PD‐1/PD‐L1 based immunochemotherapy versus chemotherapy alone for advanced esophageal squamous cell carcinoma: A meta‐analysis focus on PD‐L1 expression level

Abstract Background Immunochemotherapy has become a new treatment for advanced esophageal squamous cell carcinoma (ESCC). Aims 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 and Results Five randomized controlled trials comparing PD‐1/PD‐L1 based immunochemotherapy with 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. 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% confidence intervals [CI] 0.61–0.75; PFS: HR = 0.62, 95% CI 0.55, 0.70, respectively). Even with PD‐L1 tumor proportion score <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) < 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). Conclusion In this study, treatment‐related mortality was similar between immunochemotherapy and chemotherapy. PD‐1/PD‐L1 based immunochemotherapy significantly could improve survival outcomes in patients with advanced ESCC. For patients with CPS <1, the survival advantage of immunochemotherapy was not significant compared with chemotherapy.

significantly could improve survival outcomes in patients with advanced ESCC. For patients with CPS <1, the survival advantage of immunochemotherapy was not significant compared with chemotherapy.

| INTRODUCTION
Squamous cell carcinoma is one of the main subtypes of esophageal cancer, and the prognosis is still unsatisfactory. 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) depended on the entire body of chemotherapy, radiation therapy, and targeted therapy, but the effect was not ideal. [3][4][5] Immunotherapy is a new treatment option that has shown encouraging efficacy in many cancers. 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. 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. [9][10][11][12][13][14][15] 15 Malignant tumors, including esophageal cancer, can express PD-L1 binding to PD-1, which initiates programmed death of T lymphocytes, thereby reducing the effector activity of T lymphocytes and terminating the immune response. 16 PD-1/PD-L1 based immune checkpoint inhibitors can block the PD-1/PD-L1 pathway, reactivate tumor-specific cytotoxic T lymphocytes in the tumor microenvironment, and restore anti-tumor immune activity. 17 With the deepening of the cognition of immunotherapy, immunochemotherapy, radiotherapy and even double immunotherapy are gradually derived, and their effects are exciting. [18][19][20] 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, immunochemotherapy has officially entered the first-line treatment of advanced esophageal cancer. 21 Currently, the results of a number of clinical trials comparing immunochemotherapy versus chemotherapy alone have been published. [22][23][24][25] For ESCC patients as a whole, immunochemotherapy had better long-term outcomes than chemotherapy in all clinical trials. Compared with chemotherapy, Camrelizumab combined with chemotherapy reduced patients' risk of death by 30% and disease progression by 44% (ESCORT-1st); 22 Nivolumab combined with chemotherapy reduced the risk of death by 26% and disease progression by 19% (CheckMate-648); 23 Sintilimab combined with chemotherapy reduced the risk of death by 37% and disease progression by 44% (ORIENT-15); 24 Toripalimab combined with chemotherapy both reduced patients' risk of death and disease progression by 42% (JUPITER-06). 25 These studies also showed that patients with advanced ESCC who received immunochemotherapy had significantly higher ORR than those who received chemotherapy alone.
However, as a biomarker, PD-1/PD-L1 was not expressed at exactly the same level in all patients. Studies showed that there were differences in the efficacy of immunochemotherapy in subgroups with different PD-L1 expression levels. 23,24 This difference means that PD-1/PD-L1 based immunochemotherapy may not be appropriate for all ESCC patients. In this meta-analysis, we attempted to comprehensively analyze the efficacy and safety of PD-1/PD-L1 based immunochemotherapy for advanced ESCC, and to evaluate the effect of PD-L1 expression level on the treatment outcome.

| Literature retrieval
The search and screening procedures followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols (PRISMA) ( Figure S1). 26 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 and the deadline was August 31, 2022. In addition, we searched references of relevant published studies and review articles to supplement the insufficient keyword retrieval.

| Assessment of risk of bias
The overall risk of bias of the literature was assessed according to the Cochrane Handbook of systematic reviews. 27 The Cochrane Handbook of systematic reviews consists of seven parts: random sequence generation, allocation hiding, the 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.

| Statistical methods
For time-survival variables (OS and PFS), HR and 95% CI were extracted to calculate logHR and SE. For categorical variables, such as ORR, DCR and safety events (TRAEs, irAEs and TRM), the number of events and sample size were extracted. Meta-analyses were performed using random-effects model in Revman software. The I 2 test was used to calculate inter-study heterogeneity and p-value of heterogeneity. If inter-study heterogeneity was too high (I 2 > 50%, p < .05), sensitivity analysis was further performed to assess the robustness of the meta-analysis and determine the source of heterogeneity. Figure S1 shows the literature retrieval and screening process. Five

| Literature results
RCTs were included, all of which were multi-center phase III clinical trials with a total of 2962 patients (Table 1). [21][22][23][24][25] The KEYNOTE-590 trial included ESCC and esophageal adenocarcinoma (EAC), from which we could extract relevant data on 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 (Table S1).

| ORR and DCR
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 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 2 = 28%, p = .24, indicating no significant heterogeneity between studies.
Disease control rates were significantly higher in the immunochemotherapy group than in the chemotherapy group alone, 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 2 = 0, p = .80).
T A B L E 1 Specific data of five randomized controlled trials.

Study
Year

| OS and PFS
All of the included clinical trials showed higher long-term survival rates with immunochemotherapy in advanced ESCC patients compared with chemotherapy alone, when PD-L1 expression levels were not differentiated. The meta-analysis showed that immunochemotherapy reduced the overall risk of death by 32% and the risk of disease progression or death by 38% in advanced ESCC patients  (Figure 2A,B). There was no significant heterogeneity was found between studies comparing OS and PFS (I 2 = 0, p = .67; I 2 = 43%, p = .14, respectively).

| Safety
All clinical trials showed the incidence of the TRAEs and TRM. In addition, KEYNOTE-590 trial 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  p < .01, respectively) ( Figure S2B,D). Sensitivity analyses showed that the greatest heterogeneity came from ESCORT-1st trial ( Figure S3A,B) for any grade irAEs ( Figure S3A,B).

| Sensitivity analysis
Moderate heterogeneity was also found in subgroup analyses of OS with TPS <1% and CPS <1 (I 2 = 58, p = .12; I 2 = 54, p = .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.

| Publish bias assessment
The egger's funnel plot shows no significant publication bias in OS meta-analysis, p = .50 ( Figure S4). The treatment of early stage ESCC depends on surgical resection or endoscopic treatment. 28,29 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 NEOCR-TEC5010 trials, preoperative neoadjuvant chemoradiotherapy combined with surgery became the standard treatment for locally advanced resectable ESCC, and patients' postoperative survival was significantly improved. 30,31 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. Type 1 gastroesophageal junction adenocarcinoma. 21 The study showed that the OS of pembrolizumab plus chemotherapy group was significantly longer than that of placebo plus chemotherapy group  Although the included studies were prospective RCT 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 not 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 two studies, which would have an impact on the results of the meta-analysis. Finally, heterogeneity was found in subgroup analysis of OS with TPS <1% and CPS <1 (I 2 = 58%, p = .12; I 2 = 54%, p = .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.

| CONCLUSIONS
The treatment-related mortality of immunochemotherapy was similar to