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\begin{document}

\title{PD-1/PD-L1 based immunochemotherapy vs chemotherapy alone for advanced
esophageal squamous cell carcinoma: a meta-analysis focus on PD-L1
expression level}



\author[1]{Zixian Jin}%
\author[1]{Jiping Wang}%
\author[1]{Jiajing Sun}%
\author[1]{Chengchu Zhu}%
\author[1]{Jian Zhang}%
\author[1]{Bo Zhang}%
\affil[1]{Taizhou Hospital of Zhejiang Province}%


\vspace{-1em}



  
  \date{June 12, 2024}


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\selectlanguage{english}
\begin{abstract}
Objective: Immunochemotherapy has become a new treatment for advanced
esophageal squamous cell carcinoma (ESCC). We aimed to study the
clinical efficacy and toxicity of immunochemotherapy based on PD-1/PD-L1
compared with chemotherapy alone in the treatment of advanced ESCC,
focusing on analyzing the influence of PD-L1 expression level. Methods:
Randomized controlled trials comparing PD-1/PD-L1 based
immunochemotherapy wirh chemotherapy alone for advanced ESCC were
included. We extracted efficacy data {[}objective response rate (ORR),
disease control rate (DCR), overall survival (OS) rate, progression-free
survival (PFS) rate{]} and safety data (treatment-related adverse
events, treatment-related mortality) and performed meta-analyses.
Results: 5 articles were included. Compared with chemotherapy alone, the
ORR and DCR of immunochemotherapy increased by 2.05 times and 1.54
times, respectively. Overall, patients receiving immunochemotherapy had
a significant long-term survival advantage {[}OS: hazard ratio
(HR)=0.68, 95\% hazard ratio (CI) 0.61-0.75; PFS: HR=0.62, 95\%CI 0.55,
0.70, respectively{]}. Even with PD-L1 tumor proportion score
\textless{}1\%, immunochemotherapy also showed a significant survival
advantage {[}OS: HR=0.65, 95\%CI 0.46-0.93; PFS: HR=0.56, 95\%CI
0.46-0.69, respectively{]}. However, for PD-L1 combined positive score
(CPS)\textless{}1, the survival advantage of immunochemotherapy was not
significant {[}OS: HR=0.89, 95\%CI 0.42-1.90; PFS: HR=0.71, 95\%CI
0.47-1.08, respectively{]}. The toxicity of immunochemotherapy was
higher than that of chemotherapy alone, but there was no statistical
difference in treatment-related mortality (odds ratio=1.11, 95\%CI
0.67-1.83). Conclusions: In this study, PD-1/PD-L1 based
immunochemotherapy significantly could improve survival outcomes in
patients with advanced ESCC. For patients with CPS\textless{}1, the
survival advantage of immunochemotherapy was not significant. The
toxicity of immunochemotherapy was acceptable.%
\end{abstract}%



\sloppy


\textbf{1 Introduction:}

Squamous cell carcinoma is one of the main subtypes of esophageal
cancer, and the prognosis is still
unsatisfactory.\textsuperscript{1,2}The early stage of esophageal cancer
is often overlooked due to the lack of distinctive clinical features. By
the time patients present with typical symptoms (e.g., progressive
dysphagia, retrosternal pain), the disease is often locally advanced or
even terminal. When the disease progresses to an advanced stage, surgery
is no longer able to cure it, and the survival of the patient is greatly
threatened.

