Systematic review and adjusted indirect comparison of first-line immune checkpoint inhibitors in metastatic colorectal cancer.

Abstract

Objectives: To evaluate the efficacy and safety of immune checkpoint inhibitors in the first-line treatment of microsatellite instability or mismatch repair-deficient metastatic colorectal cancer through a systematic review and adjusted indirect comparison, determining whether they are equivalent therapeutic alternatives.

Methods: A systematic literature search was conducted in PubMed and Embase following PRISMA 2020 recommendations. Phase III randomized controlled trials evaluating immune checkpoint inhibitors in microsatellite instability or mismatch repair-deficient metastatic colorectal cancer were eligible. Efficacy was assessed using Bucher's adjusted indirect comparison method, with progression-free survival as the primary endpoint. Therapeutic equivalence was evaluated according to the Equivalent Therapeutic Alternatives framework, applying a non-inferiority margin (Δ) of 0.65. Safety outcomes included overall and treatment-related adverse events, immune-related adverse events, discontinuations due to adverse events and grade 5 events.

Results: NI demonstrated a higher probability of superior efficacy over pembrolizumab, with an adjusted Hazard Ratio of 0.53 (95%CI 0.34 to 0.84) for progression-free survival, exceeding the equivalence margin. Thus, pembrolizumab and nivolumab+ipilimumab cannot be considered Equivalent Therapeutic Alternatives regarding efficacy. In terms of safety, nivolumab+ipilimumab was associated with fewer treatment-related grade ≥ 3 adverse events but higher rates of treatment discontinuation and immune-related adverse events compared to pembrolizumab.

Discussion: Nivolumab+ipilimumab appears to offer greater efficacy than pembrolizumab in first-line treatment of microsatellite instability or mismatch repair-deficient metastatic colorectal cancer, but with a distinct safety profile. Based on current interim data, these agents should not be regarded as equivalent therapeutic alternatives. Further data, including final efficacy analyses and quality-of-life assessments, are warranted to guide optimal treatment selection.