Immune checkpoint inhibitors (ICIs) in advanced upper tract urothelial cancer (UTUC) with mismatch repair deficiency (dMMR) or microsatellite instability (MSI).
Authors: Mohammad Jad Moussa, Alexander Andreev-Drakhlin, Amishi Yogesh Shah, Surena F. Matin, Ana Cecilia Adriazola, Leah Shaw, Marihella L. Campbell, Pavlos Msaouel, Paul Gettys Corn, John Kent Lin, Sangeeta Goswami, Jianjun Gao, Charles C. Guo, Nizar M. Tannir, Arlene O. Siefker-Radtke, Omar Alhalabi, Matthew T. Campbell
Journal: Journal of Clinical Oncology (2025)

818 Background: MSI-high (MSI-H) and dMMR are three times more common in UTUC than bladder cancer. While these features enhance ICI sensitivity in solid tumors, data on ICIs in advanced UTUC with dMMR/MSI-H remain scarce. Methods: We retrospectively reviewed records of patients (pts) with locally advanced (LA) or metastatic with dMMR/MSI-H UTUC treated with ICIs at MD Anderson (2015-2024). Descriptive statistics and the Kaplan-Meier method were used. Results: Twenty-four pts with LA/unresectable (n=8) or metastatic (n=16) disease were treated with ICIs (pembrolizumab, n=17; nivolumab, n=4; atezolizumab, n=3) (Table). Tumor origin was the ureter (10, 41.7%) or renal pelvis (14, 58.3%). Twenty-two (91.7%) pts had Lynch syndrome, mostly (n=20) detected by germline mutation testing ( MSH2 , n=12; MLH1 , n=5; MSH6 , n=3).Twenty-one (87.5%) pts had IHC-proven dMMR(MSH2/MSH6 loss, n=7; PMS2/MLH1 loss, n=5; MLH1 loss, n=4; MSH2 loss , n=3; MSH6 loss, n=3). The most frequent alterations in somatic genetic testing for 22 pts were MSH2 (12 pts), CREBBP (7 pts), ARID1A (7 pts) and NOTCH3 (7 pts). Fourteen (58.3%) pts received prior platinum chemotherapy: cisplatin (n=9) or carboplatin-based (n=5), with only 35.7% showing responses (one complete response [CR] and 4 partial responses [PR]).With a median follow-up of 54.3 months (mo) [95% CI: 19.5 – 87.1], median PFS was 55.8 mo [95% CI: 19.4 – NE]. Milestone PFS probabilities at 12 and 24 mo were 90.7% [95% CI: 79.2% – 1%] and69.2% [95% CI: 51.3% – 93.4%], respectively.At a median follow-up of 51.3 mo [95% CI: 34 – 60.2], median OS was not reached. Median time on treatment was 13.5 mo [IQR: 4 – 25.8]. Eight (33.3%) pts remain progression-free beyond 4 years. ORR was 79.2%, including 16 CR (66.7%) and 3 PR (12.5%), while DCR was 95.8%.Median time to best response was 11.9 mo [IQR: 5.6 – 20]. Four (16.7%) pts were offered surgical consolidation with these outcomes: ypTaN0M0, ypT0N0M0, ypT1N0M0 and mypT1N0 M1-NED. Grade ≥3 immune-mediated toxicity events leading to ICI discontinuation (n=6) included hepatitis (n=3), pancytopenia (n=1), polyendocrinopathy (n=1) and diarrhea (n=1). Conclusions: Single-agentICIs show remarkable efficacy and durable responses in advanced dMMR/MSI-H UTUC, with one-third of pts remaining in remission after over 4 years. Our findings support dMMR/MSI-H as a predictive and prognostic biomarker in UTUC and the use of single-agent ICIs in this subpopulation. Variable Measure Age at dx of advanced disease, median [ICR] 66 [55.8 – 72.3] Sex, male (n, %) 14 (58.3%) Race/Ethnicity, n (%) White 19 (79.2%) Black 1 (4.2%) Hispanic 2 (8.3%) Asian 2 (8.3%) Urothelial carcinoma mixed with variant histology, n (%) 3 (12.5%) Liver mets at ICI start, n (%) 2 (8.3%) Bone mets at ICI start, n (%) 5 (20.8%) Hemoglobin &lt;10 g/dL at ICI start, n (%) 5 (20.8%) Bellmunt score, n (%) 0-1 19 (79.2%) 2 3 (12.5%) 3 2 (8.3%)