A Prospective Study of Neoadjuvant Pembrolizumab Plus Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma: The Keystone-001 Trial

Oncology Life Sciences Immunology Medicine Cell Biology Biochemistry
Esophageal Squamous Cell Carcinoma Neoadjuvant Therapy Pembrolizumab Chemotherapy Survival Rate

Background and Research Motivation

Esophageal Squamous Cell Carcinoma (ESCC) is a highly aggressive cancer, especially in locally advanced stages. Traditional neoadjuvant chemoradiotherapy (NCRT) is the standard treatment method for this type of cancer. Despite its significant therapeutic effects, local recurrence and distant metastasis rates remain high. Particularly in esophageal cancer patients, the local recurrence rate after NCRT can reach 35%-50%. Moreover, even in the CheckMate-577 study, the post-operative adjuvant use of nivolumab significantly prolonged disease-free survival (DFS), but improvements in overall survival (OS) were limited. Therefore, there is an urgent need to explore neoadjuvant treatment strategies that enhance tumor response rate and patient survival rate.

In recent years, the introduction of immune checkpoint inhibitors (ICI) has brought revolutionary advancements in cancer treatment, especially the anti-PD-1 antibody pembrolizumab, which has shown efficacy in various cancers and has become standard first-line treatment for advanced esophageal cancer. In neoadjuvant therapy, combining immunotherapy with chemotherapy may be more effective in suppressing early tumor development, as chemotherapy can enhance the efficacy of immunotherapy through multiple mechanisms. Based on this, Shang and colleagues conducted a phase II clinical trial named Keystone-001 to explore the safety and efficacy of neoadjuvant pembrolizumab combined with chemotherapy in locally advanced and resectable esophageal squamous cell carcinoma.

Research Source

The study was authored by Xiaobin Shang, Yongjie Xie, Jinpu Yu, and other researchers from Tianjin Medical University Cancer Hospital and several specialized laboratories and institutions. The research was published in the “Cancer Cell” journal on October 14, 2024.

Research Design and Methods

This study adopted a prospective phase II clinical trial design, enrolling a total of 47 patients with locally advanced and resectable ESCC. The research design encompassed the following major steps:

  1. Patient Enrollment and Treatment Plan: 47 patients received 3 cycles of pembrolizumab combined with chemotherapy, followed by Da Vinci robotic-assisted surgery. No grade 3 or higher adverse events occurred during treatment, and all patients completed the neoadjuvant treatment at the prescribed doses.

  2. Primary and Secondary Endpoints: Primary endpoints included safety and major pathological response (MPR), while secondary endpoints included complete pathological response (PCR) and survival rates (OS and DFS).

  3. Safety and Patient Quality of Life: During the study, no treatment-related surgical delays or grade 3 or higher adverse events were observed. Common low-grade adverse events included hair loss, rashes, and dry skin. Additionally, quality of life significantly improved, along with nutritional status.

  4. Surgery and Pathological Assessment: 46 patients underwent robotic-assisted surgery, all achieving R0 resection (i.e., complete tumor resection), with a median lymph node removal count of 37. No deaths were observed within 30 or 90 days post-surgery.

  5. Single-Cell Sequencing and Immune Biomarker Exploration: To explore responsive biomarkers, the research team extracted samples from the peripheral blood and tumor tissues of 12 patients, conducting single-cell RNA sequencing analysis. Results indicated a significant increase in TRGC2+ NKT cells (T-cell receptor gamma chain common region 2 positive natural killer-like T cells) in patients responding effectively to neoadjuvant treatment, validating TRGC2+ NKT cells as potential biomarkers for neoadjuvant treatment responsiveness.

Research Results

  1. Pathological Response and Survival Rates: Among 46 effective patients, the MPR rate was 72%, and the PCR rate was 41%. With a median follow-up of 27.2 months, the 2-year OS and DFS reached 91% and 89%, respectively, showing significant survival benefits.

  2. Immune Cell Subgroup Analysis: After neoadjuvant treatment, the TRGC2+ NKT cell subgroup showed a significant increase in peripheral blood of responsive patients, with no apparent change in non-responsive patients. Additionally, functional enrichment analysis indicated significant activity of this cell subgroup in pathways related to cytotoxicity, leukocyte-mediated cytotoxicity, and apoptosis.

  3. In Vitro Validation Experiments: In organoid models derived from ESCC patients, the research team observed a positive correlation between the proportion of TRGC2+ NKT cells and organoid apoptosis rate, further supporting the potential role of TRGC2+ NKT cells as biomarkers of immune therapy response.

  4. Comparative Analysis and Prediction: Comparing TRGC2+ NKT cells with datasets from patients with various cancers revealed that patients with higher TRGC2+ NKT cell infiltration attained better efficacy in immune therapy. ROC curve analysis showed that the predictive effect of TRGC2+ NKT cells surpassed traditional immune activation markers.

Research Conclusion and Significance

This study demonstrates that pembrolizumab combined with chemotherapy as a neoadjuvant treatment for locally advanced resectable ESCC patients has high MPR and PCR rates, along with good safety. Meanwhile, the increase of TRGC2+ NKT cells in peripheral blood may serve as a potential biomarker for predicting neoadjuvant treatment efficacy.

Furthermore, the functional analysis of TRGC2+ NKT cells reveals their significant role in tumor microenvironment cytotoxicity and antigen presentation, offering new ideas for further optimization of immunotherapy. Based on this, the research team has launched a multi-center phase III clinical trial Keystone-002 (NCT04807673), aiming to further validate the survival benefits of neoadjuvant pembrolizumab combined with chemotherapy over NCRT in resectable ESCC patients.

Research Highlights and Innovations

  1. Innovative Treatment Approach: For the first time in a phase II clinical trial, the study verifies the safety and efficacy of the pembrolizumab combined chemotherapy neoadjuvant treatment approach for locally advanced ESCC, proposing its potential to replace traditional NCRT.

  2. Biomarker Exploration: The study initially reveals the potential predictive value of TRGC2+ NKT cells in neoadjuvant treatment, providing a critical basis for personalized treatment.

  3. Improvement in Quality of Life: The research results indicate a significant enhancement in patient quality of life and nutritional status, offering new data to support improved preoperative treatment tolerance and patient compliance.

Future Prospects

Although the study demonstrates the clinical potential of pembrolizumab combined with chemotherapy as a neoadjuvant treatment for ESCC patients, further large-scale randomized controlled trials are necessary to validate its survival benefits and the feasibility of TRGC2+ NKT cells as biomarkers. Additionally, exploring the functions of different immune cells in the tumor microenvironment will provide more insights for future optimization of immunotherapy.