Efficacy of PD-1 inhibitor plus chemotherapy versus chemotherapy in advanced esophageal carcinoma: A meta-analysis of phase III clinical trials.
Authors: Anjum Zauraiz , Hussaini Helai , Mandal Shobha , Rasheed Aiman , Tariq Mahrukh , Memon Basim Aslam , Khan Muzamil , Rani Sindhu , Samreen Iqra , Patel Mehul P. , Nisar Aqsa , Ahmed Zahoor 
Published: January 2025

397

Background:
Programmed death cell death protein-1 (PD-1) inhibitors combined with chemotherapy have demonstrated survival benefits in patients with advanced esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). Our pooled analysis aims to analyze the efficacy of PD-1 inhibitor plus chemotherapy in advanced esophageal carcinoma (EC) in phase III randomized clinical trials (RCTs).
Methods:
We collected data from eligible phase III RCTs searched through PubMed, EMBASE, ClinicalTrials.gov, and meeting abstracts till July 5, 2024. Initial screening revealed 792 articles. We excluded duplicates, review articles and irrelevant studies, and we included eight RCTs that reported objective response rate (ORR), treatment-related adverse events (TRAEs), overall survival (OS) and progression-free survival (PFS). Odds ratio (OR) for ORR and TRAEs, and hazard ratio (HR) for OS and PFS were computed along with a 95% confidence interval (CI) and p-value for pooled analysis, using a random effect model in RevMan v.5.4. We performed a subgroup analysis based on a combined positive score (CPS) for programmed cell death ligand-1 (PDL-1) expression and tumor histology.
Results:
We included eight phase III RCTs (Jupiter-06, Checkmate 648, Keynote 590, ESCORT-1st, Orient-15, Checkmate 649, ESCORT-NEO, and ASTRUM-007), including 4131 patients with 2137 in group A (PD-1 inhibitor + chemotherapy) and 1994 in group B (placebo + chemotherapy, or chemotherapy). PD-1 inhibitors against EC included nivolumab, pembrolizumab, camrelizumab, sintilimab, toripalimab, and serplulimab. A total of 9.9% of patients were diagnosed with EAC, and 90.1% were ESCC. A pooled analysis showed significant achievement in ORR in group A compared to group B with an OR of 2.19 (CI: 1.77-2.69, p < 0.05, I² = 60%). In terms of OS benefit, group A led to a 29% reduction in death risk compared to group B (HR: 0.71, CI: 0.66-0.76, p < 0.05, I² = 0). Group A also showed a significantly reduced risk of disease progression compared to group B (HR: 0.62, CI: 0.54-0.70, p < 0.05, I² = 60%). Safety analysis revealed more TRAEs (OR: 1.93, CI: 1.43-2.60, p < 0.01, I² = 11%) and grade ≥3 AEs (OR: 1.34, CI: 1.08-1.67, p < 0.05, I² = 54%) in group A compared with group B. Sub-group analysis based on CPS revealed that patients with CPS ≥10 showed more OS (pooled HR: 0.59 vs 0.75) (p = 0.04) and PFS (pooled HR: (0.59 vs 0.64) (p = 0.18) benefits as compared to patients with CPS <10. Survival analysis between ESCC and EAC also exhibited statistically non-significant OS benefits (p = 0.28).
Conclusions:
PD-1 inhibitor plus chemotherapy as a first-line therapy in advanced EC, mainly in patients with CPS ≥10, showed improved antitumor efficacy in terms of superior ORR, OS, and PFS, with a manageable toxicity profile providing a benchmark for future studies.