Node-Sparing Hypofractionated Radiotherapy Plus Chemotherapy and PD-1 Inhibitor in pMMR/MSS High-Risk Locally Advanced Colon Cancer: A Prospective, Randomized, Phase II Trial

Inclusion criteria

• Voluntarily signs a written informed consent form.
• Age ≥ 18 and ≤ 75 years at enrollment.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy > 2 years.
• Histologically confirmed colon adenocarcinoma (without squamous or sarcomatoid components).
• Tumor biopsy by immunohistochemistry indicating pMMR, i.e., MLH1, MSH2, MSH6, and PMS2 all positive, or genomic testing indicating MSS.
• Per AJCC 8th edition, imaging (contrast-enhanced CT or contrast-enhanced MRI) shows T4 and/or N+ disease (stage IIB-III).
• Prior to enrollment, the subject must be evaluated by a surgery attending physician responsible for the operation, based on medical history, to confirm eligibility for R0 resection with curative intent.
• No prior systemic or local antitumor therapy for rectal cancer before study treatment, including radiotherapy, chemotherapy, immunotherapy, biologics, or small-molecule targeted therapy.
• Subject agrees to collection and study use of required tumor tissue and peripheral blood specimens during screening and throughout the study.
• Adequate organ function:

a) Hematologic (no blood components or hematopoietic growth factors within 7 days before starting study treatment): i. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L (1,500/mm³); ii. Platelets ≥ 100 × 10⁹/L (100,000/mm³); iii. Hemoglobin ≥ 90 g/L. b) Renal: i. Calculated creatinine clearance (CrCl) ≥ 50 mL/min using the Cockcroft-Gault formula: CrCl (mL/min) = {(140 - age) × weight (kg) × 0.85} / [72 × serum creatinine (mg/dL)] ii. Urine protein < 2+ or 24-hour urine protein < 1.0 g. c) Hepatic: i. Total bilirubin (TBil) ≤ 1.5 × ULN; ii. AST and ALT ≤ 2.5 × ULN; iii. Serum albumin (ALB) ≥ 28 g/L. d) Coagulation: i. INR and aPTT ≤ 1.5 × ULN. e) Cardiac: i. Left ventricular ejection fraction (LVEF) ≥ 50%.

• Women of childbearing potential (WOCBP) must have a urine or serum pregnancy test within 3 days prior to starting study treatment (if the urine test cannot be definitively interpreted as negative, a serum test is required; the serum result prevails) and the result must be negative. If a WOCBP has sexual intercourse with a non-sterilized male partner, she must begin using an acceptable contraceptive method from screening and agree to continue contraception for 120 days after the last dose of study drug; whether contraception can be discontinued thereafter should be discussed with the investigator. Periodic abstinence and calendar/rhythm methods are unacceptable.

• WOCBP are defined as females who have not undergone surgical sterilization (i.e., bilateral tubal ligation, bilateral oophorectomy, or total hysterectomy) and have not been postmenopausal (amenorrhea for ≥12 consecutive months without an alternative medical cause, with serum FSH in the postmenopausal range).
• A highly effective method of contraception is one with a low failure rate when used consistently and correctly (e.g., <1% per year). Not all methods are highly effective. Barrier methods alone are not acceptable; WOCBP must at minimum use a hormonal contraceptive (e.g., oral contraceptives) to ensure no pregnancy occurs.
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study requirements.

