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

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. 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). 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.

Jin Z ，Wang J ，Sun J ，Zhu C ，Zhang J ，Zhang B ... -  《Cancer Reports》

Efficacy and safety evaluation of frontline immunotherapy combinations in advanced esophageal squamous cell carcinoma: a network meta-analysis highlighting the value of PD-L1 expression positivity scores.

The systematic review and network meta-analysis (NMA) consolidate all relevant randomized controlled trials (RCTs) related to initial immunotherapy treatments for advanced esophageal squamous cell carcinoma (ESCC). Our goal is to thoroughly assess the effectiveness and safety of various immunotherapy methods, focusing on overall survival (OS) and progression-free survival (PFS) among patients with advanced ESCC positive for PD-L1. We conducted a systematic search of the PubMed, Embase, Cochrane Library, and Web of Science databases, covering all records from their inception until January 22, 2024. The inclusion criteria targeted patients with advanced ESCC undergoing first-line immunotherapy or chemotherapy, limiting the study selection to randomized controlled trials (RCTs) exclusively. The study upholds the values of openness, originality, and dependability, as evidenced by its enrollment in the Prospective Register of Systematic Reviews (CRD42024504992). Our analysis encompasses 7 RCTs, totaling 4688 patients, and evaluates 8 distinct immunotherapy combinations. In advanced ESCC patients irrespective of PD-L1 expression, both sintilimab-chemotherapy and toripalimab-chemotherapy regimens demonstrated comparable OS benefits (HR=0.92, 95% CI: 0.64-1.33). The most pronounced PFS advantages were seen with sintilimab-chemotherapy and camrelizumab-chemotherapy as compared to standard chemotherapy (HR=0.56, 95% CI: 0.46-0.58). Notably, camrelizumab-chemotherapy (HR=0.83, 95% CI: 0.59-1.16) and nivolumab-ipilimumab (HR=0.84, 95% CI: 0.60-1.17) demonstrated significant safety profiles over chemotherapy alone. Subgroup analysis based on PD-L1 expression revealed nivolumab-chemotherapy to yield the highest OS benefit (HR=0.54, 95% CI: 0.37-0.79) in ESCC patients with PD-L1 expression ≥1%. Furthermore, camrelizumab-chemotherapy (HR=0.51, 95% CI: 0.39-0.67) exhibited superior PFS benefits. Among patients with PD-L1 expression ≥10%, camrelizumab-chemotherapy (HR=0.52, 95% CI: 0.35-0.78) emerged as the most efficacious in improving OS, while serplulimab-chemotherapy (HR=0.48, 95% CI: 0.34-0.68) was associated with the longest PFS benefit. The integration of immune checkpoint inhibitors (ICIs) with chemotherapy appears to significantly enhance survival outcomes in patients with advanced ESCC compared to chemotherapy alone. Sintilimab-chemotherapy is potentially the optimal regimen for patients without PD-L1 expression. In contrast, nivolumab-chemotherapy and camrelizumab-chemotherapy are likely to offer the best OS and PFS benefits, respectively, in patients with PD-L1 expression ≥1%. Among those with PD-L1 expression ≥10%, camrelizumab-chemotherapy is projected to provide the greatest OS advantage, whereas serplulimab-chemotherapy is anticipated to offer the most prolonged PFS benefit. Since most of the patients in this study originated from Asia, the above findings are more applicable to the Asian population. https://www.crd.york.ac.uk/prospero/, identifier CRD42024504992.

Chen W ，Cao K ，Zhang L ，Zhao X ，Chen B ，Li W ，Shang R ，Sun L ，Jiang Z ，Wang J ，Xue W ... -  《Frontiers in Immunology》

PD-1 inhibitors versus chemotherapy as second-line treatment for advanced esophageal squamous cell carcinoma: a meta-analysis.

