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.
JCO precision oncology. 2026 Mar 30 [Epub]
Mohammad Jad Moussa, Alexander Y Andreev-Drakhlin, Aradhana M Venkatesan, Surena F Matin, Lianchun Xiao, Rebecca S S Tidwell, Amishi Y Shah, Ana C Adriazola, Leah Shaw, Jianjun Gao, John K Lin, Sangeeta Goswami, Pavlos Msaouel, Charles C Guo, Nizar M Tannir, Arlene O Siefker-Radtke, Omar Alhalabi, Matthew T Campbell
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX., Genentech, South San Francisco, CA., Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX., Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX., Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX., Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX., Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.