PPIO-004 Clinical Application of Efficacy Prediction Model Based on Epigenomics Sequencing Technology in Neoadjuvant Immunotherapy for Esophageal Cancer — PPIO-004-EC001  

Esophageal Squamous Cell Carcinoma Clinical Trial

Official title: Clinical Application of Efficacy Prediction Model Based on Epigenomics Sequencing Technology in Neoadjuvant Immunotherapy for Esophageal Cancer

Status Enrolling by invitation

Clinical Trial Summary

The goal of this observational study is to learn about in potential operable esophageal cancer patients (cT1-2N + M0 and cT3NanyM0) receiving neoadjuvant therapy. The main questions it aims to answer are: Objective response rate, Major pathological response rate. Participants will receive two to four cycles of tislelizumab plus albuminpaclitaxel and platinum-based therapy

Clinical Trial Description

Esophageal cancer is the eighth most common cancer in the world (934,870 new cases) and the sixth most common cause of cancer death (287,270 new cases). The incidence, prevalence and histological type of esophageal cancer vary by region. About 75% of cases occur in Asia, with China accounting for the highest proportion, accounting for about 50% of the total number of cases and cancer-specific deaths. According to China's National Bureau of Statistics in 2022, there were 252,500 cases of esophageal cancer and 193,900 deaths in China in 2016, making esophageal cancer the sixth most common cancer and the fifth leading cause of cancer death in the country. The etiologies of the two most common histological subtypes (esophageal squamous cell carcinoma [ESCC] and adenocarcinoma) vary widely. In the West, heavy drinking and smoking and their synergies are major risk factors for ESCC [3]. However, in low-income countries, such as parts of Asia and sub-Saharan Africa, the major risk factors for ESCC (which typically accounts for more than 90% of all esophageal cancer cases) have not been elucidated.

For subjects with locally advanced ESCC, international treatment guidelines recommend esophagectomy followed by preoperative chemoradiotherapy.

However, in the clinical practice, many subjects with locally advanced ESCC receive neoadjuvant chemotherapy rather than neoadjuvant chemoradiotherapy, due to safety concerns regarding the use of radiotherapy in neoadjuvant therapy and difficulties in cross-clinical collaboration, and may not receive the best benefit from neoadjuvant therapy. For the preoperative treatment of locally advanced esophageal cancer, preoperative chemotherapy also has a better survival benefit than surgery alone. In the Medical Research Council OEO2 study, median survival was 16.8 months in the preoperative chemotherapy group and 13.3 months in the surgery alone group, with 2-year survival rates of 43% and 34%, respectively. Long-term follow-up confirmed that preoperative chemotherapy had a survival benefit, with 5-year survival rates of 23% in the preoperative chemotherapy group and 17.1% in the surgery alone group. And data on other immune checkpoint inhibitors suggest that neoadjuvant chemotherapy combined with immunotherapy improves clinical outcomes.

PD-1 inhibitors have demonstrated significant benefits as second-line and first-line therapy for ESCC and in combination with chemotherapy for many other solid tumors. Preclinical studies have shown that the PD-1/PD-L1 axis can be activated early in solid tumors, and the preoperative induction of immune response may have a lasting protective effect. Preoperative immunotherapy is likely to be more effective given that the tumor antigen drops sharply after surgical resection and the removal of intact blood vessels and lymph nodes that deliver the drug may affect immunotherapy efficacy. Several Phase 1/2 and 2 studies have shown a controllable safety profile and preliminary demonstration of efficacy when adding PD-1/PD-L1 inhibitors to perioperative treatment in resectable EC subjects. PD-1 inhibitors have shown significant benefits in both second-line and first-line treatment. Given the evidence of antitumor activity of immunotherapy in patients with ESCC and the continuing need to improve survival and reduce recurrence rates of resectable esophageal cancer, several studies exploring the antitumor activity of immunotherapy in the treatment of resectable disease have tentatively shown promising prospects as a neoadjuvant therapy.

tislelizumab, as an innovative PD-1 inhibitor, has shown similar benefits to other PD-1 inhibitors in a variety of tumor types. Bb-a317-205 also showed preliminary antitumor activity in ESCC subjects, with a confirmed ORR of 46.7%, DCR of 80%, and DOR of 12.8 months. The median OS was 14.31 months. In addition, three pivotal Phase 3 studies in the ESCC field are underway (studies BGB-A317-302, BGB-A317-306, BGB-A317-311, and BGB-A317-213).

Therefore, the combination of neoadjuvant chemotherapy with tislelizumab may be a potential treatment option to improve the benefit of potentially resectable locally advanced ESCC subjects.

Cancer survival rates are often low, most likely due to advanced stage of diagnosis and limited access to timely and reasonable treatment. Early and accurate detection of cancer is important for clinical diagnosis, effective toxicity monitoring, and ultimately successful treatment of cancer. In the context of the current "precision medicine" concept, disease assessment should selectively obtain and extract key biological information from clinical phenotypes, pathological characteristics and molecular information of diseases, and carry out qualitative, positioning, quantitative and periodic accurate analysis of these information, laying the foundation for disease classification, clinical decision-making and prognosis. Based on accurate analysis of patients' biological information, treatment principles, rules and guidelines based on empirical evidence, combined with patients' unique physiological, psychological, social characteristics and personal will, effective treatment methods are wisely selected and integrated to form the best treatment plan that fits patients' unique characteristics.

In the context of the current "precision medicine" concept, disease assessment should selectively obtain and extract key biological information from clinical phenotypes, pathological characteristics and molecular information of diseases, and carry out qualitative, positioning, quantitative and periodic accurate analysis of these information, laying the foundation for disease classification, clinical decision-making and prognosis. At present, several prediction models for evaluating the efficacy and prognosis of patients have been developed by using public databases at home and abroad. However, due to the small sample size, less information included in the models and lack of clinical practice, the reliability is weak.

Therefore, new biomarkers need to be developed to better select patients, and the development of strong biomarkers and improved patient selection will be key to combination immunotherapy.

Objective response rate, major pathological response rate, pathological complete response rate, overall survival, progression-free survival, disease control rate, duration of response, R0 removal rate, adverse events, and potential predictive biomarkers were evaluated in patients undergoing surgery after tirelizumab combined with chemotherapy as neoadjuvant therapy. Explore potential Cancer biomarkers in patients undergoing surgery after receiving tislelizumab combined with chemotherapy as neoadjuvant therapy ;

Related Conditions & MeSH terms

• Esophageal Neoplasms
• Esophageal Squamous Cell Carcinoma

• NCT number: NCT05880082
• Study type: Interventional
• Source: Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
• Status: Enrolling by invitation
• Phase: Phase 2
• Start date: April 13, 2023
• Completion date: December 31, 2024