Aim to establish the inhibitors of programmed cell death protein 1 (PD-1) as second-line therapy for advanced esophageal squamous cell carcinoma (ESCC). Published clinical trials in the PubMed, Medline, Embase databases on PD-1 inhibitors for the treatment of ESCC were searched, along with an additional search on abstracts from the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) from inception to September 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) were synthesized using STATA. A total of 1970 patients (PD-1 inhibitors: 987; chemotherapy: 983) were enrolled in five randomized controlled trials. Compared with conventional chemotherapy, second-line PD-1 inhibitors significantly improved the OS (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.66-0.81; P < 0.001) and ORR (relative risk [RR] = 1.89, 95% CI: 1.16-3.05; P = 0.01) of advanced ESCC patients, especially significantly prolonged the OS in the patients with positive programmed death-ligand 1 (PD-L1) status (HR = 0.64, 95% CI: 0.53-0.77; P < 0.001); but did not better PFS (HR = 0.88, 95% CI: 0.68-1.14; P = 0.330) and DCR (RR = 0.89, 95% CI: 0.59-1.37; P = 0.603). Moreover, PD-1 inhibitors were associated with statistically lower incidences of grade 3-5 TRAEs. Second line PD-1 inhibitors significantly improved the OS and ORR of patients with advanced ESCC, especially the OS of those with positive PD-L1 expression, and did not result in significant improvement in PFS and DCR. Compared to chemotherapy, second-line PD-1 inhibitors had superior safety profiles for the treatment of advanced ESCC.

Zhu X ，Shanzhou Q ，Li D ，Pang X ，Ma D ... -  《BMC CANCER》

Clinical benefits of PD-1 inhibitors in specific subgroups of patients with advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis of phase 3 randomized clinical trials.

In recent years, a number of clinical trials have shown that programmed death 1 (PD-1) inhibitors offer significant survival benefits in patients with esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis to explore the antitumour efficacy of PD-1 inhibitor-based therapy in specific subgroups of patient with advanced ESCC. We searched for eligible studies from the PubMed, Embase, Web of Science, Cochrane Library databases and conference abstracts. The indicators related to survival outcomes were extracted. The pooled hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS) and duration of response (DOR) and the pooled odds ratio (OR) for objective response rate (ORR) were calculated to evaluate the efficacy of PD-1 inhibitor-based therapy in ESCC. Data regarding treatment lines, treatment regimens, programmed death ligand 1 (PD-L1) status, baseline demographic and disease characteristics were extracted. Subgroup analyses were conducted in specific populations of ESCC patients. The Cochrane risk of bias tool and sensitivity analysis were used to assess the quality of the meta-analysis. Eleven phase 3 randomized controlled trials (RCTs) involving 6267 patients with ESCC were included in this meta-analysis. Compared with standard chemotherapy, PD-1 inhibitor-based therapy provided benefits in terms of OS, PFS, ORR, and DOR in all populations, the first-line treatment group, the second-line treatment group, the immunotherapy group, and the immunochemotherapy group. Although a limited PFS benefit was observed in second-line treatments and immunotherapy alone, PD-1 inhibitor-based therapy still reduced the risk of disease progression or death. Patients with high PD-L1 expression had a better OS benefit than those with low PD-L1 expression. The HR for OS favoured PD-1 inhibitor-based therapy over standard chemotherapy for all prespecified clinical subgroups. Compared with standard chemotherapy, PD-1 inhibitor-based therapy exhibited clinically meaningful benefits in patients with ESCC. Survival benefits were better in patients with high PD-L1 expression than in those with low PD-L1 expression, suggesting that the PD-L1 expression level can be used as a predictor of survival benefit from PD-1 inhibitor therapy. PD-1 inhibitor-based therapy provided a consistent benefit in reducing the risk of death according to prespecified subgroup analyses of clinical characteristics.

Lu Y ，Wang W ，Wang F 《Frontiers in Immunology》

Clinical Benefit of First-Line Programmed Death-1 Antibody Plus Chemotherapy in Low Programmed Cell Death Ligand 1-Expressing Esophageal Squamous Cell Carcinoma: A Post Hoc Analysis of JUPITER-06 and Meta-Analysis.

Wu HX ，Pan YQ ，He Y ，Wang ZX ，Guan WL ，Chen YX ，Yao YC ，Shao NY ，Xu RH ，Wang F ... -  《-》