Efficacy of Immune Checkpoint Blockade in Advanced Upper Tract Urothelial Cancer With DNA Mismatch Repair Deficiency or Microsatellite Instability.

Deficient DNA mismatch repair (dMMR) and microsatellite instability-high (MSI-H) status, which sensitizes tumors to immune checkpoint inhibitors (ICIs), is three times more common with upper tract urothelial carcinoma (UTUC) than with bladder cancer. However, data on ICI efficacy against dMMR/MSI-H advanced UTUC remain limited. We retrospectively reviewed records of 24 patients with dMMR/MSI-H advanced UTUC treated with single-agent ICIs at a single institution (2015-2024). Descriptive statistics and the Kaplan-Meier method for survival outcomes were used. Immunohistochemistry confirmed dMMR in 22 (92%) patients, with loss of MSH2 or MSH6 in 15 (68.2%) patients and loss of PMS2 or MLH1 in seven patients (31.8%). Germline mutation testing confirmed Lynch syndrome in 16 (67%) patients. ICI monotherapy was associated with a median progression-free survival (PFS) time of 65.9 months (95% CI, 31.6 months to nonevaluable [NE]). The PFS rates at 12 and 24 months were 95.2% (95% CI, 86.1% to 100.0%) and 78.8% (95% CI, 60.1% to 97.5%), respectively. At a median follow-up duration of 56.9 months (95% CI, 42.2 to 92.2 months), the median overall survival time was not reached (95% CI, 65.9 months to NE). The confirmed overall response rate was 83%, including 16 complete responses. Four (17%) patients were offered surgical consolidation with these pathologic outcomes: ypTaN0, ypT0N0, and ypT1N0 (two patients). Eight patients (33%) experienced grade ≥3 immune-related adverse events, including bullous pemphigoid (n = 3), hepatitis (n = 1), pancytopenia (n = 1), colitis (n = 1), polyendocrinopathy (n = 1), and polyarthritis with sarcoid-like reaction (n = 1). Our hypothesis-generating findings suggest that dMMR/MSI-H may serve as a biomarker of sensitivity to single-agent ICIs in advanced UTUC. External validation in larger, ideally prospective, studies is needed to confirm the effectiveness and durability of immune checkpoint blockade in this molecular subgroup.