Node-sparing modified short-course radiotherapy combined with capecitabine and PD-1/CTLA-4 for MSS early, middle, and low rectal cancer (mRCAT-E): An open-label, single-arm, prospective multicenter clinical trial.

TPS3687 Background: The standard treatment for early-stage rectal cancer is radical resection. For patients' organ preservation and quality of life improvement, preoperative radiotherapy plus chemotherapy then "watch-and-wait" are also recommended. But the clinical complete response (cCR) rate after chemoradiotherapy is only about 30~40%. Recent studies have shown that combining radiotherapy with PD-1 blockage can improve pathological complete response (pCR) rates to 40~50% for proficient mismatch repair (pMMR) or microsatellite stable (MSS) locally advanced rectal cancer (LARC) patients. However, the irradiation to tumor-draining lymph nodes (TDLNs) may impair T-cell immunity and reduce response to immunotherapy. Our previous phase II trial demonstrated that node-sparing modified short-course radiotherapy combined with chemotherapy and PD-1 blockade could achieve a high pCR rate of 78. 8% and reduce radiation-related toxicity in pMMR/MSS LARC. 1 Iparomlimab/tuvonralimab is a novel bifunctional antibody, containing a mixture of anti-PD-1 IgG4 antibody iparomlimab and anti-CTLA-4 IgG1 antibody tuvonralimab, produced in a fixed ratio (2: 1) from the same single cell and manufactured together as one product. 2 In this trial, we hypothesize that node-sparing modified short-course radiotherapy combined with capecitabine and PD-1/CTLA-4 may induce synergistic activity and substantially improve CR rates while reducing radiation-related toxicity. Methods: This is a single-arm, prospective, multicenter, phase II study across 3 hospitals in China. The main inclusion criteria includes rectal cancer within 7 cm from the lower edge of the tumor to the anal verge and the clinical stage is cT2-3N0M0, MSI-L/MSS or pMMR. A total of 52 patients will receive node-sparing modified short-course radiotherapy of 25 Gy delivered in 5 daily fractions to the primary tumor bed (excluding TDLNs). Beginning on treatment Day 8, patients will receive 4 cycles of capecitabine (1, 000 mg/m², D1-14, q3w) and iparomlimab/tuvonralimab (5 mg/kg, D1, q3w). Tumor response will be assessed 1-2 weeks after the last chemo-immunotherapy. Patients with cCR enter a watch-and-wait program, while non-cCR proceed to local excision or total mesorectal excision. The primary endpoint is the CR rate (cCR and pCR). Secondary endpoints include organ preservation rate, 3-year local recurrence rate, overall survival, toxicity, and quality-of-life measures. As of January 2025, 5 of the planned 52 patients have been enrolled. The Data Monitoring Committee (DMC) reviewed the trial in December 2024 and recommended continuing as planned. Clinical trial information: NCT07068763. References: (1) Annals of Oncology (2024) 24 (suppl₁): 1-20. 10. 1016/iotech/iotech100744; (2) Zhao et al. Journal of Hematology & Oncology (2023) 16: 50. Clinical trial information: NCT07068763.