Short-Course Definitive Chemoradiotherapy Combined With Adjuvant or Concurrent Plus Adjuvant Camrelizumab for Locally Advanced Unresectable Esophageal Squamous Cell Carcinoma

Short-Course Definitive Chemoradiotherapy Combined With Adjuvant or Concurrent Plus Adjuvant Camrelizumab for Locally Advanced Unresectable Esophageal Squamous Cell Carcinoma: A Prospective, Multicenter, Multi-Cohort Phase II Clinical Study (STELLAR01)

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.

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.

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:

Here is the translation of the exclusion criteria into English:

1. History of other malignancies;
2. History of fistula caused by primary tumor infiltration;
3. Patients at high risk of esophageal fistula or with signs of esophageal perforation;
4. History of esophageal cancer surgery;
5. Poor nutritional status, with BMI less than 18.5 kg/m², or PG-SGA score ≥ 9;
6. Presence of clinically uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage or medical intervention (within 2 weeks prior to randomization);
7. Known intolerance or resistance to the chemotherapy regimen specified in the study protocol;
8. Prior receipt of any other anti-tumor therapy for ESCC (e.g., therapies targeting PD-1, PD-L1, PD-L2, or other tumor immunotherapies, radiotherapy, targeted therapy, ablation, or other systemic or local anti-tumor treatments);
9. Patients with active autoimmune disease or a history of autoimmune disease that may relapse;
10. Note: Patients with the following conditions are not excluded and may proceed to further screening:

a. Controlled type I diabetes; b. Hypothyroidism (controlled with hormone replacement therapy only); c. Controlled celiac disease; d. Skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis, alopecia); e. Any other disease that is not expected to relapse in the absence of external triggers; k. Presence of other active malignancies within ≤ 2 years prior to enrollment, except for the specific cancer under study in this trial and locally recurrent cancers that have been cured (e.g., resected basal cell or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast); l. Any condition requiring systemic treatment with corticosteroids (dose > 10 mg/day of prednisone or equivalent) or other immunosuppressive agents within ≤ 14 days prior to randomization;

Note: Patients who have currently or previously used any of the following steroid regimens are not excluded:

a. Adrenal replacement steroids (prednisone ≤ 10 mg/day or equivalent); b. Topical, ophthalmic, intra-articular, intranasal, or inhaled corticosteroids with minimal systemic absorption; c. Short-term (≤ 7 days) prophylactic use of corticosteroids (e.g., for prevention of contrast agent allergy) or for treatment of non-autoimmune conditions (e.g., delayed hypersensitivity reaction caused by contact allergens); m. Presence of uncontrolled diabetes, laboratory test abnormalities for potassium or sodium > Grade 1 despite standard medical therapy, or hypoalbuminemia ≥ Grade 3 within ≤ 14 days prior to enrollment; n. History of interstitial lung disease, non-infectious pneumonitis, or uncontrolled systemic diseases including pulmonary fibrosis, acute lung diseases, etc.; o. Presence of severe chronic or active infection requiring systemic antibacterial, antifungal, or antiviral therapy (including tuberculosis infection, etc.) within 14 days prior to enrollment; Note: Patients with chronic HBV or HCV infection are permitted to receive antiviral therapy; p. Known history of HIV infection; q. Major surgery performed within ≤ 28 days prior to enrollment; Note: Minimally invasive procedures (e.g., peripherally inserted central catheter [PICC]) are not considered major surgery; r. Prior allogeneic stem cell transplantation or organ transplantation; s. Presence of any of the following cardiovascular risk factors:

1. Cardiac chest pain occurring within ≤ 28 days prior to randomization, defined as moderate pain limiting instrumental activities of daily living;
2. Symptomatic pulmonary embolism occurring within ≤ 28 days prior to randomization;
3. Acute myocardial infarction occurring within ≤ 6 months prior to randomization;
4. History of heart failure reaching New York Heart Association (NYHA) Class III or IV within ≤ 6 months prior to randomization;
5. Ventricular arrhythmia ≥ Grade 2 occurring within ≤ 6 months prior to randomization;
6. Cerebrovascular accident occurring within ≤ 6 months prior to randomization;
7. Uncontrolled hypertension despite antihypertensive medication, i.e., systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg, within ≤ 28 days prior to randomization;
8. Syncope or seizure occurring within ≤ 28 days prior to randomization;

t. History of severe hypersensitivity reaction to other monoclonal antibodies or to cisplatin or paclitaxel; u. Receipt of any chemotherapy, immunotherapy (e.g., interleukins, interferons, thymosins, etc.), or any investigational treatment within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study drug; v. Use of herbal medicines for cancer control within 14 days prior to the first dose of study drug; w. Patients with toxicities from prior anti-tumor therapy that have not recovered to baseline or stable levels, unless considered as adverse events without safety risks (e.g., alopecia, neuropathy, specific laboratory abnormalities); x. Receipt of live vaccine within ≤ 28 days prior to randomization; Note: Seasonal influenza vaccines are typically inactivated vaccines and are permitted. Intranasal vaccines are live vaccines and are not permitted; y. Presence of underlying diseases (including laboratory abnormalities), alcohol or substance abuse or dependence that may interfere with study drug administration, affect interpretation of drug toxicity or adverse events, or compromise the patient's compliance with study procedures; z. Concurrent participation in another therapeutic clinical trial; aa. Other factors that, in the investigator's judgment, may necessitate premature termination of the study participation (e.g., prisoners or individuals under involuntary detention; individuals detained involuntarily for treatment of psychiatric or physical illnesses such as infectious diseases).