Early Response-guided Sequential Radiotherapy After Chemoimmunotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (Keystone006)

Early Response-guided Sequential Radiotherapy After Chemoimmunotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: A Phase II Clinical Study

Esophageal squamous cell carcinoma (ESCC) is a common and aggressive malignancy with poor prognosis, particularly in patients with locally advanced disease. Neoadjuvant chemoimmunotherapy has shown promising antitumor activity and may improve pathological response; however, a proportion of patients achieve only stable disease (SD) or progressive disease (PD) after initial treatment and may have limited benefit from proceeding directly to surgery.

This prospective, single-center, phase II clinical study aims to evaluate an early response-guided sequential selective radiotherapy strategy after neoadjuvant chemoimmunotherapy in patients with locally advanced, resectable ESCC. Patients will initially receive neoadjuvant chemotherapy combined with PD-1 inhibitor therapy. Based on radiological response assessment, patients with major response (complete response or partial response) will proceed directly to radical surgery, whereas patients with insufficient response (stable disease or progressive disease but still considered resectable) will receive sequential chemoradiotherapy followed by surgery.

The study aims to assess the safety and efficacy of this individualized treatment strategy, with primary evaluation focusing on pathological response, surgical outcomes, and treatment-related adverse events. Exploratory analyses will investigate potential biomarkers associated with treatment response and prognosis.

Study Overview

• Status: Not yet recruiting
• Conditions: Esophageal Squamous Cell Carcinoma (ESCC)
• Intervention / Treatment: Drug: Neoadjuvant Chemoimmunotherapy (Tislelizumab Plus Paclitaxel and Cisplatin); Radiation: Sequential Chemoradiotherapy

Detailed Description

Esophageal squamous cell carcinoma (ESCC) is a major subtype of esophageal cancer and remains associated with poor outcomes, particularly in patients with locally advanced disease. Neoadjuvant chemoimmunotherapy has recently emerged as a promising treatment approach for resectable ESCC, improving tumor response and pathological remission. However, a subset of patients demonstrates limited response after initial therapy, and optimal management strategies for these patients remain uncertain.

Radiotherapy may enhance antitumor immune responses through modulation of the tumor microenvironment and may provide additional tumor control in patients with insufficient response to initial systemic therapy. Therefore, an individualized treatment strategy guided by early treatment response may help optimize therapeutic benefit while preserving opportunities for curative surgery.

This study evaluates an early response-guided sequential selective radiotherapy strategy for patients with locally advanced resectable ESCC after neoadjuvant chemoimmunotherapy. Treatment decisions will be adapted according to early tumor response assessment and multidisciplinary evaluation, aiming to provide additional local treatment for patients with inadequate response while avoiding unnecessary radiotherapy in patients with favorable response.

The study will assess the safety, feasibility, and clinical outcomes of this response-guided approach. In addition, exploratory analyses will investigate potential biomarkers associated with treatment response and prognosis, including changes in the tumor immune microenvironment and peripheral blood biomarkers.

This study aims to develop a personalized treatment strategy for locally advanced ESCC based on early therapeutic response and to improve clinical outcomes through optimized treatment selection.

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hongjing Jiang, PhD,MD; Phone Number: 18622221069; Email: jianghongjing@tmu.edu.cn
• Study Contact Backup: Name: Chunyu Hou, PhD; Phone Number: 13652037579; Email: houchunyu@tjmuch.com

Study Locations

• China
  • Tianjin, China, 300060
    • Department of minimally invasive esophageal surgery, Tianjin Medical University Cancer Institute and Hospital
    • Contact: Hongjing Jiang; Phone Number: 18622221069; Email: jianghongjing@tmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

-

Participants must meet all of the following criteria:

Provide written informed consent before enrollment.

Age >18 years, male or female.

Histologically confirmed thoracic esophageal squamous cell carcinoma (ESCC).

Locally advanced, resectable disease according to AJCC/UICC 8th edition TNM staging system, defined as:

cT3-4aN0-2M0 or cT1-2N1-2M0;

No evidence of distant metastasis;

Considered initially resectable by a multidisciplinary surgical team.