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Exclusion criteria

• Suspicious metastatic lesions or the presence of unresectable locally advanced disease, regardless of stage.
• Malignancy other than colorectal cancer within 5 years prior to enrollment. Subjects cured by local therapy for other malignancies (e.g., basal or squamous cell skin cancer, superficial bladder cancer, ductal carcinoma in situ) are not excluded.
• Receipt of any investigational drug or device within 4 weeks prior to the first dose of study drug.
• Intestinal obstruction, perforation, gastrointestinal bleeding, or other conditions requiring emergency surgery.
• Multiple primary colorectal cancers.
• Prior radiotherapy to the pelvis or abdomen.
• Inability to swallow tablets, malabsorption syndrome, or any condition that affects gastrointestinal absorption.
• Any prior systemic or local antitumor therapy for locally advanced colon cancer, including curative surgery, chemotherapy, radiotherapy, immunotherapy (including immune checkpoint inhibitors/agonists or cellular immunotherapy), biologics, or small-molecule targeted therapy.
• Nonspecific immunomodulatory therapy within 2 weeks before study treatment (e.g., interleukins, interferons, thymosin, tumor necrosis factor; excluding IL-11 used for thrombocytopenia); antitumor-indicated traditional Chinese herbal medicines or patent medicines within 1 week before study treatment.
• Active autoimmune disease requiring systemic therapy within the past 2 years (e.g., with disease-modifying agents, corticosteroids, or immunosuppressants). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroids for adrenal or pituitary insufficiency) is not considered systemic therapy.
• History of or current non-infectious pneumonitis requiring systemic corticosteroids, or a history of interstitial lung disease.
• History of significant bleeding tendency or coagulopathy; prior or current long-term anticoagulation (e.g., atrial fibrillation with CHADS₂ score ≥ 2).
• Uncontrolled comorbid conditions, including but not limited to decompensated cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, severe active peptic ulcer disease or gastritis, or psychiatric/social conditions that would limit compliance with study requirements or ability to provide written informed consent.
• History of myocarditis, cardiomyopathy, or malignant arrhythmias. Within 12 months prior to study treatment: unstable angina requiring hospitalization, congestive heart failure, or vascular disease (e.g., aortic aneurysm requiring surgical repair or peripheral venous thrombosis), or other cardiac damage that may affect evaluation of study-drug safety (e.g., poorly controlled arrhythmias, myocardial infarction or ischemia); within 6 months prior: esophagogastric varices, severe ulcers, unhealed wounds, gastrointestinal perforation, enteric fistula, intestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding; within 6 months prior: any arterial thromboembolic event, NCI CTCAE v5.0 grade ≥3 venous thromboembolism, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy; within 1 month prior: acute exacerbation of COPD; current hypertension with SBP ≥160 mmHg or DBP ≥100 mmHg despite oral antihypertensive therapy.
• Active or past history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) or chronic diarrhea.
• Serious infection within 4 weeks before study treatment, including but not limited to complications requiring hospitalization, sepsis, or severe pneumonia; active infection requiring systemic anti-infective therapy within 10 days before study treatment (excluding antiviral therapy for hepatitis B or C).
• Major surgery or severe trauma within 30 days before study treatment; minor local surgery within 3 days before study treatment (excluding peripherally inserted central catheter placement).
• History of immunodeficiency; positive HIV antibody; or current long-term systemic corticosteroid or other immunosuppressive therapy.
• Known active tuberculosis (TB). Subjects with suspected active TB must be clinically ruled out (e.g., sputum for mycobacteria, chest imaging). Known active syphilis infection.
• History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• Untreated active hepatitis B (HBsAg-positive with HBV-DNA > 1,000 copies/mL \[200 IU/mL] or above the assay lower limit). Subjects with hepatitis B must receive antiviral therapy during the study; active hepatitis C (HCV-antibody positive with HCV-RNA above the assay lower limit).
• Live vaccine within 30 days before study treatment or planned receipt of a live vaccine during the study.
• Known allergy to any component of the study drugs; history of severe hypersensitivity to other monoclonal antibodies.
• Known psychiatric illness, substance abuse, alcoholism, or drug dependence.
• Pregnant or breastfeeding women.
• Any prior or current disease, therapy, or laboratory abnormality that may confound study results, interfere with full participation, or not be in the subject's best interest to participate.
• Local or systemic disease not due to malignancy, or tumor-related conditions/symptoms that may confer high medical risk and/or uncertainty in survival assessment, such as leukemoid reaction due to tumor (WBC > 20 × 10⁹/L), cachexia (e.g., >10% body-weight loss within 3 months before screening), or BMI ≤ 18 (BMI = weight[kg] / height [m²]).