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

Overview

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.

Interventions

• Radiation Short-course radiotherapy
  Total 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.
• Drug CAPOX (oxaliplatin/capecitabine)
  One 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.)
• Drug Sintilimab
  For 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.
• Drug Tafolecimab
  The 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.)

Primary outcome measures

• Complete Response (CR) Rate [Time frame: Within 4 weeks after completion of neoadjuvant therapy for cCR and within 2 weeks after the time of surgery for pCR]
• Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v5.0 [Time frame: From the first dose of neoadjuvant treatment]

Secondary outcome measures (7)

• Major Pathological Response (MPR) Rate [Time frame: within 2 weeks after the time of surgery]
• Objective Response Rate (ORR) [Time frame: Within 4 weeks after completion of neoadjuvant therapy or within 2 weeks after surgery;]
• Downstaging Rate [Time frame: Within 4 weeks after completion of neoadjuvant therapy or within 2 weeks after surgery;]
• Tumor Regression Grade (TRG) [Time frame: Within 2 weeks after surgery;]
• R0 Resection Rate [Time frame: Within 2 weeks after surgery;]
• Disease-Free Survival (DFS) [Time frame: approximately 5 years after completion of neoadjuvant chemotherapy]
• Overall Survival (OS) [Time frame: approximately 5 years after completion of neoadjuvant chemotherapy]

Eligibility criteria

Inclusion criteria

• 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.
• 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.
• Anticipated good compliance and provision of written informed consent.

Exclusion criteria

• 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.
• Prior anti-tumor therapy for rectal cancer, including radiotherapy, chemotherapy, immunotherapy, or local surgical excision.
• Previous treatment with a PCSK9 inhibitor for any indication.
• Severe or uncontrolled neurological disease, psychiatric disorder, or cognitive impairment that, in the investigator's judgment, would affect informed consent or protocol adherence.
• 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.
• Active infection requiring long-term systemic therapy (e.g., antibiotics, antivirals, or antifungals).
• Active autoimmune disease, or requirement for long-term systemic immunosuppressive therapy or corticosteroids (at a dose equivalent to prednisone > 10 mg/day).
• Known history of human immunodeficiency virus (HIV) infection, or active syphilis, or active pulmonary tuberculosis.
• Active hepatitis B (HBsAg positive and HBV DNA > 200 IU/mL or > 1000 copies/mL) or active hepatitis C (HCV RNA positive).
• 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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Guangdong Provincial People's Hospital — Guangzhou

Identifiers

NCT: NCT07686796 · PIONEER-02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