased the risk of adverse incidence
than CT alone, especially for PD-L1 + CT (p < 0.00001). For subgroups including female, young patients, patients with non-
smoker, and EGFR/ALK wild-type, PD-1 + CT was associated with prolonged OS (p < 0.05). Meanwhile, for no liver metas-
tasis of NSCLC patients, we found obviously OS advantage for patients treated with PD-1 + CT compared to PD-L1 + CT.
Conclusions ICIs + CT seemed to be more effective first-line regimen and PD-1 + CT could be recommended as the first-rank
therapy for advanced NSCLC patients with low/negative expression of PD-L1. However, we should be particularly vigilant
about the occurrence of the Grade 3–5 TRAEs.

Keywords Advanced non-small cell lung cancer (advanced NSCLC) · Immune checkpoint inhibitors (ICIs) ·
Chemotherapy · Programmed death 1 · Programmed death 1 ligand 1

Introduction radiotherapy, and chemotherapy (CT) have dominated the

field of NSCLC [3–5]. In addition, the first-line treatment
Non-small cell lung cancer (NSCLC) accounts for approxi- scheme for advanced lung adenocarcinoma is built upon
mately 85% of lung cancer with most patients diagnosed at the expression of oncogenic aberrations, such as epidermal
a metastatic or advanced stage [1, 2]. Over the past several growth factor receptor (EGFR) mutation or anaplastic lym-
decades, traditional oncologic therapeutics such as surgery, phoma kinase (ALK) fusion, derive momentous advantages
from targeted agents-tyrosine kinase inhibitors (TKIs) [6–8].
In patients with advanced NSCLC without targeted tumor-
Electronic supplementary material The online version of this specific mutations, treatment mainly includes the adminis-
article (https​://doi.org/10.1007/s1209​4-020-02502​-8) contains
tration of platinum-based chemotherapy doublets ± beva-
supplementary material, which is available to authorized users.
cizumab or necitumumab. However, these treatments still
* H. Ge could not achieve long-term survival benefits, and resist-
gehong616@126.com ance develops even in patients who initially respond [9–11].
1 Therefore, it is absolutely vital to develop a better therapeu-
Department of Radiation Oncology, The Affiliated Cancer
Hospital of Zhengzhou University, Dong Ming Road 127#, tic regimen for advanced NSCLC with low toxicity.
Zhengzhou 450008, China