Patients who have received neoadjuvant chemoimmunotherapy and have measurable disease response assessment according to RECIST v1.1, including complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).

At least one measurable lesion according to RECIST version 1.1.

Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

Expected survival time >6 months.

Adequate organ function meeting the following criteria:

Bone marrow function:

Absolute neutrophil count ≥1,500/mm³;

Platelet count ≥100,000/mm³;

Hemoglobin ≥9 g/dL.

Renal function:

Serum creatinine ≤1.5 mg/dL and/or creatinine clearance ≥60 mL/min.

Hepatic function:

Total bilirubin ≤1.5 × upper limit of normal (ULN);

AST and ALT ≤1.5 × ULN.

Participants of childbearing potential must agree to use medically approved contraception during study treatment and for 3 months after completion of treatment. Female participants of childbearing potential must have a negative serum or urine pregnancy test within 7 days before enrollment and must not be breastfeeding.

Willingness and ability to comply with study procedures, safety assessments, and survival follow-up.

Exclusion Criteria:

-

Participants will be excluded if any of the following criteria apply:

Evidence of distant metastasis.

Previous or concurrent malignancy, except adequately treated basal cell carcinoma of skin or cervical carcinoma in situ.

Previous thoracic radiotherapy.

Previous treatment with PD-1, PD-L1, or CTLA-4 inhibitors, or known hypersensitivity to PD-1 inhibitors or macromolecular protein products.

Active autoimmune disease or history of clinically significant autoimmune disease requiring systemic treatment.

Current use of immunosuppressive therapy or systemic corticosteroids exceeding the equivalent of prednisone 10 mg/day within 2 weeks before enrollment.

Clinically significant ascites or pleural effusion requiring therapeutic drainage.

Uncontrolled cardiovascular disease, including:

NYHA class II or higher heart failure;

Unstable angina;

Myocardial infarction within 1 year;

Clinically significant arrhythmias requiring treatment.

Significant coagulation abnormalities, bleeding tendency, or ongoing thrombolytic/anticoagulant therapy.

Active gastrointestinal disorders associated with bleeding or perforation risk, including esophageal varices, active gastric/duodenal ulcer, ulcerative colitis, portal hypertension, or active tumor bleeding.

History of severe bleeding, clinically significant hemoptysis, or thromboembolic events within specified periods.

Active infection or unexplained fever >38.5°C before treatment initiation.

Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks before study treatment.

History or evidence of interstitial lung disease, pulmonary fibrosis, radiation pneumonitis, drug-induced pneumonitis, pneumoconiosis, or severe pulmonary impairment.

Known immunodeficiency, including HIV infection, or active hepatitis infection requiring exclusion according to protocol criteria.

Participation in another clinical trial within 1 month before enrollment or concurrent systemic anticancer therapy.

Receipt of live vaccines within 4 weeks before treatment or planned live vaccination during study treatment.

Known history of substance abuse, alcoholism, or drug abuse.

Inability or unwillingness to comply with study-related procedures, examinations, or required costs.

Any other medical, psychological, social, or safety-related condition judged by the investigator to make the participant unsuitable for study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Response-guided Sequential Treatment; Participants will receive neoadjuvant chemoimmunotherapy followed by individualized treatment according to early tumor response assessment. Patients with favorable response will proceed to surgery, while patients with insufficient response but remaining resectable disease will receive sequential chemoradiotherapy followed by surgery.

