Anti-PCSK9 Antibody Tafolecimab and Anti-PD-1 Antibody Sintilimab Combined With Neoadjuvant Chemoradiotherapy for pMMR/ MSS Locally Advanced Rectal Cancer : A Prospective, Multicenter, Randomized, Open-Label, Parallel-Controlled Trial

Anti-PCSK9 Antibody Tafolecimab and Anti-PD-1 Antibody Sintilimab Combined With Neoadjuvant Chemoradiotherapy for pMMR/ MSS Locally Advanced Rectal Cancer : A Prospective, Multicenter, Randomized, Open-Label, Parallel-Controlled Trial

This is a randomized, controlled clinical trial based on prior exploratory findings, designed to evaluate the efficacy and safety of neoadjuvant chemoradiotherapy combined with tafolecimab(an anti-PCSK9 inhibitor) and sintilimab (an anti-PD-1 inhibitor) versus neoadjuvant chemoradiotherapy combined with sintilimab alone in patients with pMMR/MSS locally advanced rectal cancer. The primary endpoint is the complete response (CR) rate, including the pathological complete response (pCR) rate in patients who undergo surgery after neoadjuvant therapy, and the clinical complete response (cCR) rate in patients managed with a watch-and-wait strategy. Secondary endpoints include major pathological response (MPR) rate, objective response rate (ORR), downstaging rate, R0 resection rate, tumor regression grade, sphincter preservation rate, disease-free survival (DFS), overall survival (OS), and safety.

Inclusion Criteria:

1. Age 18 to 75 years, any sex.
2. Histologically confirmed rectal adenocarcinoma, determined to be pMMR (proficient mismatch repair) or MSS (microsatellite stable) by immunohistochemistry and/or genetic testing; clinical stage cT3/T4 or cN+; distal tumor margin ≤ 12 cm from the anal verge; and eligible for surgical resection.
3. No evidence of distant metastases.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
5. Adequate hematologic and biochemical function: absolute neutrophil count ≥ 1.5 × 10⁹/L, hemoglobin ≥ 90 g/L, platelets ≥ 100 × 10⁹/L, ALT/AST ≤ 2.5 times the upper limit of normal (ULN), creatinine ≤ 3.0 × ULN.
6. Anticipated good compliance and provision of written informed consent.

Exclusion Criteria:

1. Known allergy or severe adverse reaction to any study drug, including tafolecimab, PD-1 inhibitor (sintilimab), capecitabine, oxaliplatin, or any excipients.
2. Rectal cancer confirmed as dMMR (deficient mismatch repair) or MSI-H (microsatellite instability-high).
3. Pregnant or breastfeeding women, or patients of childbearing potential who refuse to use effective contraception during the study.
4. Other malignancies within the past 5 years, except for cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, papillary thyroid carcinoma, or other malignancies considered cured after adequate treatment.
5. Prior anti-tumor therapy for rectal cancer, including radiotherapy, chemotherapy, immunotherapy, or local surgical excision.
6. Previous treatment with a PCSK9 inhibitor for any indication.
7. Severe or uncontrolled neurological disease, psychiatric disorder, or cognitive impairment that, in the investigator's judgment, would affect informed consent or protocol adherence.
8. Severe cardiovascular or cerebrovascular disease, including but not limited to: unstable angina, myocardial infarction, coronary revascularization, or stroke within 6 months before enrollment; clinically significant arrhythmia requiring treatment or left ventricular ejection fraction (LVEF) < 50%; New York Heart Association (NYHA) class III or IV heart failure.
9. Active infection requiring long-term systemic therapy (e.g., antibiotics, antivirals, or antifungals).
10. Active autoimmune disease, or requirement for long-term systemic immunosuppressive therapy or corticosteroids (at a dose equivalent to prednisone > 10 mg/day).
11. Known history of human immunodeficiency virus (HIV) infection, or active syphilis, or active pulmonary tuberculosis.
12. Active hepatitis B (HBsAg positive and HBV DNA > 200 IU/mL or > 1000 copies/mL) or active hepatitis C (HCV RNA positive).
13. Any other clinical condition that, in the investigator's opinion, could interfere with study assessments, increase treatment risk, or lead to premature study discontinuation (including but not limited to severe alcohol or drug abuse).