Neoadjuvant combination versus single-agent immune checkpoint inhibition in locally advanced MSI-H/dMMR colorectal cancer: A systematic review and meta-analysis.

Abstract

e15595 Background: Immune checkpoint inhibitors (ICIs) have transformed treatment for MSI-H/dMMR colorectal cancer (CRC). Neoadjuvant studies, including NICHE and NICHE-2, demonstrated high pathologic response rates with single-agent or combination ICI therapy. However, it is unknown whether combination ICI regimens improve pathologic complete response (pCR) rates compared to single-agent regimens or whether toxicity differs between combination and single-agent regimens. Methods: We systematically searched PubMed and the Cochrane Library for studies comparing neoadjuvant ICI combination therapy with single-agent therapy in MSI-H/dMMR locally advanced CRC. Pooled effect estimates were calculated using a random-effects model in R and reported as risk ratios (RR) with 95% confidence intervals (CI). Outcomes analyzed included pCR and treatment-related adverse events. Results: Three studies with 147 patients were included. Combination therapy significantly increased pCR compared with single-agent therapy (RR = 1.80; 95% CI, 1.32–3.46; p = 0.0002). Grade 3–4 immune-related adverse events were similar between groups (RR = 0.95; 95% CI, 0.17–5.33; p = 1.00); however, any-grade adverse events were higher with combination therapy (RR = 1.42; 95% CI, 1.05–1.93; p = 0.02). Conversely, bowel obstruction of any grade (RR = 1.54), bowel obstruction of grade 3 (RR = 1.52), enterocolitis (RR = 1.40), death (RR = 2.83), thyroid dysfunction of any grade (RR = 1.34), thyroid dysfunction of grade 3 (RR = 0.31), toxiderma/rash of any grade (RR = 1.46) and toxiderma/rash of grade 3 (RR = 0.31) did not differ significantly. Conclusions: In MSI-H/dMMR locally advanced CRC, neoadjuvant ICI combination therapy improves pCR with similar grade 3-4 adverse events but increased all grade toxicity. While combination therapy may offer incremental efficacy, single-agent ICIs remain highly effective with a slightly more favorable safety profile. Larger prospective studies with long-term survival endpoints are needed to define the optimal neoadjuvant strategy. Details of the therapies. Study Intervention Comparator Dosage details (intervention) Dosage details (comparator) Deng et al, 2024 Nivolumab + Ipilimumab Pembrolizumab (n= 2) orTislelizumab (n= 3) Nivolumab 3 mg/kg for 2 cycles + Ipilimumab 1 mg/kg for 1 cycle 200 mg IV infusion every 3 weeks Lemaire et al, 2025 Nivolumab + Ipilimumab Pembrolizumab Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg for 1 cycle, followed by 1 cycle of Nivolumab 3 mg/kg monotherapy 2 weeks later 400 mg every 6 weeks (n= 12) and 200 mg every 3 weeks (n= 9)The last patient received 3 cycles at 200 mg every 3 weeks, followed by 3 cycles at 400 mg every 6 weeks Wang et al, 2025 IBI310 + Sintilimab Sintilimab IBI310 1 mg/kg + Sintilimab 200 mg during the first cycle and Sintilimab 200 mg during the second cycle Sintilimab 200mg every 3 weeks (Q3W) for 2 cycles