Drug: Neoadjuvant Chemoimmunotherapy (Tislelizumab Plus Paclitaxel and Cisplatin); Participants will receive neoadjuvant chemoimmunotherapy before surgery. The regimen includes: Tislelizumab (PD-1 inhibitor): 200 mg administered intravenously once every 3 weeks for 2 cycles. Paclitaxel: 135 mg/m² administered intravenously on Day 1 of each 3-week cycle for 2 cycles. Cisplatin: 60 mg/m² administered intravenously on Day 1 of each 3-week cycle for 2 cycles. After completion of neoadjuvant chemoimmunotherapy, tumor response will be assessed. Treatment decisions will be guided by early response evaluation and multidisciplinary surgical assessment.; Radiation: Sequential Chemoradiotherapy; Participants with inadequate response after neoadjuvant chemoimmunotherapy but remaining eligible for curative surgery will receive sequential chemoradiotherapy followed by surgery. Concurrent chemoradiotherapy consists of: Radiotherapy: 1.8 Gy per fraction, 5 fractions per week, for 5 weeks, with a total dose of 41.4 Gy in 23 fractions. Chemotherapy: weekly concurrent chemotherapy with paclitaxel and platinum-based chemotherapy during radiotherapy. The treatment aims to improve local tumor control before radical surgical resection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and Tolerability Equivalent Major Pathological Response Rate (ITT-MPR)	Up to approximately 1.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0 Resection Rate	The proportion of participants achieving microscopically complete tumor resection (R0 resection) after surgery.	At the time of surgery after completion of neoadjuvant treatment
Surgical Completion Rate	The proportion of participants who successfully complete planned surgical resection after neoadjuvant treatment.	At the time of surgery after completion of neoadjuvant treatment
Pathological Complete Response (pCR) Rate	The proportion of participants achieving pathological complete response (ypT0N0) based on surgical pathology evaluation after neoadjuvant treatment.	At the time of 1 month after resection
Tumor Regression Grade (TRG)	Tumor regression grade assessed by pathological examination after surgical resection.	At the time of surgery after completion of neoadjuvant treatment
Pathological Lymph Node Status (ypN0 Rate)	The proportion of participants without residual metastatic lymph nodes (ypN0) based on postoperative pathological evaluation.	At the time of surgery after completion of neoadjuvant treatment
Tumor Downstaging Rate	The proportion of participants achieving pathological downstaging compared with baseline clinical staging after neoadjuvant treatment.	At the time of surgery after completion of neoadjuvant treatment
Objective Response Rate (ORR)	The proportion of participants achieving complete response or partial response according to RECIST 1.1 criteria.	After completion of neoadjuvant treatment before surgery (approximately 12 weeks after initiation of study treatment)
Disease Control Rate (DCR)	The proportion of participants achieving complete response, partial response, or stable disease according to RECIST 1.1 criteria.	After completion of neoadjuvant treatment before surgery
Treatment-related Adverse Events	The incidence and severity of treatment-related adverse events assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	From initiation of study treatment until 30 days after completion of treatment
Perioperative Complications	The incidence of postoperative complications occurring after surgical resection.	Within 30 days after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival (EFS)	Event-free survival is defined as the time from initiation of study treatment to disease progression, recurrence, death, or other predefined events.	Up to 12 months after initiation of study treatment
Overall Survival (OS)	Overall survival is defined as the time from initiation of study treatment to death from any cause.	Up to 12 months after initiation of study treatment
Disease-Free Survival (DFS)	Disease-free survival is defined as the time from R0 surgical resection to disease recurrence or death from any cause.	Up to 12 months after surgery
Quality of Life Assessed by EORTC QLQ-C30	Quality of life will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).	Baseline and up to 12 months after initiation of study treatment

Collaborators and Investigators

• Sponsor: Tianjin Medical University Cancer Institute and Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): July 14, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: July 13, 2026
• First Submitted That Met QC Criteria: July 19, 2026
• First Posted (Actual): July 22, 2026

Study Record Updates

• Last Update Posted (Actual): July 22, 2026
• Last Update Submitted That Met QC Criteria: July 19, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Neoadjuvant therapy; Locally advanced esophageal cancer; Response-guided therapy; Adaptive treatment strategy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Esophageal Diseases; Carcinoma; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Organic Chemicals; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Taxoids; Cyclodecanes; Diterpenes; Platinum Compounds; Paclitaxel; Cisplatin; tislelizumab
• Other Study ID Numbers: E20260722

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will be shared based on the request from other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No