In the past, the treatment of advanced esophageal squamous cell
carcinoma (ESCC) depends on the entire body of chemotherapy, radiation
therapy and targeted therapy, but the effect is not
ideal.\textsuperscript{3-5} Immunotherapy is a new treatment option that
has shown encouraging efficacy in many cancers \textsuperscript{6,7}.
With the advent of Immunotherapy era, the treatment of advanced
esophageal cancer is gradually changing. Clinically, there are two main
immunotherapy options for patients with esophageal cancer, namely,
anti-programmed cell death 1 (anti-PD-1)/anti-programmed cell death 1
ligand 1 (anti-PD-L1) and anti-cytotoxic T-lymphocyte-associated
antigen-4 (anti-CTLA-4) therapy.\textsuperscript{8} Phase I/II studies
in pilot trials have demonstrated antitumor activity and safety of
PD-1/L1 based immunotherapy in patients with unresectable advanced or
recurrent esophageal cancer or gastroesophageal junction
cancer.\textsuperscript{9-15} With the deepening of the cognition of
immunotherapy, immunotherapy combined with chemotherapy, radiotherapy
and even double immunotherapy are gradually derived, and their effects
are exciting.\textsuperscript{16-18} However, the clinical application
of immune checkpoint inhibitors is still in its early stages. Compared
with other treatments, the survival benefit of immunotherapy has also
been widely concerned.

Since the release of KEYNOTE-590 trial results, immunotherapy combined
with chemotherapy has officially entered the first-line treatment of
advanced esophageal cancer \textsuperscript{19}. Currently, the results
of a number of clinical trials comparing immunotherapy combined with
chemotherapy versus chemotherapy alone have been
published.\textsuperscript{19-23} In this meta-analysis, we attempted to
comprehensively analyze the efficacy and safety of PD-1/PD-L1 based
immunotherapy combined with chemotherapy for advanced ESCC, and to
evaluate the effect of PD-L1 expression level on the treatment outcome.

\textbf{2 Materials and Methods}

\textbf{2.1 Literature retrieval}

We performed keyword searches in electronic databases of PubMed,
Cochrane Library, Web of Science and EMBASE to identify all relevant
records. In addition, conference abstracts published by the
International Society for Diseases of the Esophagus (ISDE), the European
Society of Medical Oncology (ESMO), and the American Society of Clinical
Oncology (ASCO) are also included in our search. Search terms included
''esophageal, esophageal carcinoma, esophageal cancer, esophageal
squamous cell carcinoma, esophageal malignancy'', ''PD-1, PD-L1,
immunotherapy, immunochemotherapy'', and ''pembrolizumab, nivolumab,
avelumab, atezolizumab, durvalumab, camrelizumab, toripalimab,
sintilimab'', language limited to English. In addition, we searched
references of relevant published studies and review articles to
supplement the insufficient of keyword retrieval. The literature search
was conducted by two independent authors following systematic review and
meta-analysis guidelines.\textsuperscript{24}

\textbf{2.2 Inclusion and exclusion criteria}

Study inclusion criteria: (1) Randomized controlled trial (RCT); (2)
Patients received chemotherapy combined with immunotherapy based on
PD-1/PD-L1 or chemotherapy alone; (3) Advanced esophageal squamous cell
carcinoma was diagnosed; (4) The outcome of interest is efficacy and
toxicity; (5) Studies published in English. Study exclusion criteria:
(1) Retrospective studies and non-randomized controlled clinical trials;
(2) Patients with a history of any other malignancy were included in the
study. If the results of a clinical trial were published in different
journals or in different years, the article with the most complete data
was selected.

\textbf{2.3 Data extraction}

Two independent authors recorded basic information about each study,
including study name, intervention, year of publication, sample size,
trial phase, and pathology. Objective response rate (ORR), disease
control rate (DCR), progression-free survival (PFS), overall survival
(OS), hazard ratios (HR), 95\% confidence intervals (CI) and safety data
{[}treatment-related adverse event (TRAE), treatment-related mortality
(TRM){]} were extracted. A more in-depth subgroup analysis of PFS and OS
was also performed according to the expression of PD-L1, namely tumor
proportion score (TPS), combined positive score (CPS).

