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

## TL;DR

Combining immunotherapy with other treatments improves outcomes for advanced esophageal cancer patients compared to using immunotherapy alone.

## Contribution

This study provides the first meta-analysis comparing combination immunotherapy to monotherapy in previously treated esophageal squamous cell carcinoma.

## Key findings

- Combination immunotherapy significantly improved response and survival rates compared to PD-1 inhibitor monotherapy.
- PD-1 inhibitors combined with anti-angiogenesis agents or chemotherapy showed high antitumor activity in treated ESCC patients.
- Combination therapy had higher but manageable toxicity compared to monotherapy.

## Abstract

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.

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.

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.

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.