S375 Determinants of Treatment Refractoriness in Immune-Mediated Diarrhea and Colitis Following Immune Checkpoint Inhibitor Therapy

Introduction: Immune checkpoint inhibitors (ICIs) can lead to immune-mediated diarrhea and colitis (IMDC), disrupting treatment continuity. First-line therapy includes ICI discontinuation and steroids for moderate to severe cases; however, a subset of patients, with pancolitis or endoscopic ulcerations, may develop refractory symptoms. Toxicity may recur in 35% of patients rechallenged ICIs, despite initial response. Selective immunosuppressive therapy (SIT) with infliximab (IFX) or vedolizumab (VDZ) is often required. This study aims to identify risk factors associated with IMDC refractoriness to SIT. Methods: In this international, retrospective study across 10 centers, 879 IMDC patients were categorized into 2 groups: responders to steroids or to subsequent SIT, and non-responders to both steroids and initial SIT agent. Treatment failure was defined as lack of ≥1-grade Common Terminology Criteria for Adverse Events (CTCAE) improvement after first SIT infusion, steroid escalation, or SIT switch for persistent symptoms. Cases with SIT change due to insurance or adverse effects were excluded. Results: Among 879 patients, 60% were male and 93% White. Treatment regimens included anti-PD-1/L1 (43.9%), anti-CTLA-4 (16.5%) and combined therapy (39.6%). Significant factors associated with refractoriness to SIT included: combined ICI regimen (odds ratio [OR]: 1.7, confidence interval [CI]: 1.2-2.4, P = 0.001), concurrent gastrointestinal adverse events [AEs] (OR: 2.1, CI: 1.4-3.4, P = 0.001), diarrhea CTCAE grade ≥2 (OR: 3.4, CI: 1.8-6.5, P < 0.0001) and colitis CTCAE grade ≥2 (OR: 6.5, CI: 4.2-10, P < 0.0001), longer steroid duration (OR: 1.02, CI: 1.0-1.03, P = 0.014), multiple steroid tapers attempts (OR: 1.7, CI: 1.4-2.0, P < 0.0001), initial use IFX (OR: 2.3, CI: 1.5-3.3, P < 0.0001), ulcerative features on colonoscopy (OR: 1.7, CI: 1.1-2.5, P = 0.006), acute histologic findings (OR: 1.7, CI: 1.1-2.4, P = 0.005), positive lactoferrin (OR: 2.0, CI: 1.2-3.8, P = 0.017), and elevated calprotectin (OR: 1.0, CI: 1.0-1.0, P < 0.0001). Protective factors included initial anti-CTLA-4 therapy (OR: 0.2, CI: 0.1-0.5, P < 0.0001), initial VDZ use (OR: 0.4, CI: 0.2-0.6, P < 0.0001), normal endoscopy (OR: 0.3, CI: 0.2-0.6, P < 0.0001) and histology (OR: 0.4, CI: 0.2-0.7, P = 0.006). Conclusion: This is the first multi-center study to identify risk factors for IMDC refractoriness. Severe clinical, endoscopic, or histologic features may warrant early escalation or switch of SITs and/or alternative therapies such as fecal microbiota transplantation. Patients with mild disease or lack of objective inflammation may respond adequately to steroids.