\textbf{2.4 Assessment of risk of bias}

The overall risk of bias of the literature was assessed according to the
Cochrane Handbook of systematic reviews \textsuperscript{25}. The
Cochrane Handbook of systematic reviews consists of 7 parts: random
sequence generation, allocation hiding, blindness of participants and
personnel, blindness of result evaluations, incomplete result data,
selective result reporting, and other sources of bias. Two independent
authors evaluated the included articles, and the other author made the
final decision on controversial sections.

\textbf{2.5 Statistical methods}

For time-survival variables, HR and 95\%CI were extracted to calculate
logHR and SE. For categorical variables, such as ORR, DCR and safety
events, the number of events and sample size were extracted.
Meta-analyses were performed using random-effects model in Revman
software. The I\textsuperscript{2} test was used to calculate
inter-study heterogeneity and p value of heterogeneity. If inter-study
heterogeneity was too high (I\textsuperscript{2}\textgreater{}50\%,
p\textless{}0.05), sensitivity analysis was further performed to assess
the robustness of the meta-analysis and determine the source of
heterogeneity.

\textbf{3 Resluts}

\textbf{3.1 Literature results}

Supplementary figure 1 shows the literature retrieval and screening
process. 5 RCTs were included, all of which were multi-center phase III
clinical trials with a total of 2962 patients (Table
1).\textsuperscript{19-23} 1 RCT included ESCC and esophageal
adenocarcinoma (EAC), from which we can extract relevant data of ESCC.
The overall risk of bias was assessed according to the Cochrane Handbook
for systematic reviews of interventions, and all the studies were of
high quality (Supplementary Table 1).

\textbf{3.2 ORR and DCR}

4 studies provided comparisons of ORR for immunochemotherapy and
chemotherapy alone. Overall, the ORR was significantly higher in
patients who received immunochemotherapy than in patients who received
chemotherapy alone. Meta-analysis showed that the ORR was approximately
2.05 times higher in the combination group than in the chemotherapy
alone group (odds ratio (OR)=2.05, 95\%CI 1.68-2.50) (Figure 1A).
Heterogeneity test I\textsuperscript{2}=28\%, p=0.24, indicating no
significant heterogeneity between studies.

4 studies provided comparisons of DCR for immunochemotherapy and
chemotherapy alone. Disease control rates were significantly higher in
the immunochemotherapy group than in the chemotherapy group alone,
approximately 1.54 times higher (OR=1.54, 95\%CI 1.22-1.95) (Figure 1B).
Similarly, according to the results of heterogeneity test, there was no
significant heterogeneity between studies (I\textsuperscript{2} =0,
p=0.80).

\textbf{3.3 OS and PFS}

5 studies provided comparisons of OS and PFS for immunochemotherapy and
chemotherapy alone. The meta-analysis showed that, without
distinguishing the level of PD-L1 expression, compared with chemotherapy
alone, the immunochemotherapy significantly improved the overall
survival and disease-free survival of patients {[}OS: HR=0.68, 95\%CI
0.61-0.75; PFS: HR=0.62, 95\%CI 0.55-0.70, respectively{]} (Figure
2A,B). There was no significant heterogeneity was found between studies
comparing OS (I\textsuperscript{2}=0, p=0.67; I\textsuperscript{2}=43\%,
p=0.14, respectively).

\textbf{3.4 Stratified according to TPS}

Subgroup analysis with TPS=10\% as cutoff value, whether TPS[?]10\% or
TPS\textless{}10\%, showed that the OS {[}TPS[?]10\%: HR=0.54, 95\%CI
0.41-0.70; TPS\textless{}10\%: HR=0.72, 95\%CI 0.60-0.88,
respectively{]} (Figure 3A,B) and PFS {[}TPS[?]10\%: HR=0.53, 95\%CI
0.42-0.66; TPS\textless{}10\%: HR=0.57, 95\%CI 0.49-0.68,
respectively{]} (Figure 3C,D) of patients in the immunochemotherapy
group were better than those in the chemotherapy group.

