Radiotherapy Plus CAPOX, and Iparomlimab and Tuvonralimab (QL1706) as Neoadjuvant Therapy for LARC

Neoadjuvant Chemoradiotherapy Combined Cith Iparomlimab and Tuvonralimab (QL1706) Therapy for Locally Advanced Rectal Cancer：a Single-center, Prospective, Randomized, Phase II Clinical Trial

This study is a single-center, prospective, randomized, double-arm, Phase II clinical trial designed to evaluate the efficacy of radiotherapy combined with CAPOX, and Iparomlimab and Tuvonralimab (QL1706) as neoadjuvant therapy for locally advanced rectal cancer. Additionally, the study seeks to explore the relationship between biomarkers in blood and tumor tissue and treatment efficacy.

Eligible participants (locally advanced rectal cancer) were randomly assigned in a 1:1 ratio to two groups.

Participants will:

Group A patients received radiotherapy, chemotherapy, and immunotherapy. During the first week of radiotherapy, they received one cycle of CAPOX concurrent chemoradiotherapy. Two weeks after the completion of radiotherapy, they continued with four cycles of CAPOX combined with QL1706 immunotherapy.

Group B patients received radiotherapy and chemotherapy. After completing the concurrent radiotherapy and chemotherapy, they rested for 2-3 weeks before completing 3 cycles of CAPOX consolidation chemotherapy.

Two to three weeks after the completion of neoadjuvant therapy in groups A and B, the efficacy was evaluated, and a decision was made on whether to proceed with surgery or watchful waiting based on the efficacy.

Improving the tumor downstaging rate and complete response rate of neoadjuvant therapy remains a key focus and hot topic in clinical research. Neoadjuvant immunotherapy has been recommended by clinical guidelines for locally advanced rectal cancer (LARC) with DNA mismatch repair deficiency/high microsatellite instability (dMMR/MSI-H), achieving a pCR rate as high as 60-70%. However, the efficacy of immunotherapy in locally advanced rectal cancer with microsatellite stable disease (pMMR/MSS), which accounts for the vast majority, remains controversial. Recent phase II studies have shown that combining chemotherapy and immunotherapy with long-course or short-course radiotherapy may further improve the pCR rate to 30-40% compared to traditional concurrent chemoradiotherapy. In a study by Professor Zhang Zhen's team at Fudan University, short-course radiotherapy combined with consolidation or induction chemotherapy and immunotherapy even achieved a cCR rate exceeding 50%. A meta-analysis published in 2025 also showed that in pMM locally advanced rectal cancer patients receiving neoadjuvant radiotherapy combined with immunotherapy, patients receiving short-course radiotherapy combined with PD-1 inhibitors or concurrent immunoradiotherapy showed better treatment outcomes, while the toxic side effects were tolerable. However, these studies have small sample sizes, lack consistency in drug use and study design, and have insufficient levels of evidence, requiring further exploration and verification.

This study will explore the efficacy and safety of neoadjuvant chemoradiotherapy combined with erato combination antibody for the treatment of locally advanced pMMR rectal cancer through a prospective phase II randomized controlled clinical trial, aiming to provide a reference for achieving higher cCR/pCR rates and preservation of anal function in patients with locally advanced rectal cancer.

Specifically, the study will assess the pathological complete response (pCR) rate two weeks after neoadjuvant therapy, the clinical complete response (cCR) rate under the "watch-and-wait" strategy, R0 resection rate, tumor regression grade (TRG), and sphincter preservation rate. Additionally, the study will evaluate the 3-year disease-free survival (DFS) and overall survival (OS) following dual-inhibitor combined neoadjuvant chemoradiotherapy. The safety and tolerability of this combination therapy will also be comprehensively assessed based on NCI-CTCAE 4.03 criteria.

Inclusion Criteria:

• (1) The patient is histologically diagnosed with rectal adenocarcinoma. (2) Age ≥18 years, <75 years (3) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 (4) AJCC stage of rectal cancer: cT3-4N0M0 or TanyN1-2M0 (5) The lower margin of the rectal tumor is ≤10cm from the anus. (6) At least one evaluable lesion based on RECIST 1.1 assessment. (7) Subjects should have adequate bone marrow and liver and kidney function reserves:

