PD-1 Inhibitor Plus Chemotherapy With or Without Radiotherapy in Patients With Metastatic Esophageal Cancer

Study Overview
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Brief Summary
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The treatment efficacy for stage IVb esophageal cancer has been improved through chemotherapy combined with immunotherapy recently. On this basis, the investigators intend to conduct a prospective, multicenter phase III clinical trial to assess whether radiotherapy with concurrent chemotherapy and immunotherapy could further improve the survival of patients with metastatic esophageal cancer. Accompanied tissue samples, blood samples and urine samples will be analyzed by molecular biological detection (Including Whole Exome Sequencing and proteomics) to explore potential biomarkers for predicting outcomes, efficacy and toxicity.

Detailed Description
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Esophageal cancer (EC) is one of the most common carcinomas with high morbidity and mortality worldwide. More than 30% of the patients were stage IV when diagnosed. Fluoropyrimidine plus platinum-based chemotherapy is recommended as first-line treatment for patients with metastatic EC for approximately four decades, however, only minimal improvement has been reached in overall survival (OS). Recently, immune checkpoint inhibitors have shown effective antitumor activity in patients with unresectable, advanced or metastatic EC. Several randomized trials have demonstrated the PD-1 inhibitor could further improve the OS in patients with advanced esophageal squamous cell carcinoma (ESCC) on the basis of chemotherapy. Chemotherapy combined with immunotherapy has become one of the the standard treatment modality for advanced EC. As reported, for the patients with metastatic lung cancer or EC, locoregional radiotherapy could improve survival. However, high-level evidence is still needed to assess whether these patients can benefit from local radiotherapy. The efficacy of immunotherapy combined with chemotherapy is obviously better than that of chemotherapy alone. On this basis, locoregional radiotherapy may help some patients with advanced EC improve local control, relieve the local symptoms and improving the quality of life. Therefore, the investigators intend to conduct a prospective, multicenter phase III trial to assess the efficiency and safety of radiotherapy with chemotherapy and immunotherapy of patients with metastatic EC. Accompanied tissue samples, blood samples and urine samples will be analyzed by molecular biological detection to explore potential biomarkers for predicting outcomes, efficacy and toxicity.

Official Title
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PD-1 Inhibitor Plus Chemotherapy With or Without Radiotherapy in Patients With Metastatic Esophageal Cancer: A Randomized Multicenter Phase III Trial

Conditions
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Esophageal Neoplasms

