The current standard first-line treatment for metastatic colorectal cancer is chemotherapy combined with targeted therapy, yet the prognosis remains poor. Although combining immunotherapy, anti-angiogenic agents, and chemotherapy has shown some efficacy in MSS/pMMR metastatic patients, progression-free survival (PFS) remains suboptimal. Radiotherapy-particularly high-dose radiotherapy-can enhance tumor antigen release and potentially improve the response of MSS/pMMR colorectal cancer to PD-1 inhibitors. Tumor-draining lymph nodes (TDLNs) are key sites for PD-1-mediated anti-tumor activity, but radiation-induced damage and fibrosis may impair their immune function. Prior studies have reported a remarkable pathologic complete response (pCR) rate of 77.8% using node-sparing radiotherapy in locally advanced rectal cancer. This phase II/III study aims to evaluate whether node-sparing modified short-course radiotherapy combined with chemotherapy, bevacizumab, and PD-1 blockade can improve objective response rate (ORR) in phase II and progression-free survival (PFS) in phase III, together with treatment tolerance, and overall prognosis in patients with pMMR/MSS metastatic colorectal cancer.
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Aged between 18 and 75 years at the time of enrollment.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Expected survival of more than 3 months.
• Known MSI-H or dMMR status.
History of other malignancies within the past 3 years, except for those cured by local treatment, such as basal cell carcinoma, squamous cell carcinoma of the skin, superficial bladder cancer, or ductal carcinoma in situ of the breast.
Prior immunotherapy, including immune checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies), immune agonists (e.g., ICOS, CD40, CD137, GITR, OX40), or immune cell-based therapies targeting tumor immunity.
Prior adjuvant or neoadjuvant therapy targeting EGFR or VEGF/VEGFR pathways (e.g., bevacizumab, cetuximab, panitumumab, aflibercept, regorafenib, or biosimilars).
Parallel
Node-Sparing Radiotherapy plus first-line therapy
Combination productPatients will receive node-sparing modified short-course radiotherapy, followed by 8 cycles of FOLFOX chemotherapy combined with bevacizumab and a PD-1 inhibitor. After induction therapy, patients will continue with maintenance therapy using bevacizumab, PD-1 inhibitor, and 5-fluorouracil (5-FU), administered every 2 weeks (Q2W).
First-line treatment
Combination productPatients will receive 8 cycles of FOLFOX chemotherapy combined with bevacizumab, followed by maintenance therapy with bevacizumab and 5-fluorouracil (5-FU), administered every 2 weeks (Q2W).
Objective Response Rate(ORR)
Phase II: To evaluate whether node-sparing modified short-course radiotherapy combined with chemotherapy, bevacizumab, and a PD-1 inhibitor can improve Objective Response Rate(ORR) in patients with metastatic pMMR/MSS colorectal cancer.
Progression-free survival (PFS)
Phase III: To evaluate whether node-sparing modified short-course radiotherapy combined with chemotherapy, bevacizumab, and a PD-1 inhibitor can improve progression-free survival (PFS) in patients with metastatic pMMR/MSS colorectal cancer.
Duration of response
Disease control rate
Overall survival (OS) rate
Treatment related adverse effect
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