Subgroup analysis with TPS=5\% as cutoff value, whether TPS[?]5\% or
TPS\textless{}5\%, showed that the OS {[}TPS[?]5\%: HR=0.64, 95\%CI
0.51-0.80; TPS\textless{}5\%: HR=0.68, 95\%CI 0.54-0.86, respectively{]}
(Figure 4A,B) and PFS {[}TPS[?]5\%: HR=0.53, 95\%CI 0.43-0.65;
TPS\textless{}5\%: HR=0.58, 95\%CI 0.49-0.70, respectively{]} (Figure
4C,D) of patients in the immunochemotherapy group were better than those
in the chemotherapy group.

Subgroup analysis with TPS=1\% as cutoff value, whether TPS[?]1\% or
TPS\textless{}1\%, showed that the OS {[}TPS[?]1\%: HR=0.62, 95\%CI
0.52-0.75; TPS\textless{}1\%: HR=0.65, 95\%CI 0.46-0.93, respectively{]}
(Figure 5a,b) and PFS {[}TPS[?]1\%: HR=0.57, 95\%CI 0.48-0.68;
TPS\textless{}1\%: HR=0.56, 95\%CI 0.46-0.69, respectively{]} (Figure
5C,D) of patients in the immunochemotherapy group were better than those
in the chemotherapy group.

\textbf{3.5 Stratified according to CPS}

Subgroup analysis with CPS=10 as cutoff value, whether CPS[?]10 or
CPS\textless{}10, showed that the OS {[}CPS[?]10: HR=0.61, 95\%CI
0.51-0.73; CPS\textless{}10: HR=0.62, 95\%CI 0.48-0.80, respectively{]}
(Figure 6A,B) and PFS {[}CPS[?]10: HR=0.60, 95\%CI 0.49-0.74;
CPS\textless{}10: HR=0.54, 95\%CI 0.44-0.68, respectively{]} (Figure
6C,D) of patients in the immunochemotherapy group were better than those
in the chemotherapy group.

Subgroup analysis with CPS=1 as cutoff value, for patients with CPS[?]1,
the OS {[}HR=0.60, 95\%CI 0.49, 0.72{]} and PFS {[}HR=0.55, 95\%CI
0.47-0.65{]} in the immunochemotherapy group were significantly better
than those in the chemotherapy group (Figure 7A,C). However, for
patients with CPS\textless{}1, the significant benefit of OS {[}HR=0.89,
95\%CI 0.42-1.90{]} and PFS {[}HR=0.71, 95\%CI 0.47-1.08{]} in the
immunochemotherapy group did not exist (Figure 7B,D).

\textbf{3.6 Safety}

5 studies showed the incidence of the TRAEs and TRM. In addition, one
study (KEYNOTE-590) presented the incidence of the TRAEs and TRM for EAC
and ESCC, which was included in the meta-analysis considering that
adverse events were mostly multiorgan systemic. Compared with the
chemotherapy group, the incidence of any grade or [?] grade 3 TRAEs in the
immunochemotherapy group was higher {[}OR=1.74, 95\%CI 1.32-2.29;
OR=1.32, 95\%CI 1.00-1.75, respectively{]} (Supplementary Figure 2A,B).
In addition, the incidence of serious TRAEs, any grade immune-related
adverse events (irAEs), and [?] grade 3 irAEs was reported in four studies
respectively, and the incidence of immunochemotherapy group was
significantly higher than that of chemotherapy group {[}OR=1.65,
1.29-2.09; OR=3.39, 95\%CI 1.56-7.36; OR=3.16, 95\%CI 2.05-4.89,
respectively{]} (Supplementary Figure 2C,D,E). Although patients in the
immunochemotherapy group were more likely to develop TRAEs, there was no
significant difference in TRM between the two groups {[}OR=1.11, 95\%CI
0.67-1.83{]} (Supplementary Figure 2F).