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There’s large amount of research pinpointing the deter- Material and methods
mining role of immunotherapy (IO) in cancer treatment;
meanwhile, many new challenges are raised. Anticancer IO Data retrieval strategies
targeting immune checkpoints with antibodies to programmed
death-1 (PD-1) and its ligand PD-L1 has been suggested to PubMed, Embase, Web of Science, Cochrane Library data-
improve OS compared to CT in patients with advanced bases and other major international conference (American
NSCLC contributing better survival outcome [9, 10, 12, 13]. Society of Clinical Oncology, European Society for Medical
For most cancer patients, inhibiting immune checkpoints Oncology, and World Conference on Lung Cancer) were
alone is insufficient to promote tumor regression; IO in com- searched for available studies published from their respec-
bination with other traditional anti-tumor therapies appears to tive inception dates to March 2020. The following keywords
be a promising strategy [14–16]. Recent meta-analysis [17] included immune checkpoint inhibitors (PD‐1 inhibitors and
published by Wang et al. implicated that immune checkpoint PD‐L1 inhibitors), especially for (nivolumab, pembroli-
inhibitor (ICI) plus CT resulted in greater PFS benefit than zumab, atezolizumab), and non-small cell lung cancer (The
ICI monotherapy with the statistical difference compared with search strategy is detailed in Supplementary material 1).
CT (p < 0.01). Meanwhile, equal OS and ORR benefits were All the studies were well designed randomized controlled
observed evenly in both ICI + CT and ICI-monotherapy com- phase III trials. Following the exclusion of studies that did
pared with CT (p = 0.77 and p = 0.78). Results from another not meet the inclusion criteria, 8 trials [14, 19, 22–27] com-
systematic study [18] adopting indirect comparison proved paring PD-1/PD-L1 immunotherapy plus chemotherapy vs.
that patients treated with pembrolizumab plus CT had bet- chemotherapy alone were included (summarized in Table 1).
ter clinical outcomes including ORR ­(RRpem + chemo/pem 1.62;
p = 0.003) and PFS (­ HRpem + chemo/pem 0.55; p = 0.037) than
those treated with pembrolizumab alone. Furthermore, the Inclusion and exclusion criteria
combination of atezolizumab and carboplatin-paclitaxel-bev-
acizumab (AEV) has been approved by the FDA as a first-line The eligible RCTs that meet the following criteria were
treatment for lung adenocarcinoma [19]. Likewise, pembroli- included in our meta-analysis: (a) histologically confirmed
zumab in combination with carboplatin and taxanes has been advanced patients with NSCLC; (b) phase III randomized
approved by the FDA for squamous histology NSCLC [20]. controlled trials (RCTs) with primary endpoints, such as
In this context, for patients with advanced NSCLC, more overall survival (OS), progression-free survival (PFS), or
and more attention has turned to choose the optimal ICI objective response rate (ORR); (c) the intervention group
combined CT to improve the efficacy and survival. Unfortu- was treated with immunotherapy plus chemotherapy,
nately, there is not yet head-to-head clinical studies to identify whereas the control group was treated with chemotherapy
which ICI + CT performs best. Zhang et al.investigated the alone. Studies were excluded based on the following crite-
effect of PD-1 + CT versus PD-L1 + CT for patients of squa- ria as follows: (a) designed as retrospective or prospective
mous NSCLC; results showed that PD-1 + CT is superior to observational cohort studies; (b) lack of related data; (c)
PD-L1 + CT most notable in PD-L1 low/negative subgroup of published as reviews, case reports, letters, commentaries,
NSCLC patients [21]. But, this report only included two stud- editorials, or meta‐analysis; and (d) duplicated articles.
ies, KEYNOTE-407 [22] and IMpower131 [23], which have a
large bias and might compromise the evidence level. Besides,
the proportion of PD-L1 high patients was slightly higher in Data extraction and quality assessment
KEYNOTE-407, while the proportion of PD-L1 negative
patients was slightly higher in IMpower131, both in the experi- The two authors (Yang and Luo) independently extracted
mental group and control group. Therefore, it is imperative the relevant information from eligible studies: first author,
to conduct an indirect comparative meta-analysis of currently year of publication, trial phase, number of included patients,
available trials comparing PD-1 + CT with PD-L1 + CT to pro- treatment regimen, and clinical outcomes (OS, PFS, ORR,
vide a suitable treatment option and clinically useful informa- and TRAEs). Among these studies, 6 were published in
tion for patients with NSCLC. peer-reviewed journals and 2 were presented in major pro-
fessional meetings only. 4 trials investigated PD-1 blocking
agents (one with nivolumab and three with pembrolizumab),
whereas 4 trials investigated atezolizumab, a PD-L1 block-
ing antibody.
The methodological quality of RCTs was assessed by
Cochrane risk of bias tool [28], which consists of the
following five domains: sequence generation, allocation

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Table 1  Characteristics of patients comparing PD-1/PD-L1 inhibitors plus chemotherapy or PD-1/PD-L1 inhibitors alone with chemotherapy in
8 randomized controlled trials included in the meta-analysis
Study Author Year Trial phase Study group Control group Inclusion criteria
(regime and no. (regime and no. of
of Pts.) Pts.)

CheckMate 227 Hellmann 2018 III NIV plus PBC 177 PBC alone 160 Stage IV or recurrent NSCLC without
targetable genetic aberration, with a
high tumor mutational burden (≥ 10
mutations per megabase)
KEYNOTE-021 Langer 2016 III PEM plus PBC 60 PBC alone 63 Stage IIIB or IV, non-squamous
NSCLC without targetable genetic
aberration
KEYNOTE-189 Gandhi 2018 III PEM plus PBC 410 PBC alone 206 Stage IV non-squamous NSCLC with-
out targetable genetic aberration
KEYNOTE-407 Paz-Ares 2018 III PEM plus PBC 278 PBC alone 281 Stage IV, squamous NSCLC
Impower 130 West 2019 III ATE plus PBC 447 PBC alone 226 Stage IV, non-squamous NSCLC with-
out targetable genetic aberration
Impower 131 Jotte 2018 III ATE plus PBC 343 PBC alone 340 Stage IV, squamous NSCLC
Impower 132 Papadimitra 2018 III ATE plus PBC 292 PBC alone 286 Stage IV non-squamous NSCLC with-
-kopoulou out targetable genetic aberration
Impower 150 Socinski 2018 III ATE plus PBC 353 PBC alone 331 Stage IIIB or IV, non-squamous
NSCLC without targetable genetic
aberration

