S445 Severe Colitis in BRAF/MEK Inhibitor Therapy and the Effect of Prior Immune Checkpoint Inhibitor Use: A Case Series and Systematic Review

Introduction: BRAF/MEK inhibitors (BRAF/MEKi) are used as first- or second-line therapy for metastatic melanoma and non-small cell lung cancer (NSCLC). While mild gastrointestinal (GI) side effects are common, severe GI toxicity such as colitis is rare and primarily reported in patients with prior immune checkpoint inhibitor (ICI) exposure. We present 2 cases of severe BRAF/MEKi-associated colitis without prior ICI use and conduct a systematic review to characterize this entity and compare ICI-exposed and non-ICI cases. Methods: Following PRISMA guidelines, PubMed, EMBASE, and Web of Science were searched from inception to November 2024. Two reviewers independently extracted and summarized data. In case 1, a 62-year-old man with NSCLC on BRAF/MEKi for 3 months developed diarrhea with hematochezia. Colonoscopy revealed 2 large ileocecal valve (ICV) ulcers with stenosis and erosions, most severe in the right colon and rectum. Biopsy showed eosinophilic infiltration and mucosal ulceration. Symptoms resolved within a week of drug discontinuation; BRAFi was resumed at half dose without recurrence. In case 2, a 69-year-old man with NSCLC on BRAF/MEKi for 3 months developed diarrhea and hematochezia. Colonoscopy showed ulcerated ICV and pan-colonic mucosa. Biopsy revealed active colitis with neutrophil infiltration and focal cryptitis. Symptoms improved after stopping BRAF/MEKi. Results: Eight studies including 22 patients were identified. Mean age was 65; 91% had melanoma. Colitis occurred significantly later in ICI-exposed patients (6.3 vs 2.5 months, P= 0.025). Right-sided colitis predominated (91%), with 59% isolated to the right colon and 45% involving the ICV. Discontinuation of BRAF/MEKi led to symptom resolution in 94%, while steroids (0/7) and biologics (0/4) were ineffective; 2 patients required surgery. Among those re-challenged, relapse occurred in 60%; however, no relapse was seen in 4 patients continued or resumed on BRAFi monotherapy. Conclusion: Severe BRAF/MEKi colitis is a distinct entity marked by ulcerative, right-predominant inflammation, often involving the ICV. MEK inhibition likely disrupts the non-immune-mediated MAPK pathway, essential for GI epithelial survival, leading to mucosal injury. Optimal management involves drug cessation; immunosuppressive therapy is often ineffective. ICI-exposed patients typically present later and fare worse, possibly due to misdiagnosis as ICI colitis and delayed discontinuation of BRAF/MEKi.