\textbf{3.7 Sensitivity analysis}

Significant inter-study heterogeneity was found in the comparison of
grade [?]3 TRAEs and any grade irAEs {[}I\textsuperscript{2}=70\%, p=0.01;
I\textsuperscript{2}=94\%, p\textless{}0.01, respectively{]}
(Supplementary Figure 2B,D). Sensitivity analyses showed that the
greatest heterogeneity came from ESCORT-1st trial (Supplementary Figure
S1a,b). After omitting the escort-1st test, OR=1.47 (95\%CI 1.18-1.83)
for grade [?]3 TRAEs and OR=2.30 (95\%CI 1.65-3.21) for any grade irAEs
(Supplementary Figure 3A,B).

Moderate heterogeneity was also found in subgroup analyses of OS with
TPS \textless{}1\% and CPS \textless{}1 {[}I\textsuperscript{2}=58,
p=0.12; I\textsuperscript{2}=54, p=0.14, respectively{]} (Figure 5B,
Figure 7B). As only two studies were included, the source of
heterogeneity could not be judged. Since the heterogeneity is moderate
and the random effect model has been used to avoid the influence of
heterogeneity as much as possible, the results have certain reliability.

\textbf{3.8 Publish bias assessment}

The egger's funnel plot showed no significant publication bias in OS
meta-analysis, p=0.50 (Supplementary Figure 4).

\textbf{4 Discussion}

Our study demonstrated that compared with the chemotherapy alone,
PD-1/PD-L1-based immunochemotherapy significantly improved survival
outcomes in patients with advanced ESCC. More importantly,
immunochemotherapy had excellent long-term efficacy regardless of TPS
value. This could help to provide useful guidance for future research
and treatment programs. However, in patients with CPS\textless{}1, there
was no significant survival advantage in patients receiving
immunochemotherapy. In addition, TAREs were significantly increased in
the immunochemotherapy group compared with the chemotherapy group, but
TRM was not significantly different between the two groups.

The treatment of early stage ESCC depends on surgical resection or
endoscopic treatment.\textsuperscript{26-28} When the disease progresses
to a locally advanced stage, the efficacy of surgery alone is very
limited. After the publication of the results of the CROSS and
NEOCRTEC5010 trials, preoperative neoadjuvant chemoradiotherapy combined
with surgery became the standard treatment for locally advanced
resectable ESCC, and patients' postoperative survival was significantly
improved.\textsuperscript{29,30} However, for patients with advanced
esophageal cancer, surgery has been unable to achieve a radical cure. In
terms of survival, surgery has lost its meaning. In addition,
traditional treatment methods such as chemotherapy and radiotherapy have
limited effect on patients with advanced esophageal cancer, so the
treatment of these patients has always been a difficult problem.

In recent 10 years, immune checkpoint inhibitors have become a new entry
point for cancer treatment.\textsuperscript{6,7} Currently, three
commonly used immune checkpoint inhibitors are anti-PD-1, anti-PD-L1 and
anti-CTLA4 derivatives. Inhibition of activated CTLA-4, PD-1 and PD-L1
pathways can reverse T helper cell-mediated immunosuppression. As an
epoch-making groundbreaking treatment, immunotherapy has demonstrated
efficacy in many advanced cancers.\textsuperscript{6,7} Immunotherapy
based on PD-1/PD-L1 has long been applied in the field of esophageal
cancer. Many phase I/II trials have proved that immunotherapy is
effective as a second-line or multi line treatment for advanced
esophageal cancer.\textsuperscript{9-15} There was also a study
comparing the efficacy of immune checkpoint inhibitors and chemotherapy,
further confirming that immunotherapy could improve the long-term
survival rate of patients.\textsuperscript{31} This increased great
confidence for immunotherapy to advance into the field of first-line
treatment of advanced esophageal cancer.