NIV nivolumab, PBC platinum-based chemotherapy, PEM pembrolizumab, ATE atezolizumab

concealment, blinding, incomplete data, and selective Results

reporting. An RCT was finally rated as “low risk of bias”
(all key domains indicated as low risk), “high risk of bias” Search results and study quality assessment
(one or more key domains indicated as high risk), and
“unclear risk of bias”. The literature search results and study selection process
are shown in Fig. 1. The initial search retrieved a total of
917 studies. After removing the duplicates, 605 citations
Statistical analysis were identified, and 542 of them were excluded through an
abstract review. The remaining 53 studies were screened
All direct statistical analyses were performed using through a full-text review for further inclusion criteria.
Review Manager (RevMan, version 5.3), while the indi- Finally, 8 RCTs that involved 4253 patients who received
rect analyses were adopted by ITC (Indirect Treatment anti-PD-1/anti-PD-L1 treatments were included in the meta-
Comparisons). Risk ratios (RRs) and hazard ratios (HRs) analysis. The study characteristics are shown in Table 1. 5
with 95% confidence intervals (CIs) were calculated for studies enrolled patients with non-squamous NSCLC, 2
dichotomous data. Heterogeneity among these included trials enrolled those with squamous NSCLC, and 1 trial
studies was evaluated using I­ 2 statistics, where the ran- accepted patients with either cell type. In addition, 4 trials
dom effect models were chosen if I 2 ≥ 50%, implying investigated anti-PD-1 agents (1 with Nivolumab and 3 with
obvious heterogeneity, otherwise, the fixed‐effect models Pembrolizumab), whereas 4 trials investigated atezolizumab,
were applied. Sensitivity analysis using both fixed and a PD-L1 blocking antibody. All of the studies were of high
random-effect models for the same data was conducted to quality. The detailed quality assessment of each included
confirm the robustness and reliability of the results. The study is shown in Table S1.
primary outcomes were OS and PFS, presented with HRs,
95% CIs, and p values. The integrated analysis for ORR, Primary analysis
Grade 1–5 TRAEs, and Grade 3–5 TRAEs were conducted
based on the Mantel–Haenszel method. The Bucherʼs Efficacy
method was employed to make each of the pairwise indi-
rect comparisons separately. Subgroup analysis was con- ORR (objective response rate) Of the 4253 NSCLC patients
ducted to explore the potential source of heterogeneity. p based on 8 RCTs [14, 19, 22–27], 2360 (55.5%) were ran-
value < 0.05 was considered statistically significant. domized to PD-1/PD-L1 + CT groups, and 1,893 (44.5%)

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Fig. 1  Flow chart depicting the

