Combination of nivolumab plus ipilimumab in microsatellite instability-high metastatic colorectal cancer: A systematic review and meta-analysis.

Abstract

e15516 Background: Approximately 4-5% of patients with metastatic colorectal cancer (mCRC) exhibit tumors with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). Conventional chemotherapy, with or without targeted therapies, is largely ineffective for this subset of patients. However, in randomized controlled trials, the combination of nivolumab and ipilimumab has shown significant therapeutic benefits in treating MSI-H metastatic colorectal cancer, offering promising treatment options for this challenging patient group. Methods: PubMed, Embase, Cochrane, and ClinicalTrials.gov databases were systematically searched using relevant keywords from inception until December 2024. Outcomes were reported as disease control rate (DCR), progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and complete response rate (CRR). Statistical calculations were performed using Review Manager 5.4.1 (The Cochrane Collaboration, Copenhagen, Denmark), with a p-value of < 0.05 indicating statistical significance. Interstudy heterogeneity was assessed using I² and X² statistics (I²>50%=significant heterogeneity). Results: Three trials yielded 479 patients, of which 378 received nivolumab plus ipilimumab combination therapy. At a median follow-up of 31.5 months, progression-free survival was significantly better with nivolumab plus ipilimumab than with chemotherapy; the combined PFS Hazard Ratio (HR) was 0.676 (95% CI: 0.583–0.770). Regarding disease progression, the overall analysis showed a pooled estimate of 0.177 (95% CI: 0.000- 0.353), demonstrating a significant reduction in the risk of disease progression. The overall response rate was 0.631 (95% CI: 0.560- 0.702) and showed no significant heterogeneity (I 2 =0%). The pooled analysis of the disease control rate showed a combined estimate of 0.849 (95% CI: 0.763–0.935), but a significant heterogeneity was observed (I 2 =61.76%). While reporting any grade adverse effects, the total estimate was 0.828 (95% CI: 0.790, 0.866) with no significant heterogeneity (I 2 =0%). The pooled analysis of Grade 3-5 adverse effects yielded an overall estimate of 0.273 (95% CI: 0.212-0.334). Conclusions: In comparison to chemotherapy, the combination of nivolumab and ipilimumab significantly improved progression-free survival in patients who had previously undergone systemic therapy. The overall survival was 31.5 months with the combination treatment, and both the response rate and disease control rate were higher. While side effects were common, their overall incidence was manageable. However, further studies with larger sample sizes are needed to provide conclusive evidence.