Navanita Biswas, Shoja Rahimian
Background and Clinical Significance: Enfortumab vedotin combined with pembrolizumab has emerged as an effective first-line therapy for advanced urothelial carcinoma. While immune checkpoint inhibitors are associated with digestive tract toxicities, upper gastrointestinal involvement such as esophagitis remains rare, and its presentation in combination with enfortumab vedotin is not well characterized. Case Presentation: A 72-year-old man with metastatic urothelial carcinoma presented with generalized weakness, poor oral intake, odynophagia, dysphagia, anemia, and systemic symptoms following the second cycle of combination therapy of enfortumab vedotin and pembrolizumab. Endoscopic evaluation revealed diffuse circumferential ulcerative esophagitis involving the entire esophagus, with associated duodenitis. Infectious workup, including Clostridioides difficile, cytomegalovirus, and human immunodeficiency virus testing, was negative, and HSV-1 IgG was positive, consistent with prior exposure rather than active infection; however, tissue-based testing for active HSV infection was not performed. Lower gastrointestinal evaluation demonstrated nonspecific rectal inflammation. The patient was treated with high-dose intravenous corticosteroids (intravenous methylprednisolone 1 mg/kg/day) with rapid clinical improvement within 48-72 h, followed by a steroid taper and supportive care. Conclusions: This case represents a severe and diffuse manifestation of esophagitis associated with enfortumab vedotin and pembrolizumab therapy. While immune-mediated esophagitis is rare, the combination of antibody-drug conjugate therapy with immune checkpoint inhibition may contribute to synergistic mucosal injury. Early recognition and prompt initiation of immunosuppressive therapy are critical for favorable outcomes. Clinicians should be aware of severe esophagitis as a potential complication of enfortumab vedotin and pembrolizumab therapy. Timely diagnosis and management with corticosteroids can lead to rapid symptom resolution and may prevent serious complications.