selection algorithm and screen-
ing process

were randomly assigned to CT group. The results showed and PD-L1 + CT (HR, 0.65; 95% CI 0.59–0.71; p < 0.00001)
that compared to CT alone, PD-1/PD-L1 + CT had sig- notably decreased the risk of death compared with CT alone
nificant benefit with respect to ORR (RR, 1.51; 95% CI (Fig. 3a). Furthermore, the indirect analysis evaluated that
1.31–1.73; p < 0.00001) (Fig. 2a). The heterogeneity in the there was no statistical significance between the two groups
PD-1 + CT group was less than in the PD-L1 + CT group for PFS (HR, 0.89; 95% CI 0.77–1.04, p = 0.11; Fig. 3b).
(I2: 29% vs 72%). Figure 3b showed the relationship of the
indirect comparisons and the results indicated that patients Safety
treated with PD-1 + CT were equal to PD-L1 + CT about
ORR (RR, 1.30; 95% CI 0.96–1.74, p = 0.90). The pooled results showed (Fig. 4a) compared with CT
alone, the combination of PD-1/PD-L1 immunotherapy and
OS (overall survival) The greatest OS benefit was observed CT did not increase the risk of Grade 1–5 TRAEs (RR, 1.03;
in terms of PD-1 + CT vs CT (HR, 0.56; 95% CI 0.47–0.66; 95% CI 1.00–1.06) with PD-1 (RR, 1.04; 95% CI 0.98–1.11)
p < 0.00001; heterogeneity, p = 0.37). And for PD-L1 + CT and PD-L1 (RR, 1.03; 95% CI 0.99–1.06). Conversely, in
vs CT, the pooled HR was 0.83 (95% CI 0.75–0.93; terms of Grade 3–5 TRAEs (Fig. 4b), subgroup analysis
p = 0.0007; heterogeneity, p = 0.47) (Fig. 2b). In addition, results demonstrated the risk of PD-L1 + CT was appar-
for indirect analysis (Fig. 3b), the results suggested that ently stronger than CT alone (RR, 1.22; 95% CI 1.15–1.31;
patients treated with PD-1 + CT had better clinical outcomes p < 0.00001).
(HR, 0.68; 95% CI 0.55–0.83, P = 0.0004).
Subgroup analysis
PFS (progression‑free survival) Based on fixed-effects
model analysis, in terms of progression-free survival (PFS), We performed subgroup analyses according to PD-L1
both PD-1 + CT (HR, 0.58; 95% CI 0.51–0.65; p < 0.00001) expression, age, sex, smoker, ECOG PS, liver metastasis,

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Fig. 2  Forest plots of ORR(objective response rate) and OS(overall survival) comparing PD-1 + CT or PD-L1 + CT versus chemotherapy alone.
PD-1 anti-PD-1 immune checkpoint inhibitor, PD-L1 anti-PD-L1 immune checkpoint inhibitor, CT chemotherapy

EGFR/ALK, and pathology. The pooled results showed can significantly prolong the survival of patients compared
that for PFS, regardless of PD-L1 expression, PD-1 + CT with CT, unrelated to the expression of PD-L1. However,
and PD-L1 + CT were better than the results of CT alone when PD-L1 expression is negative or low, the effect of
(p < 0.001 or p < 0.05, Fig. S2 and Table S3). In addition, PD-L1 + CT was equivalent to the CT alone ­(HRPD-L1+CT/CT,
with the increase of PD-L1 expression, ICIs + CT have more 0.87; 95% CI 0.76–1.00; p = 0.05; ­HRPD-L1+CT, 0.86; 95%
significant results in reducing the risk of death (Table 2). CI 0.63–1.17; p = 0.34). Indirectly comparing which inhibi-
We further conducted indirect comparison meta-analysis tors are more effective when PD-L1 is highly expressed,
and found that no matter the PD-L1 expression (negative the results showed that both PD-1 inhibitors and PD-L1
or positive, high or low), the combination of two ICIs has inhibitors combined with CT are superior to chemotherapy
the same effect with no statistical significance (p ≥ 0.05, alone and have comparable effects (­ HRPD-1+CT, 0.51; 95% CI
Table S3). In terms of OS (Fig. S1 and Table 3), PD-1 + CT 0.34–0.76; p = 0.001; ­HRPD-L1+CT, 0.71; 95% CI 0.55–0.90;

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Fig. 3  Forest plots of progression-free survival (PFS) comparing between PD-1 + CT versus PD-L1 + CT. The size of the circle cor-
PD-1 + CT or PD-L1 + CT versus chemotherapy alone and indi- responds to the enrolled patient number. PD-1 anti-PD-1 immune
rect comparison between PD-1 + CT versus PD-L1 + CT. In B, solid checkpoint inhibitor, PD-L1 anti-PD-L1 immune checkpoint inhibi-
lines represented the existence of direct comparisons between treat- tor, CT chemotherapy, ORR objective response rate, OS overall sur-
ment regimens, and dashed line represented the indirect comparison vival, PFS progression-free survival

