Biomarker Based Neoadjuvant Strategies for Locally Advanced Resectable ESCC

Official title

Biomarker Based Neoadjuvant Strategies for Locally Advanced Resectable Esophageal Squamous Cell Carcinoma: an Exploratory Phase II Single-arm Clinical Study

Overview

This study aims to evaluate the impact of the neoadjuvant treatment strategy based on CPS score on the pathological complete response (pCR) rate in patients with resectable locally advanced esophageal cancer.

Detailed description

Esophageal cancer is a malignant tumor with a high incidence in China, with most patients diagnosed at the advanced stage. Traditional treatment modalities include surgery, chemoradiotherapy, and chemotherapy. However, under current standard treatments, approximately 50% of patients remain incurable, primarily due to postoperative recurrence and distant metastasis. Therefore, seeking a new treatment strategy to improve efficacy is crucial.

This clinical trial aims to evaluate the use of immune checkpoint inhibitors in neoadjuvant therapy based on CPS scoring to enhance the pathologic complete response (pCR) rate. Patients pathologically confirmed with esophageal squamous cell carcinoma (ESCC) will undergo surgical assessment for operability. Eligible patients will further undergo CPS testing and will receive different neoadjuvant treatment strategies based on CPS results: patients with CPS ≥20 will receive neoadjuvant immunotherapy alone; CPS 10-20 patients will receive neoadjuvant chemotherapy followed by immunotherapy; and CPS \<10 patients will receive standard neoadjuvant chemoradiotherapy.

After completing neoadjuvant therapy, patients will rest for 4-6 weeks before undergoing curative surgery, which will be reassessed by thoracic surgeons for R0 resection feasibility preoperatively. Postoperatively, pathological evaluation will assess the pCR rate and other secondary study endpoints, with the most severe toxicities included in the analysis.

This study anticipates a group-wide pCR rate of 45% based on a PD-L1 biomarker-guided neoadjuvant treatment strategy. The trial is designed to exclude a pCR rate of 30% or lower using a one-sided 95% confidence interval (α set at 0.025) and 80% statistical power, with a total sample size of 90. The null hypothesis will be rejected if fewer than 34 patients achieve pCR in the entire cohort.

Based on reference studies (EC-CRT-001, ESCORT-1, JUPITER-06, and KEYNOTE-590) and CPS distribution data for esophageal squamous cell carcinoma from our institution, it is expected that the proportions of patients with CPS ≥20, 10-20, and \<10 will be 10%, 40%, and 50%, respectively, corresponding to 9, 36, and 45 eligible patients for each group. It is anticipated that biological specimens will be obtained from more than 30 patients.

Interventions

• Drug Serplulimab
  Serplulimab (300 mg) administered intravenously on day 1 of each 21-day cycle for 2 cycles.
• Drug Paclitaxel+Cisplatin (Neoadjuvant Chemotherapy)
  Paclitaxel (175 mg/m²) and Cisplatin (75 mg/m²) administered intravenously on day 1 of each 21-day cycle for 2 cycles as part of neoadjuvant chemotherapy.
• Drug Paclitaxel+Cisplatin(Concurrent Chemoradiotherapy)
  Paclitaxel (50 mg/m²) and Cisplatin (25 mg/m²) administered intravenously on days 1, 8, 15, and 22 of a 4-week cycle as part of concurrent chemoradiotherapy.
• Radiation Radiotherapy
  Radiotherapy at a dose of 40 Gy, delivered in 20 fractions over 4 weeks.

Primary outcome measures

• Pathological Complete Response (pCR) Rate [Time frame: after the pathological examination of surgical speciments within 14 days after the operation]

Secondary outcome measures (7)

• R0 Resection Rate [Time frame: after the pathological examination of surgical speciments ie within 14 days after the operation]
• Treatment-Related Toxicity [Time frame: From the start of treatment to 30 days post-surgery]
• 3-Year Disease-Free Survival (DFS) [Time frame: 36 months after treatment completion]
• Tumor Mutational Burden (TMB) [Time frame: 36 months after treatment completion.]
• Microsatellite Instability (MSI) [Time frame: 36 months after treatment completion]
• Circulating Tumor DNA (ctDNA) [Time frame: 36 months after treatment completion]
• major pathological response [Time frame: Patients were evaluated 2 to 4 weeks postoperatively.]

Eligibility criteria

Inclusion criteria

• Diagnosis: Histologically confirmed esophageal squamous cell carcinoma (ESCC).
• Stage: Resectable locally advanced ESCC (clinical stage II-III according to the AJCC/UICC 8th edition).
• Age: 18-75 years old.
• Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• PD-L1 Expression: Available PD-L1 expression level (CPS).
• Surgical Eligibility: Assessed as eligible for surgical resection by a thoracic surgeon.
• Laboratory Requirements:

• Adequate bone marrow function: Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L, Platelets ≥ 100 x 10\^9/L, Hemoglobin ≥ 9 g/dL.
• Adequate liver function: Total bilirubin ≤ 1.5 x upper limit of normal (ULN), AST and ALT ≤ 2.5 x ULN.
• Adequate renal function: Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 mL/min.
• Informed Consent: Ability to understand and willingness to sign a written informed consent document.

Exclusion criteria

• Distant Metastasis: Presence of distant metastasis.
• Other Malignancies: History of other malignancies within the past 5 years, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin carcinoma, or other localized non-invasive malignancy.
• Autoimmune Diseases: History of active autoimmune diseases requiring systemic treatment within the past 2 years.
• Infections: Active infection requiring systemic therapy.
• Uncontrolled Conditions: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Previous Treatment: Previous treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies.
• Pregnancy and Lactation: Pregnant or breastfeeding women. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization.
• Allergies: Known allergy or hypersensitivity to study drugs or any excipient of these medications.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Fujian Medical University Union Hospital — Fuzhou

Identifiers

NCT: NCT06601309 · BIONS-R

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