Atezolizumab following definitive chemoradiotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma – a multicenter phase 2 trial (EPOC1802)

Oncology Immunology Life Sciences Medicine
Atezolizumab Esophageal squamous cell carcinoma Chemoradiotherapy Immunotherapy Unresectable tumors

Background

Esophageal cancer ranks as the seventh most prevalent cancer globally and is the sixth leading cause of cancer-related deaths, accounting for over half a million deaths annually. Esophageal Squamous Cell Carcinoma (ESCC) is one of the primary types of esophageal cancer, particularly prevalent in Asian regions. For patients with unresectable locally advanced ESCC, platinum-based Definitive Chemoradiotherapy (DCRT) is the standard treatment. However, despite its role in treatment, the Complete Response Rate (CRR) remains low, ranging from 11% to 25%, resulting in poor patient survival. Therefore, finding new therapeutic strategies to improve complete response rates and survival outcomes has become an urgent priority.

In recent years, Immune Checkpoint Inhibitors (ICIs) have shown significant progress in the treatment of various cancers, particularly in advanced stages. Atezolizumab, an anti-PD-L1 antibody, has demonstrated promising anti-tumor effects in multiple cancers. However, its efficacy in patients with unresectable locally advanced ESCC remains unclear. To address this, researchers conducted this multicenter, single-arm phase II clinical trial to evaluate the efficacy and safety of Atezolizumab following DCRT.

Source of the Paper

This study was conducted by researchers from multiple institutions in Japan, including the National Cancer Center Hospital East, National Cancer Center Hospital, Saitama Cancer Center, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Shizuoka Cancer Center, and Aichi Cancer Center, among others. The findings were published in the March 2025 issue of Nature Cancer under the title “Atezolizumab following definitive chemoradiotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma – a multicenter phase 2 trial (EPOC1802).”

Research Process

1. Study Design and Patient Recruitment

This study was a phase II, multicenter, single-arm clinical trial that enrolled 40 patients with unresectable locally advanced ESCC. These patients were recruited from seven medical centers in Japan and had all undergone DCRT. The primary endpoint was the Confirmed Complete Response Rate (CCR), while secondary endpoints included Progression-Free Survival (PFS), Overall Survival (OS), and the incidence of Adverse Events (AEs).

2. Treatment Protocol

Patients initially received two cycles of cisplatin and 5-fluorouracil (5-FU) combined with 60 Gy of radiotherapy. Following the completion of DCRT, patients began Atezolizumab monotherapy, administered every three weeks for 12 months (up to 17 doses). Throughout the treatment, researchers collected tumor tissue and peripheral blood samples multiple times to assess the dynamics of immune responses.

3. Biomarker Analysis

To explore predictive biomarkers, researchers collected tumor tissue and blood samples at three time points: before treatment, after DCRT, and four weeks after the first dose of Atezolizumab. Using Whole-Exome Sequencing (WES), RNA-Sequencing (RNA-Seq), Flow Cytometry (FCM), and Multiplex Immunohistochemistry (mIHC), they analyzed immune cell infiltration and gene expression changes in the Tumor Microenvironment (TME).

4. Data Analysis

Researchers employed Gene Set Enrichment Analysis (GSEA) and Single-Sample Gene Set Enrichment Analysis (ssGSEA) to evaluate changes in the expression of immune-related gene sets. Additionally, they analyzed phenotypic changes in Tumor-Infiltrating Lymphocytes (TILs) and Peripheral Blood Mononuclear Cells (PBMCs) using flow cytometry and multiplex immunohistochemistry.

Key Findings

1. Complete Response Rate

In the primary analysis cohort, the Confirmed Complete Response Rate (CCR) for the first 38 patients was 42.1% (90% confidence interval: 28.5%-56.7%). This result met the study’s primary endpoint, indicating that Atezolizumab demonstrated promising anti-tumor effects following DCRT.

2. Survival Analysis

The median Progression-Free Survival (PFS) for all 40 patients was 3.2 months, with a 12-month PFS rate of 29.6%. The preliminary median Overall Survival (OS) was 31.0 months, with a 12-month OS rate of 65.8%. These results suggest that Atezolizumab treatment significantly extended patient survival.

3. Immune Response Analysis

The study found that DCRT significantly upregulated Interferon (IFN) responses and antigen presentation-related gene expression in tumor cells, while increasing the infiltration of Antigen-Presenting Cells (APCs) and effector T cells in the Tumor Microenvironment (TME). Atezolizumab treatment further enhanced these immune responses, particularly in patients who achieved complete remission, where PD-1 expression in CD8+ T cells was significantly increased.

4. Biomarkers

Researchers found no significant correlation between Tumor Mutational Burden (TMB) or PD-L1 expression levels and treatment efficacy. However, the proportion of PD-1+ CD8+ T cells and Regulatory T Cells (Tregs) in the TME was significantly associated with treatment outcomes. Additionally, certain gene mutations (e.g., EGFR, PIK3CA, PTEN, and KEAP1) and Epithelial-Mesenchymal Transition (EMT) phenotypes were linked to treatment resistance.

Conclusion and Significance

This study demonstrates that Atezolizumab following DCRT shows promising efficacy in patients with unresectable locally advanced ESCC, significantly improving complete response rates and survival outcomes. Furthermore, the study reveals dynamic changes in immune responses within the Tumor Microenvironment (TME), providing a crucial foundation for the development of new immunotherapeutic strategies.

Highlights of the Study

  1. Innovative Treatment Protocol: This study is the first to evaluate the efficacy of Atezolizumab following DCRT, offering a new treatment option for patients with unresectable locally advanced ESCC.
  2. In-Depth Immune Response Analysis: Through multi-omics analysis, researchers detailed the impact of DCRT and Atezolizumab on immune responses in the TME, providing new insights into the mechanisms of immunotherapy.
  3. Predictive Biomarkers: The study found that the proportion of PD-1+ CD8+ T cells and Tregs in the TME was significantly associated with treatment outcomes, offering potential biomarkers for personalized therapy.

Additional Valuable Information

The study also identified that certain gene mutations and EMT phenotypes were associated with treatment resistance, suggesting that future therapeutic strategies could target these mechanisms. Additionally, researchers recommend further phase III randomized controlled trials to validate the efficacy of Atezolizumab in a broader patient population.

This study offers new hope for patients with unresectable locally advanced ESCC and lays a significant foundation for the future development of immunotherapy.