p = 0.006; ­HRPD-1+CT/PD-L1+CT, 0.72; 95% CI 0.45–1.15; PD-1 + CT than PD-L1 + CT ([HR, 0.56; 95% CI 0.47–0.67]
p = 0.17). and [HR, 0.83; 95% CI 0.75–0.93], respectively, difference
In parallel to PD-L1 expression, Table 2 and Table S2 p = 0.0004). For subgroups including female, young patients,
revealed the OS and PFS differences in the efficacy of patients with nonsmoker, non-squamous/squamous lung
PD-1 + CT and PD-L1 + CT. As shown in OS (Table 2), the cancer, and EGFR/ALK wild-type, PD-1 + CT was associ-
magnitude of OS benefit was greater in patients treated with ated with prolonged OS compared with PD-L1 + CT (all

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Fig. 4  Forest plots of RRs comparing Grade 1–5 TRAE (a) and grade PD-L1 immune checkpoint inhibitor, CT chemotherapy, RR risk ratio,
3–5 TRAE (b) between PD-1 + CT and PD-L1 + CT. CI confidence TRAE treatment‐related adverse event
interval, PD-1 anti-PD-1 immune checkpoint inhibitor, PD-L1 anti-

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Table 2  Differences in OS benefits of Immunotherapy in PD-1 + CT and PD-L1 + CT by subgroups

Variable Study Pooled HR (95%CI) Test for difference
Direct comparison Indirect comparison P value
PD-1 + CT vs CT PD-L1 + CT vs CT PD-1 + CT vs PD-L1 + CT

Overall 7 0.56 [0.47; 0.66] 0.83 [0.75; 0.93] 0.68 [0.55; 0.83] 0.0004
Sex
Male 5 0.69 [0.55; 0.87] 0.80 [0.69; 0.93] 0.86 [0.66; 1.13] 0.26
Female 5 0.32 [0.23; 0.46] 0.80 [0.66; 0.96] 0.40 [0.27; 0.59] < 0.00001
Age
≥ 65 year 5 0.69 [0.53; 0.91] 0.82 [0.69; 0.97] 0.84 [0.61; 1.16] 0.29
< 65 year 7 0.46 [0.36; 0.60] 0.77 [0.66; 0.97] 0.60 [0.43; 0.82] 0.003
Smoker
Never 7 0.36 [0.15; 0.85] 1.01 [0.79; 1.29] 0.36 [0.15; 0.88] 0.02
Ever 9 0.74 [0.56; 0.97] 0.78 [0.68; 0.90] 0.95 [0.70; 1.29] 0.74
Histological type
Squamous 2 0.64 [0.49; 0.84] 0.96 [0.78; 1.18] 0.67 [0.48; 0.94] 0.02
Non-squamous 5 0.49 [0.38; 0.63] 0.79 [0.71; 0.89] 0.62 [0.47; 0.82] 0.0007
ECOG PS
0 5 0.47 [0.33; 0.68] 0.82 [0.67; 1.00] 0.57 [0.37; 0.87] 0.01
1 5 0.59 [0.47; 0.73] 0.79 [0.68; 0.91] 0.75 [0.57; 0.97] 0.04
EGFR/ALK
Mutant 2 / 0.66 [0.40; 1.10] /
WT 4 0.49 [0.38; 0.63] 0.79 [0.70; 0.90] 0.62 [0.47; 0.82] 0.0007
Liver metastasis
Yes 4 0.62 [0.39; 0.99] 0.77 [0.59; 1.00] 0.81 [0.47; 1.38] 0.45
No 4 0.58 [0.45; 0.75] 0.80 [0.70; 1.18] 0.73 [0.56; 0.96] 0.02

CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio, PD-1 + CT anti-PD-1 immune
checkpoint inhibitor combined with chemotherapy, PD-L1 + CT anti-PD-L1 immune checkpoint inhibitor combined with chemotherapy, CT
chemotherapy, PD‐1 programmed cell death 1, PD‐L1 programmed cell death 1 ligand 1, OS overall survival

Table 3  Differences of PD-L1 expression in OS benefits of Immunotherapy in PD-1 + CT and PD-L1 + CT by subgroups
PD-L1 expression Study Pooled HR (95% CI) Test for difference
Direct comparison Indirect comparison P value
PD-1 + CT vs CT PD-L1 + CT vs CT PD-1 + CT vs PD-L1 + CT

