Yang et al. Anti-PD-1/CTLA-4 Dual Immunotherapy for LARC

This is a prospective, multicenter, randomized controlled trial aimed at comparing different radiotherapy fractionation regimens combined with sequential dual immunotherapy versus traditional chemoradiotherapy in neoadjuvant treatment for locally advanced rectal cancer (LARC). A total of 342 pMMR/MSS LARC patients will be enrolled and randomly assigned in a 1:1:1 ratio to short-course radiotherapy (5×5Gy) followed by sequential dual immunotherapy (paromlimab + tuvonralimab + CAPEOX), long-course radiotherapy followed by sequential dual immunotherapy, or conventional long-course chemoradiotherapy. The primary endpoint is the complete response rate (pCR + cCR). Secondary endpoints include the proportion of patients adopting the "watch-and-wait" strategy, disease-free survival, overall survival, and safety. This study innovatively explores the synergistic mechanism of different radiotherapy fractionations with dual immunotherapy, optimizes the timing of immunotherapy initiation, and constructs a clinical-imaging-pathology multimodal efficacy prediction model, aiming to advance LARC treatment from empirical to precision therapy while achieving organ and function preservation.

Inclusion Criteria: 1. Age between 18 and 80 years; ECOG performance status 0-1; 2. Histopathologically confirmed rectal adenocarcinoma via colonoscopy; pMMR or MSS phenotype; 3. Rectal MRI stage II/III (excluding T4b); distal tumor margin ≤ 12 cm from the anal verge; 4. Willingness to comply with study procedures; consent to use tissue and blood samples for medical research purposes; 5. No prior history of radiotherapy, chemotherapy, or immunotherapy; 6. No immune system diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, hyperthyroidism/hypothyroidism, ulcerative colitis, autoimmune hemolytic anemia, HIV infection, etc.); 7. No severe cardiac, pulmonary, hepatic, or renal dysfunction; no jaundice or gastrointestinal obstruction; 8. No concurrent acute infection; 9. Baseline laboratory evaluations completed as required, with results obtained within 14 days before randomization, and laboratory values meeting the following criteria (per CTCAE 5.0): * White blood cell count ≥ 2000/μL; * Neutrophil count ≥ 1500/μL; * Platelet count ≥ 100×10³/μL; * Hemoglobin ≥ 9.0 g/dL; * Serum creatinine ≤ 1.5×upper limit of normal (ULN) or creatinine clearance \> 50 mL/min (female: creatinine clearance = \[140 - age (years)\] × body weight (kg) × 0.85 / (72 × serum creatinine (mg/dL)); male: creatinine clearance = \[140 - age (years)\] × body weight (kg) × 1.00 / (72 × serum creatinine (mg/dL))); * AST ≤ 3×ULN, ALT ≤ 3×ULN, total bilirubin ≤ 1.5×ULN; 10. No psychiatric/psychological disorders affecting social function; 11. Negative serum pregnancy test (blood HCG) within 1 week before randomization for women of childbearing potential; 12. Women of childbearing potential must agree to use effective contraception during the study period and for 5 months after the last dose of study drug; 13. Male subjects who are sexually active with women of childbearing potential must agree to use effective contraception during the study period and for 7 months after the last dose of study drug, and must refrain from sperm donation during this period. Exclusion Criteria: 1. Multiple primary cancers or concurrent other malignant tumors; 2. Patients requiring emergency surgery due to intestinal obstruction, intestinal perforation, gastrointestinal bleeding, etc.; 3. Factors affecting oral drug absorption (e.g., inability to swallow, nausea/vomiting, diarrhea, intestinal obstruction, etc.); 4. Any uncontrolled, severe concomitant diseases; 5. Hypersensitivity to any component of the study drugs; 6. Expected survival \< 5 years for any reason; 7. Planned or previous organ/bone marrow transplantation; 8. Treatment with immunosuppressants or corticosteroids within 1 month before enrollment; 9. Central nervous system disorders that may impair ability to provide informed consent or comply with study procedures, as determined by the investigator; 10. Other conditions that may prevent completion of study treatment (e.g., alcoholism, drug addiction, etc.); 11. Pregnant or breastfeeding women.