A number of clinical trials are underway around first-line treatments.
KEYNOTE-590 trial (pembrolizumab and chemotherapy
(cisplatin/5-fluorouracil) vs. placebo and chemotherapy) is the first
clinical trial to report results of immunochemotherapy as first-line
treatment for locally advanced/unresectable or metastatic
adenocarcinoma, ESCC, or Siewert Type 1 gastroesophageal junction
adenocarcinoma.\textsuperscript{19} The study showed that the OS of
pembrolizumab plus chemotherapy group was significantly longer than that
of placebo plus chemotherapy group (12.4 months vs. 9.8 months, HR=0.73,
p\textless{}0.0001,), and the benefit of OS was superior in patients
with ESCC and CPS[?]10 (median survival time: 13.9 vs. 8.8 months;
HR=0.57; P\textless{}0.0001). This study paved the way for pembrolizumab
to enter the first-line treatment of advanced esophageal cancer. On
March 22, 2021, the USFDA approved pembrolizumab in combination with
platinum and fluorouracil for the first-line treatment of advanced
esophageal cancer and gastroesophageal junction cancers. Since then, the
results of various clinical trials have been published. The results of
ESCORT-1st (Camrelizumab), CheckMate-648 (Nivolumab), ORIENT-15
(sintilimab), and JUPITER-06 (toripalimab) trials all showed that for
advanced ESCC, the long-term efficacy of immunochemotherapy as a
first-line treatment regimen was significant than chemotherapy
alone.\textsuperscript{20,22-24} Our meta-analysis showed that
immunochemotherapy reduced the overall risk of death by 32\% (HR=0.68,
95\%CI 0.61-0.75) and the risk of disease progression by 38\% (HR=0.62,
95\%CI 0.55, 0.70) in patients with advanced ESCC compared with
chemotherapy alone. To date, no clinical trials have been conducted for
EAC alone, so we did not analyze this group of patients. Before the
KEYNOTE-590 trial, the CheckMate-649 trial conducted a comparative study
of nivolumab combined chemotherapy and chemotherapy alone in the
treatment of gastric cancer, gastroesophageal junction cancer and
EAC.\textsuperscript{19,32} Encouragingly, both KEYNOTE-590 and
CheckMate-649 trials showed that immunochemotherapy improved overall
survival of EAC {[}HR=0.74, 95\%CI 0.54-1.02; HR=0.82, 95\%CI 0.60-1.13,
respectively{]}.

In addition, we also conducted an in-depth study according to the
expression level of PD-L1 in ESCC. When the expression level of PD-L1
was evaluated by TPS value, we found that the immune checkpoint
inhibitors had excellent long-term efficacy regardless of TPS value, and
the long-term efficacy of immunochemotherapy was significantly better
than that of chemotherapy alone. When the expression level of PD-L1 was
evaluated by CPS value, it was found that in patients with
CPS\textless{}1, although immunochemotherapy reduced the risk of
long-term death and disease progression compared with chemotherapy
alone, there was no significant difference {[}OS: HR=0.89, 95\%CI
0.42-1.90; PFS: HR=0.71, 95\%CI 0.47-1.08, respectively{]}. Although we
only included two studies, it still reminds us that PD-1/PD-L1 pathway
inhibitors may not be suitable for all patients, and the cutoff value of
PD-L1 expression level and other characteristic biomarkers still needs
to be further studied.

While immunotherapy brings hope for survival, TRAEs, especially irAEs,
should not be ignored. These have been reported in all cancers, and in
severe cases leads to drug withdrawal and even
death.\textsuperscript{33-35} In the clinical trials we included, almost
all of the studies reported higher toxicity of immunochemotherapy than
chemotherapy alone. The meta-analysis after summary confirmed this
point: compared with chemotherapy alone, the incidence of any grade
TRAEs, grade [?]3 TRAEs, serious TRAEs, any grade irAEs, grade [?]3 irAEs in
patients with immunochemotherapy were significantly higher. However,
there was no significant difference in TRM between the two treatments.
This is not difficult to understand, as the use of immune checkpoint
inhibitors becomes more widespread and physicians become better equipped
to manage their related adverse reactions.