Negative 6 0.60 [0.43; 0.83] 0.87 [0.76; 1.00] 0.69 [0.48; 0.99] 0.045
Positive 10 0.55 [0.40; 0.75] 0.79 [0.66; 0.96] 0.70 [0.48; 1.00] 0.05
Low 6 0.56 [0.40; 0.78] 0.86 [0.63; 1.17] 0.64 [0.42; 0.98] 0.04
High 6 0.51 [0.34; 0.76] 0.71 [0.55; 0.90] 0.72 [0.45; 1.15] 0.17

Low PD-L1 expression: PDL1 1–49% or TC1/2 (TC ≥ 1% and < 50%) or IC1/2 (IC ≥ 1% and < 10%). High PD-L1 expression: PD-L1 ≥ 50% or
TC3 (TC ≥ 50%) or IC3 (IC ≥ 10%). TC: tumor cells. IC: tumor-infiltrating immune cells
CI confidence interval, HR hazard ratio, PD-1 + CT anti-PD-1 immune checkpoint inhibitor combined with chemotherapy, PD-L1 + CT anti-
PD-L1 immune checkpoint inhibitor combined with chemotherapy, CT chemotherapy, PD‐1 programmed cell death 1, PD‐L1 programmed cell
death 1 ligand 1, OS overall survival

difference p < 0.05). The OS benefit of PD-1 + CT for liver compared to PD-L1 + CT (­HR PD-1+CT, 0.58; 95% CI
metastasis of NSCLC patients was similar in the PD-L1 + CT 0.45–0.75; p = 0.001; ­HRPD-L1+CT, 0.80; 95% CI 0.70–1.18;
­(HRPD-1/PD-L1,0.81; 95% CI 0.47–1.38, p = 0.45), Meanwhile, p = 0.006; ­HRPD-1+CT/PD-L1+CT, 0.73; 95% CI 0.56–0.96;
for no liver metastasis of NSCLC patients, we found obvi- p = 0.02). Unlike what was observed regarding OS, for
ously OS advantage for patients treated with PD-1 + CT PFS about subgroups (Table S2), the effect of PD-1 + CT

