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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
108
Neoadjuvant chemoradiotherapy + immunotherapy: Pelvic radiotherapy (IMRT), 36 Gy/12 fractions/3 weeks; adaptive radiotherapy booster of 5-6 Gy/2 fractions is permitted for residual lesions. During the first week of radiotherapy, one cycle of CAPOX regimen concurrent chemoradiotherapy is administered (oxaliplatin, 100 mg/m2, D1, IV drip; capecitabine, 850 mg/m2, BID, oral on the day of radiotherapy). Two weeks after radiotherapy, four cycles of IT-CAPOX regimen immunotherapy combined with chemotherapy are continued (epaloliposide (QL1706) 5 mg/kg, D1, IV drip; oxaliplatin, 130 mg/m2, D1, IV drip; capecitabine, 1000 mg/m2, BID, PO, D1-14, Q3W). Two to three weeks after the completion of immunotherapy and chemotherapy, a comprehensive follow-up evaluation of efficacy is conducted, and surgical treatment is planned.
Neoadjuvant concurrent chemoradiotherapy: Pelvic radiotherapy, IMRT 45-50.4 Gy/25-28 F, for a total of 5-6 weeks. During radiotherapy, administer oral capecitabine concurrent chemoradiotherapy (capecitabine, 850 mg/m2, BID, orally on the day of radiotherapy). After radiotherapy, rest for 2-3 weeks, then complete 3 cycles of CAPOX consolidation chemotherapy (oxaliplatin, 130 mg/m2, D1, IV drip; capecitabine, 1000 mg/m2, BID, PO, D1-14, Q3W). 2-3 weeks after the completion of consolidation chemotherapy, conduct a comprehensive follow-up assessment of the efficacy, and surgical treatment is planned.
Zhongnan Hospital of Wuhan University
Wuhan, Hubei, China
Complete response (CR)
Complete response: Pathological complete response and clinical complete response
Time frame: 1 year
R0 Resection Rate
The proportion of surgical patients who achieve an R0 resection. R0 resection: All gross disease has been removed, and microscopic examination reveals all surgical margins free of tumor.
Time frame: 1 year
Organ Preservation Rate (OPR)
The 1-year organ preservation rate is the percentage of patients attaining a complete clinical response (cCR) or near-complete clinical response (near-cCR) following neoadjuvant therapy, who then proceeded with non-surgical management or local excision, was monitored under a Watch \& Wait strategy or for 1 year post-local resection without undergoing radical surgery.
Time frame: 1 year
Disease-free survival (DFS)
DFS is defined as the time from randomization to the earliest occurrence of any of the following events: Tumor progression by imaging according to RECIST 1.1, Tumor recurrence (local or distant), confirmed by imaging or biopsy, for patients with no residual tumor after surgery, Death from any cause. Note: A second primary malignancy is not considered an DFS event.
Time frame: 3 years
Overall survival (OS)
The time interval between the date of randomization to the date of death. If the patient has been alive, the time until the last follow-up is taken as the overall survival period.
Time frame: 3 years
Incidence of adverse events
Assessed by Common Terminology Criteria for Adverse Events version 4.0. The overall adverse event rates and the immune-related adverse event rates will be compared between treatment arms using Chi-square test or Fisher's exact test, as appropriate.
Time frame: During neoadjuvant chemoradiotherapy combined with immunotherapy, an average of 6 months
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