Journal Article

Clinical Benefits of Combination Immunotherapy Over Standard Immunotherapy Monotherapy in Previously Treated Advanced Esophageal Squamous Cell Carcinoma: A Systematic Review and Meta‐Analysis

Li, Ying, Wu, Yunjiang, Han, Fang, Guo, Hong, Zhou, Heng, Zhang, Zhengrong, Chen, Zixuan, Chen, Yong, Deng, Yizhou, Wang, Rui, Mao, Haiyan

2025

Overview

Purpose Programmed cell death protein 1 (PD‐1) inhibitor monotherapy is the standard second‐line treatment for esophageal squamous cell carcinoma (ESCC), but the clinical response and survival outcomes still remain unsatisfactory. This systematic review aims to assess the efficacy and safety of combined immunotherapy strategies in previously treated ESCC patients. Methods and Materials Studies involving previously treated ESCC patients treated with either combined immunotherapy or PD‐1 inhibitor monotherapy as second‐ or later‐line treatment were searched up to November 30, 2023. Pooled rates of objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), and treatment‐related adverse events (TRAEs) were compared. Results A total of 19 studies involving 3007 ESCC patients were included in the pooled analysis. Among them, 1308 patients received immunotherapy monotherapy. Combination immunotherapy included PD‐1 inhibitor combined with chemotherapy (123 patients), anti‐angiogenesis therapy (291 patients), chemoradiotherapy (49 patients), TIGIT inhibitor (62 patients), and anti‐EGFR antibody (28 patients). Patients receiving combination immunotherapy had significantly higher ORR, DCR, PFS, and OS rates compared to those receiving PD‐1 inhibitor monotherapy or chemotherapy (ORR: 35.5% vs. 19.8% vs. 13.0%, p = 0.000; DCR: 84.8% vs. 51.2% vs. 55.2%, p = 0.000). Subgroup analysis demonstrated that second‐line combination immunotherapy significantly improved response and survival rates compared to PD‐1 inhibitor monotherapy in immunotherapy‐naive ESCC patients. The limited data showed that PD‐1 inhibitors combined with both anti‐angiogenesis agents and chemotherapy as second‐line therapy improved response and survival rates compared to PD‐1 inhibitor monotherapy. Notably, the PD‐1 inhibitor combined with anti‐angiogenesis therapy or chemotherapy also showed high antitumor activity in immunotherapy‐treated ESCC patients. Combination therapy was associated with higher treatment‐related but manageable toxicity compared with PD‐1 inhibitor monotherapy. Conclusions Based on the limited data, combined immunotherapy provides additional clinical benefits over standard PD‐1 inhibitor monotherapy in second‐line treatments for both immunotherapy‐naive and previously immunotherapy‐treated ESCC patients.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Angiogenesis / Angiogenesis inhibitors / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Antitumor activity / Apoptosis / Bias / Cancer therapies / Cell death / Cell survival / Chemoradiotherapy / Chemotherapy / Clinical medicine / Cohort analysis / combination immunotherapy / Combined Modality Therapy / Disease control / Esophageal cancer / Esophageal carcinoma / Esophageal Neoplasms - drug therapy / Esophageal Neoplasms - immunology / Esophageal Neoplasms - mortality / Esophageal Neoplasms - pathology / Esophageal Neoplasms - therapy / esophageal squamous cell cancer / Esophageal Squamous Cell Carcinoma - drug therapy / Esophageal Squamous Cell Carcinoma - immunology / Esophageal Squamous Cell Carcinoma - mortality / Esophageal Squamous Cell Carcinoma - pathology / Esophageal Squamous Cell Carcinoma - therapy / FDA approval / Humans / Immune Checkpoint Inhibitors - adverse effects / Immune Checkpoint Inhibitors - therapeutic use / Immunotherapy / Immunotherapy - adverse effects / Immunotherapy - methods / Medical prognosis / Meta-analysis / Metastasis / Oncology / Patients / PD-1 protein / PD‐1 inhibitor / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Radiation therapy / second‐line therapy / Squamous cell carcinoma / Systematic review / Toxicity / Treatment Outcome