Efficacy and risk analysis of monotherapy and dual immunotherapy in dMMR/MSI-H metastatic colorectal cancer: a meta-analysis based on randomized controlled trials

Clinical Snapshot

Key Findings

• P Value: P = 0.04 (monotherapy); P = 0.001 (dual therapy)

• Effect Size: ORR OR 1.52 for monotherapy vs chemotherapy; OR 1.77 for dual vs monotherapy

• Primary Outcome: Objective response rate significantly improved with PD-1/PD-L1 monotherapy vs chemotherapy (OR = 1.52, 95% CI: 1.02-2.27, P = 0.04) and dual therapy vs monotherapy (OR = 1.77, 95% CI: 1.25-2.49, P = 0.001)

• Nnt Or Sensitivity: Grade ≥3 adverse events significantly lower with monotherapy (OR = 0.14, 95% CI: 0.08-0.23) but higher with dual therapy (OR = 1.73, 95% CI: 1.22-2.44)

• Confidence Interval: 95% CI: 1.02-2.27 (monotherapy); 95% CI: 1.25-2.49 (dual therapy)

Clinical Application

Both monotherapy and dual immunotherapy are available treatment options, though dual therapy requires careful patient selection due to increased toxicity Pembrolizumab is PBS-listed for MSI-H/dMMR mCRC. TGA-approved options include pembrolizumab monotherapy and nivolumab/ipilimumab combination. RACGP guidelines support immunotherapy as first-line treatment for this molecular subtype Patients with confirmed dMMR/MSI-H metastatic colorectal cancer suitable for systemic therapy

Abstract

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for metastatic colorectal cancer (mCRC) exhibiting DNA mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). However, the comparative efficacy and safety of monotherapy versus dual immunotherapy remain inadequately quantified. This meta-analysis aims to evaluate the benefits and risks of these strategies by quantitatively synthesizing data from randomized controlled trials (RCTs) to inform clinical decision-making. DESIGN: We systematically searched major databases (PubMed, Web of Science, Cochrane, Embase) from inception to September 2025 for relevant RCTs. Outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and adverse events. Statistical analyses were performed using RevMan 5.3 and Stata 18.0. RESULTS: Six RCTs (1,460 patients) were included. Pooled analysis showed that PD-1/PD-L1 monotherapy significantly improved ORR compared with chemotherapy (OR = 1.52, 95% CI: 1.02-2.27, P = 0.04), based on two RCTs (n = 429), and demonstrated a significantly lower incidence of grade ≥ 3 adverse events (OR = 0.14, 95% CI: 0.08-0.23, P < 0.00001; 2 studies). Dual immunotherapy with nivolumab plus ipilimumab significantly improved ORR versus monotherapy (OR = 1.77, 95% CI: 1.25-2.49, P = 0.001), based on one RCT (n = 582), with a significantly increased toxicity risk (OR = 1.73, 95% CI: 1.22-2.44, P = 0.002). For PFS, KEYNOTE-177 (HR = 0.59, 95% CI: 0.45-0.79) and CheckMate 8HW (HR = 0.62, 95% CI: 0.48-0.81) showed significant benefits, while SAMCO-PRODIGE 54 and CheckMate 9 × 8 did not demonstrate statistically significant PFS improvement. OS hazard ratios across four studies ranged from 0.74 to 1.03, with all 95% confidence intervals crossing 1.0, indicating no statistically significant survival benefit in any individual study. DOR was consistently longer with immunotherapy, with median not reached for pembrolizumab versus 10.6 months for chemotherapy in KEYNOTE-177. CONCLUSIONS: Effect estimates for PFS, OS, and DOR generally favored immunotherapy; however, confidence intervals were wide and statistical significance was not consistently observed across trials. PD-1/PD-L1 monotherapy demonstrated a favorable safety profile and a statistically significant improvement in ORR compared with chemotherapy (OR = 1.52, 95% CI: 1.02-2.27, P = 0.04). Dual immunotherapy significantly improved ORR compared with monotherapy (OR = 1.77, 95% CI: 1.25-2.49, P = 0.001), but this benefit was accompanied by significantly increased toxicity (OR = 1.73, 95% CI: 1.22-2.44, P = 0.002) and did not consistently translate into statistically significant PFS or OS benefits across trials. These findings highlight the need for personalized risk-benefit assessment. Future research should focus on biomarker-driven patient selection and strategies to overcome resistance.

References

1. 1.Wang, S., Gu, R., Lu, J., Wang, S., Tao, S., Zhang, X., Chen, L., An, Y., Gu, X., Li, Z., & Qu, M. (2026). Efficacy and risk analysis of monotherapy and dual immunotherapy in dMMR/MSI-H metastatic colorectal cancer: a meta-analysis based on randomized controlled trials. BMC Cancer. https://doi.org/10.1016/S1470-2045(22)00197-8