Node-sparing modified short-course radiotherapy combined with CAPOX and tislelizumab versus conventional short-course preoperative chemoradiotherapy for proficient mismatch repair or microsatellite stable locally advanced rectal cancer (mRCAT-III): A multicenter, randomized, open-label, phase 3 trial.

Abstract

LBA3515 Background: Total neoadjuvant chemoradiotherapy is the standard of care for locally advanced rectal cancer (LARC) to control local recurrence and achieve organ preservation. However, for proficient mismatch repair (pMMR) or microsatellite stable (MSS) LARC, which accounts for nearly 90% of rectal cancers, conventional chemoradiotherapy has limited efficacy and is associated with significant side effects. Recent studies have shown that combining radiotherapy with immunochemotherapy can improve pathological complete response (pCR) rates, but the inclusion of tumor-draining lymph nodes (TDLNs) in the conventional irradiation field may impair T-cell immunity and reduce response to immunotherapy. Our previous single-arm 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% in pMMR LARC. 1 Building on these findings, we initiated this phase III trial to compare this new treatment regime with conventional short-course chemoradiotherapy in improving pCR rates. 2 Methods: This is a phase III, open-label, multicenter, randomized trial conducted across 17 hospitals in China. A total of 154 eligible MSS/pMMR middle or low rectal cancer patients (cT3-4N0/+M0) will be recruited and randomly assigned (1:1) to two groups: control group (conventional short-course chemoradiotherapy), experimental group (node-sparing modified short-course chemoradiotherapy plus PD-1 blockade). The innovative node-sparing modified short-course radiotherapy targets only the primary tumor bed, excluding TDLNs. Following randomization, patients will receive short-course radiotherapy (conventional or node-sparing) followed by four cycles of CAPOX ± tislelizumab: tislelizumab 200 mg IV on day 1, oxaliplatin 130 mg/m² IV on day 1, and capecitabine 1000 mg/m² orally on days 1-14, and Total mesorectal excision (TME) will be performed at weeks 14-15. The primary endpoint is pCR rate, while secondary endpoints include organ preservation rate, disease-free survival, overall survival, adverse effects, and quality of life. The primary and secondary endpoints will be analyzed in the intent-to-treat (ITT) population. Safety analyses will be performed in the safety population, defined as patients who received at least one dose of study treatment. Results: 247 patients were assessed for eligibility, a total of 154 patients were enrolled in the ITT population (77 per group). Baseline characteristics were well balanced between the two groups. In the ITT population, the experimental group demonstrated a significantly superior pCR rate compared to the Control group: 61.4% (47/77) vs 28.6% (22/77) (P < 0.001). The MPR rate was also significantly higher in the experimental group (80.5% vs 50.6%). All patients in both groups received sphincter-sparing surgery. Regarding safety, the incidence of grade 3-4 treatment-related adverse events (TRAEs) was comparable between the experimental and control groups (23.4% vs 22.1%). Immune-related adverse events (irAEs) occurred in 7.8% (6/77) of patients in the experimental group, primarily grade 1-2. Conclusions: Compared with conventional short-course preoperative chemoradiotherapy, node-sparing modified radiotherapy combined with CAPOX and PD-1 blockade significantly improved pCR rates in patients with pMMR/MSS LARC, with a manageable safety profile. This regimen represents a promising and highly effective neoadjuvant strategy for MSS rectal cancer. Clinical trial information: NCT06507371. Reference：1. Annals of Oncology (2024) 24 (suppl_1): 1-20. 10.1016/iotech/iotech100744; 2. 2025;43 16_suppl. https://doi.org/10.1200/jco.2025.43.16_suppl.tps3641. Clinical trial information: NCT06507371 .