Intervention / Treatment
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* Radiation: Radiation
* Drug: TP or PF regimen depended on investigator's choice.
* Biological: PD-1 inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. ≥18 years, any gender 2. Histologically or cytologically confirmed squamous cell carcinoma of esophageal cancer. The initial clinical stage is IVb (2018 American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th Edition) , with distant metastasis involving no more than 2 organs (lymph node metastasis is not counted); 3. ECOG (Eastern Cooperative Oncology Groupper) formance status <= 1. Patients aged 65 years and over need to complete G8 screening or Comprehensive Geriatric Assessment, and the final evaluation is good; 4.There was no significant abnormality in laboratory routine indicators such as blood routine and liver and kidney function; 5.No prior history of thoracic radiation; 6.Expected survival is more than 12 weeks; 7.Informed consent provided. Exclusion Criteria: 1.Patients with other cancer history except hypopharyngeal carcinoma in situ, non-malignant skin cancer and cervical carcinoma in situ. 2.Received surgery (except ostomy), chemotherapy or other anti-tumor treatment before enrollment； 3. Active infection currently exists . The following conditions occurred within 6 months before randomization: myocardial infarction, cerebrovascular accident, or received gastrointestinal, neurological, cardiopulmonary surgery; 4. History of allergy to chemotherapy drugs or autoimmune disease; 5. Participate in other clinical trials at present or within 4 weeks before enrollment; 6.There are factors such as high risk of fistula that radiotherapy cannot be safely carried out as assessed by the radiation oncologist.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PD-1 inhibitor plus chemotherapy arm<br>Drugs: TP or PF regimen depended on investigator's choice. A maximum of six cycles was recommended for chemotherapy. Biological: PD-1 inhibitor (Camrelizumab). | Drug: TP or PF regimen depended on investigator's choice.<br>* A maximum of six cycles was recommended for chemotherapy. Chemotherapy Regimen 1(TP regimen A): Nab-paclitaxel(Albumin-bound paclitaxel) 110-130mg/ m2，d1，d8; Cisplatin 60-75mg/ m2，d1；Q3W； Chemotherapy Regimen 2 (TP regimen B): Paclitaxel 150-175 mg/m2, d1; Cisplatin 60-75mg/ m2，d1；Q3W； PD-1 inhibitor 200mg, d1, Q3W Chemotherapy Regimen 3 (PF regimen): Capecitabine 800mg/m2, bid, d1-14; Cisplatin 25-30mg/m2, d1,d2, Q3W.<br>* Other names: Chemotherapy;Biological: PD-1 inhibitor<br>* Camrelizumab (200mg, d1, Q3W) was continued until disease progression, unacceptable toxicity, death, physician or patient decision to withdraw, non-compliance, or discontinuation for administrative reasons (up to 35 cycles).<br>* Other names: Camrelizumab;|
| Experimental: Radiotherapy arm<br>Radiation: Intensity-modulated Radiation Therapy/Volumetric Modulated Arc Therapy (IMRT/VMAT) technique. Patients will receive radiotherapy between the first and third cycle of chemotherapy. Drugs: TP or PF regimen depended on investigator's choice. Biological: PD-1 inhibitor (Camrelizumab). | Radiation: Radiation<br>* IMRT/VMAT technique. Patients receive radiotherapy once daily, 5 days a week for an average of 5 weeks. Radiotherapy is delivered to achieve a dosage of 50Gy in 25 fractions to planning gross tumor volume (PGTV) with involved site included.<br>* Other names: Modern intensity modulated radiotherapy;Drug: TP or PF regimen depended on investigator's choice.<br>* A maximum of six cycles was recommended for chemotherapy. Chemotherapy Regimen 1(TP regimen A): Nab-paclitaxel(Albumin-bound paclitaxel) 110-130mg/ m2，d1，d8; Cisplatin 60-75mg/ m2，d1；Q3W； Chemotherapy Regimen 2 (TP regimen B): Paclitaxel 150-175 mg/m2, d1; Cisplatin 60-75mg/ m2，d1；Q3W； PD-1 inhibitor 200mg, d1, Q3W Chemotherapy Regimen 3 (PF regimen): Capecitabine 800mg/m2, bid, d1-14; Cisplatin 25-30mg/m2, d1,d2, Q3W.<br>* Other names: Chemotherapy;Biological: PD-1 inhibitor<br>* Camrelizumab (200mg, d1, Q3W) was continued until disease progression, unacceptable toxicity, death, physician or patient decision to withdraw, non-compliance, or discontinuation for administrative reasons (up to 35 cycles).<br>* Other names: Camrelizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Overall survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. OS is reported for all participants of the Intent-To-Treat (ITT) population (all randomized). | Up to approximately 33 months (through Primary Analysis cut-off date of 30-May-2026). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, or death due to any cause, whichever occurred first. | Up to approximately 33 months (through Primary Analysis cut-off date of 30-May-2026). | 
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. as assessed by the investigator. | Up to approximately 33 months (through Primary Analysis cut-off date of 30-May-2026). | 
| Acute toxicity Rate | Acute toxicity rate was defined as the frequency of toxicities related to the treatment, which arises within one month after administration, according to National Cancer Institute Common Terminology Criteria for Adverse Event,Version 5.0 (CTC Adverse Event 5.0). | One month within the end of one specific treatment. | 
| Late toxicity rate | Late toxicity rate was defined as the frequency of toxicities related to the treatment, which arises after one month after administration, according to National Cancer Institute Common Terminology Criteria for Adverse Event,Version 5.0 (CTC Adverse Event 5.0). | One month after the end of one specific treatment. | 
| QUALITY OF LIFE: Change From Baseline in the EORTC QLQ-C30 Subscale Score in Participants | The score of the participants evaluated by The EORTC core quality of life questionnaire (QLQ-C30) . The scale and single-item measure range in score from 0 to100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high/healthy level of functioning. | 24 months | 
| QUALITY OF LIFE: Change From Baseline in the EORTC QLQ-OES18 Subscale Score in Participants | The score of the participants evaluated by The EORTC Quality of Life Questionnaire - Oesophageal Cancer Module (EORTC QLQ-OES18). The scale and single-item measure range in score from 0 to100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high/healthy level of functioning. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiotherapy, PD-1 inhibitor