Locally Advanced Unresectable Esophageal Squamous Cell Carcinoma
Conditions
Keywords
esophageal carcinoma, Definitive Chemoradiotherapy, immunotherapy
Brief summary
This study aims to compare the efficacy and safety of short-course definitive concurrent chemoradiotherapy plus immunotherapy followed by immunotherapy maintenance versus short-course definitive chemoradiotherapy plus immunotherapy maintenance in the treatment of locally advanced unresectable esophageal squamous cell carcinoma, and to exploratorily identify molecular biomarkers associated with treatment efficacy and toxicity.
Detailed description
The RTOG 8501 trial established definitive chemoradiotherapy (dCRT) as the standard treatment for patients with locally advanced unresectable esophageal cancer. Although long-term survival and even cure have been observed in a subset of patients treated with dCRT, the overall short- and long-term outcomes remain unsatisfactory. For example, the complete response (CR) rate after dCRT is only approximately 25%, most patients eventually experience local recurrence or distant metastasis, and the 5-year overall survival rate is only about 20%. Therefore, there remains a substantial unmet medical need for improving the treatment of patients with locally advanced unresectable esophageal cancer.In patients with unresectable esophageal cancer, several small-sample exploratory studies have investigated the combination of immunotherapy with dCRT. The EC-CRT-001 study preliminarily demonstrated that dCRT combined with toripalimab achieved a CR rate of 62% and a 1-year overall survival rate of 78.4% in patients with locally advanced unresectable esophageal squamous cell carcinoma. A study by Zhao et al. explored induction chemo-immunotherapy followed by concurrent chemoradiotherapy, reporting a 1-year overall survival rate of 88.0% and a 2-year local control rate of 81.7%, which were also superior to those reported in traditional studies of chemoradiotherapy alone. Taken together, these findings suggest that the incorporation of immune checkpoint inhibitors (ICIs) into definitive chemoradiotherapy-based multimodal treatment may improve outcomes in patients with locally advanced unresectable esophageal squamous cell carcinoma.Currently, several large randomized controlled trials, such as RATIONALE 311 and KUNLUN, are ongoing to evaluate the efficacy of immunotherapy maintenance following concurrent chemoradiotherapy compared with placebo. However, the optimal integration strategy of chemoradiotherapy and immunotherapy remains unclear. In lung cancer, the PACIFIC trial established the cornerstone role of immunotherapy maintenance in patients with unresectable stage III disease. In esophageal cancer, other studies such as SKYSCRAPER-07 are also investigating the efficacy and safety of immunotherapy maintenance following definitive chemoradiotherapy. Nevertheless, which combination strategy of conventional chemoradiotherapy and ICIs can best balance efficacy and toxicity remains to be elucidated and warrants further clinical investigation.Based on this background, the present study aims to investigate and compare the efficacy and safety of short-course definitive concurrent chemoradiotherapy plus immunotherapy followed by immunotherapy maintenance versus short-course definitive chemoradiotherapy plus immunotherapy maintenance in patients with locally advanced unresectable esophageal squamous cell carcinoma, and to exploratorily identify molecular biomarkers associated with treatment efficacy and toxicity.
Interventions
BIOLOGICALCamrelizumab
This study aims to compare the efficacy and safety of two novel treatment strategies-short-course definitive chemoradiotherapy combined with adjuvant camrelizumab, and short-course definitive chemoradiotherapy combined with concurrent plus adjuvant camrelizumab-in patients with locally advanced unresectable esophageal squamous cell carcinoma.
Sponsors
Ning Jiang, M.D./Ph.D.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. The patient or their legal representative is able to sign the written informed consent form and understands and agrees to comply with the study requirements; 2. Age ≥ 18 years and \< 75 years at the time of signing the informed consent form, regardless of gender; 3. Histologically confirmed esophageal squamous cell carcinoma, confirmed by imaging examinations such as CT, MRI, or PET-CT as locally advanced unresectable ESCC (medically unsuitable for surgery or refusal of surgical intervention), and suitable for cCRT, including: stages II-IVa and certain cases of stage IVb (involving only supraclavicular lymph node metastasis) (AJCC version 8 ) meeting the criteria; 4. Estimated life expectancy of at least 6 months; 5. ECOG performance status score of 0-2; 6. Presence of measurable and/or non-measurable lesions as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1); 7. No prior systemic anti-tumor therapy (including but not limited to systemic chemotherapy, radiotherapy, molecular targeted therapy, immunotherapy, biological therapy, local therapy, or other investigational treatments); 8. Adequate organ function, as indicated by laboratory test results obtained within 14 days prior to enrollment: 9. a. Achieved without the need for blood transfusion, growth factor therapy, or other supportive medications that significantly affect neutrophil count, platelet count, or hemoglobin within ≤ 14 days before sample collection during screening: absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; platelet count ≥ 100 × 10⁹/L; hemoglobin ≥ 90 g/L; 10. b. Estimated glomerular filtration rate ≥ 60 mL/min/1.73 m² using the Chronic Kidney Disease Epidemiology Collaboration equation (Appendix 9); 11. c. Serum total bilirubin ≤ 1.5 × ULN (for patients with Gilbert's syndrome, total bilirubin must be ≤ 3 × ULN); 12. d. Aspartate aminotransferase and ALT \< 3 × ULN; 13. For patients with inactive/asymptomatic carriers, chronic or active HBV infection, the following criteria must be met: 14. HBV DNA \< 500 IU/mL (or 2500 copies/mL) during screening; 15. Note: Patients with positive hepatitis B surface antigen or detectable HBV DNA should be managed according to treatment guidelines. Patients receiving antiviral therapy during screening must have undergone treatment for \> 2 weeks prior to enrollment; 16. Female patients of childbearing potential must voluntarily agree to use highly effective contraception during the study period, for ≥ 120 days after the last dose of camrelizumab or placebo, and for ≥ 180 days after the last dose of chemoradiotherapy, and must have a negative urine or serum pregnancy test result within ≤ 7 days prior to enrollment; 17. Male patients who are not sterilized must voluntarily agree to use highly effective contraception during the study period, for ≥ 120 days after the last dose of camrelizumab or placebo, and for ≥ 180 days after the last dose of chemoradiotherapy.
Exclusion criteria
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Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 1-year Progression- Free Survival | from study enrollment to tumor progression (in any aspect) or death from any cause within 1 year. | 1-year progression-free survival (PFS) defined as the probability from study enrollment to tumor progression (in any aspect) or death from any cause within 1 year. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| complete response rate | 3 months after completion of radiotherapy | Complete response rate at 3 months after completion of radiotherapy: assessed by CT, high-resolution MRI and/or PET-CT, in combination with endoscopic ultrasound-guided bite-on-bite biopsy. |
| treatment-related adverse events | from study enrollment until 90 days after the final administration of chemoradiotherapy | Grade ≥3 treatment-related adverse events will be recorded according to CTCAE version 5.0 during the treatment period, from study enrollment until 90 days after the final administration of chemoradiotherapy. |
| Overall Survival | From study enrollment to death from any cause, assessed up to 100 months | Defined as from date of enrollment until the date of death from any cause or the date of last follow-up, whichever came first, assessed up to 100 months |
| Duration of Response | From the time of first response to disease progression or death from any cause, whichever came first, assessed up to 100 months | From the time of first response to disease progression or death from any cause, whichever came first, assessed up to 100 months |
Countries
China
Contacts
CONTACTXiangzhi Zhu
CONTACTNing Jiang
STUDY_DIRECTORXiangzhi Zhu
Jiangsu Cancer Institute & Hospital
Outcome results
None listed