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Background <p>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.</p> Design <p>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.</p> Results <p>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, <i>P</i> = 0.04), based on two RCTs (<i>n</i> = 429), and demonstrated a significantly lower incidence of grade ≥ 3 adverse events (OR = 0.14, 95% CI: 0.08–0.23, <i>P</i> &lt; 0.00001; 2 studies). Dual immunotherapy with nivolumab plus ipilimumab significantly improved ORR versus monotherapy (OR = 1.77, 95% CI: 1.25–2.49, <i>P</i> = 0.001), based on one RCT (<i>n</i> = 582), with a significantly increased toxicity risk (OR = 1.73, 95% CI: 1.22–2.44, <i>P</i> = 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.</p> Conclusions <p>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, <i>P</i> = 0.04). Dual immunotherapy significantly improved ORR compared with monotherapy (OR = 1.77, 95% CI: 1.25–2.49, <i>P</i> = 0.001), but this benefit was accompanied by significantly increased toxicity (OR = 1.73, 95% CI: 1.22–2.44, <i>P</i> = 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.</p>

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

  • 期刊论文

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  • 发表日期：

    2026年5月21日

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  • Shengqian Wang,
  • Renjun Gu,
  • Jiajie Lu,
  • Shenghao Wang,
  • Sijia Tao,
  • Xiaoyu Zhang,
  • Lerou Chen,
  • Yongming An,
  • Xin Gu,
  • Ziyun Li,
  • Minye Qu

摘要

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.