In colorectal cancer (CRC), ICIs show strong therapeutic associations with microsatellite instability-high (MSI-H) status, while patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors exhibit poor responses. Dual immunotherapy may represent a promising strategy for MSS populations. The Dutch NICHE trial reported a 27% pathological response rate (4/15) in MSS CRC patients with clinical stage I-III disease treated with neoadjuvant ipilimumab plus nivolumab. In advanced or metastatic CRC, a study by Jin Li et al. demonstrated that iparomlimab/tuvonralimab combined with bevacizumab and the XELOX regimen achieved an objective response rate of 70.6% (95% CI: 56.2%-82.5%).
Radiotherapy may synergize with ICIs through multiple immunomodulatory mechanisms. For pMMR/MSS LARC, combining CRT with ICIs holds promise to overcome the "immune-cold" tumor microenvironment and improve therapeutic efficacy. In this clinical trial, the investigators aim to evaluate the efficacy and safety of integrating immunotherapy with CRT as a novel total neoadjuvant therapy for pMMR/MSS rectal cancer.
Age 18-75 years old, male and female
Histologically confirmed pMMR/MSS rectal adenocarcinoma, defined by MRI as clinical stage II (T3-4, N-) or stage III (any T, N+)
Tumor within 12 cm of the anal verge with at least one of the following high-risk factors: cT4, cN2, extramural vascular invasion [EMVI+], mesorectal fascia involved [MRF+], lateral lymph node [LN+], tumor deposit, or low rectal cancer (≤5 cm from the anal verge)
Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1.
dMMR or MSI-H patients
Myelosuppression without obvious causes
Locally advanced rectal cancer without high-risk factors
Prior or concurrent other malignancies (except cured basal cell carcinoma of the skin and carcinoma in situ of the cervix)
Single group
Total neoadjuvant therapy integrating iparomlimab/tuvonralimab with chemoradiotherapy
Combination product1. Radiotherapy: Radiotherapy location: primary site and the corresponding draining lymph node. Radiotherapy techniques: IMRT/VMRT. Radiotherapy dose and fractionation pattern: conventional external irradiation, 50Gy/25 fx/5 weeks or 25Gy/5fx/1 week. 2. Chemotherapy: Long-course radiotherapy concurrent with chemotherapy: capecitabine 825mg/m2, bid, d1-5/week. Short-course radiotherapy without concurrent chemotherapy. Consolidation chemotherapy and immunotherapy: QL1706 (iparomlimab and tuvonralimab 5mg/kg, d1) and CAPOX (Oxaliplatin 130mg/m2, d1 + capecitabine 1000mg/m2, bid, d1-14), repeated on a 21-day cycle, for 6 cycles. 3. Surgery or watch-and-wait Total mesorectal excision (TME), or watch-and-wait (for patients with clinical complete response).
Overall complete response (CR) rate
Overall complete response (CR) rate, meaning the rates of pathological complete response (pCR) plus clinical complete response (cCR).
Overall survival (OS)
From date of radiotherapy initiation until the date of death from any cause or last follow-up, whichever came first.
Rate of surgical complications
Rate of surgical complications, such as intraoperative hemorrhage, anastomotic leakage, intestinal obstruction, etc.
Organ preservation rate
3 year disease free survival (DFS) rate
From date of surgery completion until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months
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