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.
Age 18 to 75 years, any sex.
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.
No evidence of distant metastases.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
Known allergy or severe adverse reaction to any study drug, including tafolecimab, PD-1 inhibitor (sintilimab), capecitabine, oxaliplatin, or any excipients.
Rectal cancer confirmed as dMMR (deficient mismatch repair) or MSI-H (microsatellite instability-high).
Pregnant or breastfeeding women, or patients of childbearing potential who refuse to use effective contraception during the study.
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.
Parallel
Short-course radiotherapy
RadiationTotal dose: 25 Gy, to be completed in 5 sessions (once a day for 5 days). After the short-course radiotherapy, a 1-week rest is required before moving on to the next stage of treatment.
CAPOX (oxaliplatin/capecitabine)
DrugOne week after short-course radiotherapy, 6 cycles of CAPOX chemotherapy combined with PD-1 inhibitor immunotherapy were administered. Each cycle lasted for 3 weeks, for a total of 6 cycles. (One cycle is defined as: Oxaliplatin, 130 mg/m², intravenous infusion, on day 1. Capecitabine, 1000 mg/m², orally, twice a day (morning and evening), from day 1 to day 14.)
Sintilimab
DrugFor patients with a body weight of less than 60 kg, the dose is 3 mg/kg, administered by intravenous infusion on the first day; for patients with a body weight of 60 kg or more, the dose is 200 mg, also administered by intravenous infusion on the first day.
Tafolecimab
DrugThe entire course of treatment with PCSK9 inhibitor (Tafolecimab) was administered, with 450 mg of Tafolecimab administered subcutaneously. (The treatment involved neoadjuvant radiotherapy and chemotherapy combined with immunotherapy and Tafolecimab. The treatment was carried out from the time the patient began receiving short-course radiotherapy. Each cycle consisted of 4 weeks, with injection on the first day of each cycle, for a total of 6 times.)
Complete Response (CR) Rate
Defined as the Proportion of Participants Achieving Pathological Complete Response (pCR) After Surgery or Clinical Complete Response (cCR) Under Watch-and-Wait Strategy Following Neoadjuvant Therapy
Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v5.0
Major Pathological Response (MPR) Rate
Objective Response Rate (ORR)
Downstaging Rate
Tumor Regression Grade (TRG)
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Guangdong Provincial People's Hospital
Lead sponsor
Beijing Friendship Hospital
Collaborator
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Collaborator
Fudan University
Collaborator
Sixth Affiliated Hospital, Sun Yat-sen University
Collaborator
Sun Yat-Sen University Cancer Center
Collaborator
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Collaborator
Affiliated Hospital of Qinghai University
Collaborator
Zhangzhou Hospital, Fujian Province
Collaborator
The First Affiliated Hospital of Xiamen University
Collaborator
Ruijin Hospital
Collaborator
The First Hospital of Jilin University
Collaborator
Peking University Cancer Hospital & Institute
Collaborator
Nanchang University Second Affiliated Hospital
Collaborator
The First Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine
Collaborator
Third Affiliated Hospital, Sun Yat-Sen University
Collaborator
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Collaborator
Meizhou People's Hospital
Collaborator
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