Microsatellite instability (MSI-H) in metastatic urothelial carcinoma (mUC): A biomarker of divergent responses to systemic therapy.

Abstract

566 Background: MSI frequently arises from deficiencies in mismatch repair mechanisms (dMMR) and are associated with higher response rates to anti-PD1/PDL1 checkpoint inhibitors (CPI) in different cancer types, including mUC (Iyer et al, ASCO 2017). Here, we sought to (1) assess the platinum-based chemotherapy response in MSI-H mUC, and (2) present an updated analysis of CPI response in MSI-H mUC from a database of > 1000 sequenced UC. Methods: From an institutional database of UC tumors genomically characterized using the MSK-IMPACT assay, we identified tumors with high MSIsensor score > 10 (MSI-H) for in-depth analysis. MSIsensor has been shown to correlate strongly with MSI status (Middha et al, JCO Precis Oncol 2017). Patient and disease characteristics, as well as response to (1) platinum-based chemotherapy and (2) CPI were analyzed. Results: A total of 1,333 UC from 1,194 pts were sequenced. 26 pts (2%) had an MSI score > 10. Of these, 20 (77%) were male, 17 (65%) were current or former smokers, and 20 (77%) had upper tract UC. 23/26 pts had alterations in MMR genes (MSH2, n = 15; MLH1, n = 6; MSH6 and PMS2, n = 1), 18 of which underwent germline testing which was positive in 14 cases (78%). 10/26 MSI-H patients developed metastatic UC. Six received first-line platinum-based chemotherapy with median PFS of 2.6 months, four with primary progressive disease. Ten patients received CPI in the mUC setting, two of them in combination with non-CTLA4 agents, six as second or third-line therapies, two following recurrence of disease within 12 months of peri-operative chemotherapy, and two as first line therapy. With a median follow-up of 24.3 months, PFS rate was 90% and 77% at 12 and 24 months, respectively, with near-complete or complete response in 9 patients. Conclusions: MSI-H status in UC predicts deep and durable responses to CPI and is associated with inferior chemotherapy responses. CPI should be considered for first-line treatment in this subset of patients. Pts with somatic MSI-H bladder or upper tract UC should be offered genetic testing for Lynch syndrome.