Machine learning integrated explainable artificial intelligence in predicting toxicities of enfortumab vedotin in urothelial carcinoma: an exploratory study.

BACKGROUND: Enfortumab vedotin (EV) therapy for advanced urothelial carcinoma is limited by adverse events (AEs). Early identification of high-risk patients is needed. This proof-of-concept study evaluated whether machine learning (ML) with explainable AI (SHAP) could predict EV toxicities using real-world data. RESEARCH DESIGN AND METHODS: Data from 542 patients (51 centers, 24 countries) were analyzed. Six outcomes were predicted including grade 3-4 AEs. Four ML algorithms were trained on an 80% split and tested on 20%. Performance was evaluated via standard metrics with SHAP for interpretability. RESULTS: In this exploratory analyses, Random Forest achieved highest overall performance, yielding best AUC for diarrhea, severe AEs, and dose skipping. XGBoost led for cutaneous toxicity and diabetes; LASSO led for neuropathy (differences modest). Age was the most important associated variable, followed by prior immunotherapy and ECOG status. Liver metastases influenced diabetes and cutaneous toxicity; lung metastases impacted diarrhea, neuropathy, and skin toxicity. SHAP showed atezolizumab/nivolumab linked to lower cutaneous risk, and female sex to higher risk. CONCLUSION: These preliminary, hypothesis-generating findings suggest ML may predict EV-related toxicities, but single train-test split, small event counts, and lack of external validation preclude clinical use. Prospective validation is essential.