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in patients with advanced NSCLC who are younger than protein on T cells, it will block both PD-1 and PD-L1 Bind-
65 years old and without liver metastasis showed a huge ing to PD-L2, and PD-L1 antibodies can only interact with
advantage over the effect of PD-L1 + CT (p = 0.01 and PD-L1 on the surface of tumor cells, so it will only prevent
P = 0.03). For other subgroups such as gender, history of the binding of PD-1 to PD-L1. When treated with anti-PD-
smoking, pathological type, ECOG score, and whether L1 antibody, the interaction between PD-L2 and PD-1 still
EGFR/ALK mutations, ICIs + CT was associated with pro- exists, which may inhibit the function of T cells [31, 32].
longed PFS compared with CT alone, and PFS benefit from For patients with high PD-L1 expression, anti-PD-L1 and
PD-1 + CT was equivalent to that from PD-L1 + CT without anti-PD-1 treatments may be similar because PD-L1 expres-
significant differences in the two groups (all p > 0.05). sion may predominate in these patients. However, for PD-L1
low / negative patients, the expression profile of immune
molecules may be more complex, such as enhanced PD-L2
Discussion expression. As a result, anti-PD-L1 therapy may not be suf-
ficient compared to anti-PD-1 therapy in patients with low
Our study contained 8 clinical trials involving 4253 patients, / negative PD-L1. Further research is needed to understand
including 4 trials for PD-1 inhibitors and others for PD- the role of activation of PD-1 pathway in the antitumor
L1inhibitors, which compared the efficacy of PD-1/PD-L1 immunity on the whole landscape.
inhibitors with CT for advanced NSCLC patients. This is the Previous studies have shown that CT alone is associ-
first meta-analysis adopting indirect comparison to explore ated with serious side effects for a long time, and PD-1/
the efficacy and safety of PD-1/PD-L1 + CT on ORR, OS PD-L1 inhibitors seemed to be safer than chemotherapy in
and PFS for advanced NSCLC patients. most adverse events for patients [12, 33–35]. Surprisingly,
During recent decades, a substantial number of prospec- recent researches suggested that patients with PD-1/PD-L1
tive clinical studies have shown that the combination of inhibitors exclusively have a higher risk of certain immune-
ICIs and CT is more effective than CT alone. The results related adverse events (irAEs), such as pneumonia, colitis,
of the KEYNOTE-189 [14] study demonstrated in patients and hyperthyroidism, compared with chemotherapy [36–38].
with previously untreated metastatic non-squamous NSCLC In the present study, our results confirmed that for Grade 1–5
without EGFR or ALK mutations, an advantage of the addi- TRAEs, patients receiving PD-1 + CT were not at higher risk
tion of pembrolizumab to standard CT over CT alone with than chemotherapy alone. In parallel to Grade 1–5 TRAEs,
regards to significantly longer OS and PFS. Additionally, the results of Grade 3–5 TRAEs showed PD-1/PD-L1 + CT
adverse events of grade 3 or higher occurred in 67.2% of the exclusively increased the risk of adverse incidence than
patients in the pembrolizumab-combination group and in chemotherapy, especially for PD-L1 + CT. Taken together,
65.8% of those in the placebo-combination group. Another our finding suggested that more attention needs to be paid
result of KEYNOTE-407 [22] which recruited treatment- on advanced NSCLC patients, when considering treating by
naïve stage IV squamous NSCLC patients demonstrated PD-1/PD-L1 + CT.
patients in the pembrolizumab plus CT enduring a pro- A previous meta-analysis failed reveal that the relative
longed OS (HR, 0.71; 95% CI 0.58–0.88))and PFS (HR, benefit of immunotherapy (predominantly single agent) is
0.57; 95% CI 0.47–0.69) versus CT alone. However, the greater in female, never-smoker and PD-L1 low expression
Impower131 [23] study invalidated the KEYNOTE-407 cancer patients [39, 40]. Interestingly, these findings were
studies, maintained that there was no significant advantage in contrast with other meta-analysis [41], which performed
of atezolizumab plus CT over CT alone observed in terms robust efficacy of IO + CT over CT alone among female
of long-term survival among patients. Based on all the avail- patients and those with negative PD-L1 expression, and
able information extracted from the included trials, we found more importantly, demonstrated a relatively lower efficacy
that PD-1/PD-L1 + CT as a first-line therapy had a favora- in never-smoker patients. Our research further illustrated
ble longer-term effect than CT alone which were consistent PD-1 + CT conferred the OS superiority compared with
with the previous meta-analysis [29, 30]. Correspondingly, PD-L1 + CT in condition with the lack of PD-L1 expres-
we found that PD-1 + CT seemed to be superior in terms of sion, female gender, and the absence of prior exposure to
OS compared to PD-L1 + CT, most notable in low/negative tobacco. However, the PFS results showed that the treat-
expression of PD-L1 subgroup for NSCLC patients. In con- ment effects of the two ICIs + CT were equally. Addition-
trast to the outcome about OS, we also found that patients ally, we also showed that for elderly patients (≤ 65 years
treated with PD-1 + CT were equal to PD-L1 + CT about old), PD-1/PD-L1 + CT are more effective than CT alone.
PFS (HR 0.89; 95% CI 0.77–1.04; p = 0.11) and ORR (RR, When patients are younger (< 65 years old), PD-1 + CT is
1.30; 95% CI 0.96–1.74; p = 0.90). Now the mainstream significantly better than PD-L1 + CT. This finding is differ-
view about the difference between PD-1 antibodies and ent from Kiichiro’s meta-analysis [42] which revealed simi-
PD-L1 antibodies is that PD-1 antibodies can bind to PD-1 lar efficacy with ICI monotherapy in patients younger vs.

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older than 65 years old. Moreover, we also found that for Informed consent Informed consent was obtained from all individual
patients with no EGFR / ALK mutation and no liver metasta- participants included in the study.
ses before treatment, PD-1 + CT is superior to PD-L1 + CT.
Such results can give us a lot of clinical implications: for
young, female patients, patients with low or no expression
of PD-L1, and patients who have never smoked, we prefer References
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