Although the included studies were prospective RCT\textsubscript{S} and
all were of high quality as assessed by the Cochrane Handbook,
limitations remained in this meta-analysis. First, we did not have
access to data on every patient, so we could't do a more detailed
analysis. Second, although all the drugs we studied were derived from
PD-1/PD-L1, the use of chemotherapy drugs was not completely consistent.
Third, not all trials reported the study endpoints we wanted to analyze,
and some endpoints only included 2 studies, which would have an impact
on the results of the meta-analysis. Finally, heterogeneity was found in
subgroup analysis of OS with TPS\textless{}1\% and CPS\textless{}1
(I\textsuperscript{2}=58\%, p=0.12; I\textsuperscript{2}=54\%, p=0.14,
respectively) (Figure 5B, Figure 7B). Although we used the random effect
model to avoid the effect of heterogeneity as much as possible, the
source of heterogeneity could not be analyzed because only two studies
were included, so the interpretation of the results should be cautious.
Because the heterogeneity of these two subgroup analyses was moderate,
the results were somewhat convincing.

\textbf{5 Conclusions}

Overall, PD-1/PD-L1 based immunotherapy combined with chemotherapy
significantly improve survival outcomes in patients with advanced ESCC.
The toxicity of immunochemotherapy is acceptable. In ESCC with
CPS\textless{}1, the survival advantage of immunochemotherapy is not
significant compared with chemotherapy alone. Larger clinical trials are
needed to further analyze the effect of PD-L1 expression levels on the
efficacy of immune checkpoint inhibitors.

\textbf{6 Abbreviations}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Programmed cell death 1 & PD-1\tabularnewline
Programmed cell death 1 ligand 1 & PD-L1\tabularnewline
Cytotoxic T-lymphocyte-associated antigen-4 & CTLA-4\tabularnewline
Randomized controlled trial & RCT\tabularnewline
Objective response rate & ORR\tabularnewline
Disease control rate & DCR\tabularnewline
Progression-free survival & PFS\tabularnewline
Overall survival & OS\tabularnewline
Hazard ratios & HR\tabularnewline
Confidence intervals & CI\tabularnewline
Treatment-related adverse event & TRAE\tabularnewline
Treatment-related mortality & TRM\tabularnewline
Tumor proportion score & TPS\tabularnewline
Combined positive score & CPS\tabularnewline
Esophageal squamous cell carcinoma & ESCC\tabularnewline
Esophageal adenocarcinoma & EAC\tabularnewline
Odds ratio & OR\tabularnewline
Immune-related adverse event & irAE\tabularnewline
\bottomrule
\end{longtable}

\textbf{7 Ethics approval and consent to participate:} Not applicable.

\textbf{8 Consent for publication:} Not applicable.

\textbf{9 Availability of data and materials:} Not applicable.

\textbf{10 Conflict of Interest:} The authors declare that they have no
competing interests.

\textbf{11 Funding:} None.

\textbf{12 Authors' contributions:} (1) Study concept and design: JZ,
BZ; (2) Analysis and interpretation of data: ZJ, JW;
\textbf{(3)}Drafting of the manuscript: ZJ, JW, JS; (4) Critical
revision of the manuscript for important intellectual content: ZJ, JZ,
BZ, CZ; (5) All authors reviewed the manuscript.

