The Efficacy and Safety of Pembrolizumab, Ipilimumab, and Nivolumab Monoteraphy and Combination for Colorectal Cancer: A Systematic Review and Meta-Analysis

Abstract

Background Colorectal cancer (CRC) ranks third globally in cancer-related mortality, with rising incidence, particularly in Asia, projecting a 60% surge by 2030. Metastatic CRC (mCRC) presents a significant challenge with a grim 5-year survival rate of 14%. Emerging evidence suggests that tumors with DNA mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H) respond well to immune checkpoint inhibitors (ICIs), marking a paradigm shift in therapeutic approaches. This systematic review and meta-analysis aim to comprehensively assess Pembrolizumab, Nivolumab, and the combination of Nivolumab and Ipilimumab in advanced CRC, considering their significant antitumor efficacy in MSI-H/dMMR mCRC. Methods Following PRISMA guidelines and Cochrane Handbook standards, this study covers 2014 to 2024, involving advanced CRC patients treated with ICIs. A comprehensive literature search employed 12 independent authors across eight databases. Parameters such as overall survival, progression-free survival, and objective response rate were extracted. The Cochrane Collaboration's Risk of Bias version 2 tool assessed risk. Statistical analysis utilized mean difference and risk ratios with random-effect models due to anticipated heterogeneity. Robustness was ensured through publication bias analysis and sensitivity meta-analysis. Linear regression explored associations in subgroup analysis. Results The meta-analysis evaluated ORR and OS across different immunotherapy interventions. Nivolumab, Nivolumab+Ipilimumab, and Pembrolizumab exhibited varying ORR and OS effect sizes with corresponding heterogeneity levels. Progression-free survival (PFS) analysis also showed diverse effect sizes and heterogeneity levels across the three interventions. The study provides a comprehensive overview of response rates and survival outcomes for these immunotherapies in advanced CRC. Conclusions The study concludes that combination immunotherapy, particularly Nivolumab and Ipilimumab, presents a promising avenue for advanced CRC treatment, showing superior efficacy. Pembrolizumab monotherapy also exhibited promise. While the study offers valuable insights, the identified heterogeneity emphasizes the need for additional research. Adverse effects were generally low, supporting the viability of the studied immunotherapies. The study acknowledges limitations and calls for ongoing investigation to refine and validate these findings, marking a pioneering effort in systematically comparing short-term and long-term effects of anti-CTLA-4 and anti-PD-1 therapies in CRC.