Efficacy and safety of immune checkpoint inhibitors in colorectal cancer: A network meta-analysis of randomized controlled trials.

Abstract

170 Background: Colorectal cancer (CRC) remains a leading cause of cancer mortality, with limited survival in advanced disease. Immune checkpoint inhibitors (ICIs), targeting PD-1, PD-L1, and CTLA-4 pathways, have emerged as promising therapeutic strategies. Comparative data across regimens are limited. Methods: We performed a systematic review and network meta-analysis (NMA) following PRISMA-NMA guidelines. PubMed, Embase, Scopus, and ClinicalTrials.gov were searched from inception through 2024. Eligible randomized controlled trials (RCTs) included patients with CRC treated with PD-1, PD-L1, or CTLA-4 inhibitors, alone or in combination, compared against standard therapy or placebo. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes included objective response rate (ORR) and treatment-related adverse events (AEs). Hazard ratios (HRs) were pooled for time-to-event outcomes and odds ratios (ORs) for binary outcomes using a frequentist random- effects NMA. Heterogeneity was assessed using T ² , and inconsistency was tested with design-by- treatment interaction models. Results: Nineteen RCTs enrolling 3,488 patients were included. For OS, PD-1 inhibitors showed a significant survival benefit compared with standard therapy (HR 0.80, 95% CI 0.68–0.94, p=0.0068). For PFS, PD-1 plus CTLA-4 combination demonstrated the greatest benefit (HR 0.43, 95% CI 0.33–0.56, p<0.0001), while PD-1 monotherapy also improved outcomes (HR 0.67, 95% CI 0.58–0.78, p<0.0001). ORR was highest with PD-1 plus CTLA-4 therapy (OR 3.89, 95% CI 1.72–8.81, p=0.0011), followed by PD-1 monotherapy (OR 2.20, 95% CI 1.35–3.60, p=0.0015). Safety analysis showed increased grade 3–4 AEs with PD-L1 plus CTLA-4 combinations (OR 7.12, 95% CI 0.99–51.16, p=0.051), while PD-L1 monotherapy had the most favorable AE profile (OR 0.81, 95% CI 0.33–1.98, p=0.6502). Heterogeneity and inconsistency tests indicated acceptable model fit. Conclusions: This NMA suggests that PD-1 inhibitors provide the greatest overall survival benefit in CRC, while PD-1 plus CTLA-4 combinations maximize PFS and response rates at the cost of higher toxicity. PD-L1 monotherapy demonstrated the best tolerability with modest efficacy. These findings highlight the importance of balancing efficacy with safety when selecting ICIs for CRC.