  • Neutrophils ≥1.5×10⁹/L, platelets ≥75×10⁹/L, and hemoglobin ≥9 g/dL

    • Total bilirubin ≤1.5×Upper limit of normal (UNL); ASAT (SGOT) and/or ALAT (SGPT) ≤2.5×UNL (≤5×UNL if liver metastasis occurs); alkaline phosphatase ≤2.5×UNL (≤5×UNL if liver metastasis occurs, ≤10×UNL if bone metastasis occurs); LDH <1500 U/L

      • Creatinine clearance (calculated according to the Cockcroft and Gault formula) >60 mL/min or serum creatinine ≤1.5×UNL; (8) Voluntarily participate in this study and sign the informed consent form

Exclusion Criteria:

• (1) Histopathological examination confirms the presence of other pathological types, such as squamous cell carcinoma, undifferentiated carcinoma, neuroendocrine carcinoma, etc.

  (2) Pathological examination confirms microsatellite highly unstable dMMR/msi-H (3) Presence of intestinal obstruction, intestinal perforation, bleeding, or other conditions requiring emergency surgery (4) History of pelvic radiotherapy (5) Comorbid malignant tumors (excluding cervical carcinoma in situ that has been cured for more than 2 years) (6) Receiving any other anti-tumor treatment (chemotherapy, radiotherapy, surgery, targeted therapy, immunotherapy) or participating in other new drug clinical trials within the past 4 weeks (7) Presence of the following cardiovascular and cerebrovascular diseases or risks:

  1. Myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, acute or persistent myocardial ischemia, symptomatic heart failure (Class 2 or above as determined by the New York Heart Association functional classification) within 6 months prior to randomization, symptomatic or poorly controlled arrhythmia
  2. 3 years prior to first use of the drug a. History of pulmonary embolism or other serious thromboembolism within the past month
  3. Presence of aortic aneurysm, aortic dissection aneurysm, internal carotid artery stenosis or other major vascular diseases that may endanger life or require surgery within the past 6 months
  4. History of myocarditis or cardiomyopathy or current examination suggests myocarditis
  5. Left ventricular ejection fraction (LVEF) <50%
  6. Complete left bundle branch block, third-degree atrioventricular block (8) Active autoimmune disease requiring systemic treatment within 2 years prior to the start of study treatment, or an autoimmune disease that the investigator judges may relapse or is planned for treatment. The following are excluded:
  1. Skin diseases that do not require systemic treatment (e.g., vitiligo, alopecia, psoriasis, or eczema)
  2. Hypothyroidism caused by autoimmune thyroiditis that requires only stable doses of hormone replacement therapy
  3. Type I diabetes that requires only stable doses of insulin replacement therapy
  4. Childhood asthma that has completely resolved and requires no intervention in adulthood
  5. The investigator determines that the disease will not recur without external triggering factors (9) Known or suspected active pulmonary tuberculosis (10) Subjects with active hepatitis B, inactive or asymptomatic hepatitis B virus (HBV) carriers (HBsAg positive) with HBV DNA > 500 IU/mL or > 2500 copies/mL), and subjects with active hepatitis C should be excluded. Inactive or asymptomatic carriers of hepatitis B who are treated and stable and meet the criteria of HBV DNA ≤500 IU/mL or ≤2500 copies/mL are eligible for enrollment. Subjects with cured hepatitis C who are HCVAb positive and HCV RNA negative are eligible for enrollment. (11) Subjects who require systemic treatment with glucocorticoids (>10 mg/day prednisone or equivalent dose) or other immunosuppressive drugs within 14 days prior to randomization. The following are exceptions:

  a. Inhaled, ophthalmic, or topical corticosteroids are permitted if there is no active autoimmune disease.

  b. Corticosteroids are used as a pretreatment for infusion-related reactions or allergic reactions (e.g., medication before CT scans).

  (12) Pregnant or lactating women (13) Patients with currently uncontrolled comorbidities, such as decompensated cirrhosis, nephrotic syndrome, uncontrolled hyperglycemia, uncontrolled metabolic disorders, severe active peptic ulcer disease or gastritis, severe bleeding tendency, or coagulation disorders.

  (14) Patients with known allergies to any component of the study drug (oxaliplatin, capecitabine, QL1706); a history of severe allergic reactions to other monoclonal or bispecific antibodies; or known allergies to multiple substances or severe allergic diseases.

  (15) Patients who have received a live vaccine within 30 days prior to randomization or who plan to receive a live vaccine during the study period.

  (16) Patients with cognitive impairment or severe comorbid mental disorders, or those deemed by the investigator to have poor chemotherapy adherence; or other cases deemed unsuitable for participation in clinical trials by the investigator.