\textbf{13 Reference}

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\end{enumerate}

\textbf{Table 1.} Specific data of 5 randomized controlled trials.\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllllll@{}}
\toprule
Study & Year & Histology & ICI & N1 & N2 & OS & OS & PFS & PFS & TRAE &
irAE & TRD\tabularnewline
& & & & & & HR & 95\%CI & HR & 95\%CI & & &\tabularnewline
KEYNOTE-590 & 2021 & ESCC & PEMBRO & 274 & 274 & 0.72 & 0.60-0.88 & 0.65
& 0.54-0.78 & 364 vs 360 & 95 vs 43 & 9 vs 5\tabularnewline
KEYNOTE-590 & 2021 & EAC & PEMBRO & 99 & 102 & 0.74 & 0.54-1.02 & 0.63 &
0.46-0.87 & & &\tabularnewline
ESCORT-1st & 2021 & ESCC & CAMRE & 298 & 298 & 0.70 & 0.56-0.88 & 0.56 &
0.46-0.68 & 296 vs 288 & 252 vs 98 & 9 vs 11\tabularnewline
CheckMate-648 & 2022 & ESCC & NIVO & 321 & 324 & 0.74 & 0.58-0.96 & 0.81
& 0.64-1.04 & 297 vs 275 & - & 5 vs 6\tabularnewline
ORIENT-15 & 2022 & ESCC & SINTI & 327 & 332 & 0.63 & 0.51-0.78 & 0.56 &
0.46-0.68 & 321 vs 326 & 155 vs 81 & 9 vs 6\tabularnewline
JUPITER-06 & 2022 & ESCC & TORIPA & 257 & 257 & 0.58 & 0.43-0.78 & 0.58
& 0.46-0.74 & 183 vs 158 & 95 vs 68 & 1 vs 2\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: ICI, immune checkpoint inhibitor; OS, overall survival;
PFS: progression-free survival; HR, hazard ratio; 95\%CI, 95\%
confidence interval; TRAE, treatment-related adverse event; irAE,
immune-related adverse event; TRD, treatment-related death; ESCC,
esophageal squamous cell carcinomas; EAC, esophageal adenocarcinoma;
PEMBRO, pembrolizumab; CAMRE, camrelizumab; NIVO, nivolumab; SINTI,
sintilimab; TORIPA, toripalimab.

\textbf{Figure Legends}

\textbf{Figure 1.} Forest plot of ORR (A) and DCR (B) comparison between
immunochemotherapy and chemotherapy.

\textbf{Figure 2.} Forest plot of OS (A) and PFS (B) comparison between
immunochemotherapy and chemotherapy.

\textbf{Figure 3.} TPS=10\% was used as cutoff value to classify
patients and compare the efficacy of immunochemotherapy and
chemotherapy. (A) OS of TPS[?]10\%; (B) OS of TPS\textless{}10\%; (C) PFS
of TPS[?]10\%; (D) PFS of TPS\textless{}10\%.

\textbf{Figure 4.} TPS=5\% was used as cutoff value to classify patients
and compare the efficacy of immunochemotherapy and chemotherapy. (A) OS
of TPS[?]5\%; (B) OS of TPS\textless{}5\%; (C) PFS of TPS[?]5\%; (D) PFS of
TPS\textless{}5\%.

\textbf{Figure 5.} TPS=1\% was used as cutoff value to classify patients
and compare the efficacy of immunochemotherapy and chemotherapy. (A) OS
of TPS[?]1\%; (B) OS of TPS\textless{}1\%; (C) PFS of TPS[?]1\%; (D) PFS of
TPS\textless{}1\%.

\textbf{Figure 6.} CPS=10 was used as cutoff value to classify patients
and compare the efficacy of immunochemotherapy and chemotherapy. (A) OS
of CPS[?]10; (B) OS of CPS\textless{}10; (C) PFS of CPS[?]10; (D) PFS of
CPS\textless{}10.

\textbf{Figure 7.} CPS=1 was used as cutoff value to classify patients
and compare the efficacy of immunochemotherapy and chemotherapy. (A) OS
of CPS[?]1; (B) OS of CPS\textless{}1; (C) PFS of CPS[?]1; (D) PFS of
CPS\textless{}1.\selectlanguage{english}
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