Tumor Mutational Burden Predicts the Outcome of Patients With Muscle-invasive bladder Cancer Undergoing Immune-checkpoint Inhibitor-Based Neoadjuvant Therapy

Introduction: Immune checkpoint inhibitors (ICI) have demonstrated meaningful activity as neoadjuvant therapy in muscle-invasive bladder cancer (MIBC). Identifying patients most likely to respond to ICI-based neoadjuvant strategies remains an unmet need. Materials and methods: Tumor mutational burden (TMB) from baseline transurethral resection of bladder (TURB) tumor samples of MIBC patients treated with neoadjuvant ICI across PURE-01 (NCT02736266), SURE-02 (NCT05535218), and NURE-Combo (NCT04876313) trials was analyzed. Probabilities of complete response ( CR; yT0N0‑x at radical cystectomy or re-TURB tumor), event‑free survival, and overall survival were assessed across different TMB cutoffs. Logistic regression models evaluated predictors of CR. Results: 202 patients (85% male, median age 66) were included. 57% had cT2 disease. Median TMB was 10.5 mut/Mb; 88 patients (44%) achieved CR. Optimal TMB threshold for CR was 13 mut/Mb with a predicted probability (PP) of 43% (95% confidence interval [CI]: 36.6-50.6); higher TMB showed incremental PP. At TMB ≥ 20 threshold, PP was 54% (95% CI: 43.7-63.1), with significant association with CR at multivariable analysis (AUC: 0.65). No significant effect by therapeutic regimen was observed. With a median follow-up of 63 months (interquartile range 25-77), 60m-event‑free survival for TMB ≥ 20 pts was 97% (95% CI: 90.4-100) versus 73% (95% CI: 65.6-80.7), P=0.03, and 60m-overall survival was 100% versus 78.8% (95% CI: 71.9-86.4), P = .01. Conclusions: Our analysis support TMB as a clinically informative biomarker in MIBC patients treated with neoadjuvant ICI, identifying a subset of exceptional responders associated with higher TMB levels.