PD-1/PD-L1 inhibitors improve response in dMMR/MSI-H metastatic colorectal cancer

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BMC cancer Published May 22, 2026 Medically reviewed May 22, 2026 Study authors: Wang Shengqian, Gu Renjun, Lu Jiajie, Wang Shenghao, Tao Sijia, Zhang Xiaoyu, Chen Lerou, An Yongmin… PubMed ↗ DOI ↗ By Dr. Julia Lee, PhD · Oncology, Genomics & Drug Development

Key Takeaway

Consider PD-1/PD-L1 monotherapy for improved responses in dMMR/MSI-H metastatic colorectal cancer, but note variable survival benefits and increased toxicity with dual immunotherapy.

This is a meta-analysis synthesizing evidence on immunotherapy for patients with dMMR/MSI-H metastatic colorectal cancer. The analysis included 1460 patients across multiple studies, though specific study settings and individual trial populations were not reported. The primary intervention was PD-1/PD-L1 monotherapy or dual immunotherapy with nivolumab plus ipilimumab, compared against chemotherapy or monotherapy.

For the primary outcome, objective response rate (ORR) with PD-1/PD-L1 monotherapy versus chemotherapy was significantly improved (OR = 1.52, 95% CI: 1.02-2.27, P = 0.04) in an analysis of n = 429 patients. Dual immunotherapy also showed a significantly improved ORR versus monotherapy (OR = 1.77, 95% CI: 1.25-2.49, P = 0.001) in an analysis of n = 582 patients.

Key secondary outcomes included progression-free survival (PFS). Significant PFS benefits were reported for KEYNOTE-177 (HR = 0.59, 95% CI: 0.45-0.79) and CheckMate 8HW (HR = 0.62, 95% CI: 0.48-0.81). However, SAMCO-PRODIGE 54 and CheckMate 9 x 8 did not demonstrate statistically significant PFS improvement. Overall survival (OS) across four studies showed no statistically significant benefit, with HR ranging from 0.74 to 1.03 and all 95% confidence intervals crossing 1.0. Duration of response (DOR) with pembrolizumab versus chemotherapy in KEYNOTE-177 was longer, with median DOR not reached versus 10.6 months.

Safety findings indicated a significantly lower incidence of grade ≥ 3 adverse events with PD-1/PD-L1 monotherapy versus chemotherapy (OR = 0.14, 95% CI: 0.08-0.23, P < 0.00001) based on 2 studies. Conversely, toxicity risk was significantly increased with dual immunotherapy versus monotherapy (OR = 1.73, 95% CI: 1.22-2.44, P = 0.002). Specific adverse event rates, discontinuations, and tolerability details were not reported.

These results align with prior landmark trials like KEYNOTE-177, which established immunotherapy as a standard for this population. The meta-analysis confirms improved response rates but highlights inconsistent survival benefits across trials, a pattern noted in earlier studies.

Key methodological limitations include wide confidence intervals and inconsistent statistical significance across trials, which may reduce the certainty of findings. The analysis is limited by the lack of reported study settings and individual trial details, introducing potential bias.

Clinically, these findings support considering PD-1/PD-L1 monotherapy for eligible patients, with dual immunotherapy reserved for those who may benefit from enhanced response despite higher toxicity. Personalized risk-benefit assessment is essential.

Unanswered questions include the optimal sequencing of therapies, long-term survival outcomes, and biomarkers beyond dMMR/MSI-H status to refine patient selection.

Study Details

Study typeMeta analysis

Sample sizen = 1,460

EvidenceLevel 1

Follow-up10.6 mo

PublishedMay 2026

PMID42168914

View Original 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.