Real-world outcomes of microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) biliary tract cancers (BTC).

4128 Background: Immune checkpoint inhibitors have revolutionized the treatment of microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) cancers. MSI-H/dMMR represents a rare molecular subset (1%) within biliary tract cancers (BTC). The role of immunotherapy alone remains unknown. We investigated clinical features, treatment outcomes, and genomic characteristics of MSI-H/dMMR BTCs in two real world cohorts. Methods: Multicenter retrospective study of BTC patients with MSI-H/dMMR status by immunohistochemistry (IHC) and/or PCR. Patients were from two independent cohorts: MD Anderson Cancer Center (MDACC) and the RETUD registry of the Spanish Cooperative Group for Digestive Tumor Therapy (TTD) group. Results: 46 patients with MSI-H BTC were included in this study; with 21 from MDACC and 25 patients from TTD Cohort. Median age 46 years (95% CI38-80), (35 (76.1%) had intrahepatic cholangiocarcinoma 8 (17.4%) had extrahepatic cholangiocarcinoma and 3 (6.5%) had gallbladder cancer. Patient characteristics are summarized in Table 1. The median OS was 24.4 months (95% CI: 19.9, 40.6). The median follow-up time was 50.2 months (95% CI: 36.2, NA). Thirty-one (68.9%) patients received immunotherapy as part of their treatment course, and 14 (31.1%) did not. For first-line therapy (n=40), the median progression-free survival (PFS) for chemotherapy was 3.19 months (95% CI: 2.56-6.6) and for immunotherapy alone was not reached (95% CI: 8.25-NR, p=0.0006), while among those receiving second-line therapy (n=21), the median PFS for chemotherapy was 4.04 months (95% CI: 2.73-NR) and for immunotherapy alone was 9.69 months (95% CI: 4.43-NR, p=0.044). The median OS was 24.7 months (95% CI: 19.91, NA) in patients with IO, and 19.1 months (95% CI: 13.83, NA) without IO (log rank test p value = 0.085). Conclusions: MSI-H/dMMR BTC patients may derive limited benefit with frontline chemotherapy. Immune checkpoint inhibition may drive durable disease control, supporting early dMMR/MSI-H testing to optimize treatment. Summary of patient characteristics. Covariate N (%) Gender F 18(39.1%) M 28(60.9%) Race Asian 2(4.3%) Black 1(2.2%) White/Caucasian 43(93.5%) Grade G2:Moderately differentiated 8(42.1%) G3:Poorly differentiated 11(57.9%) Stage >II 33(71.7%) I-II 13(28.3%) Mismatch Repair Gene Loss MLH1 5(12.2%) MLH1,MSH6 3(7.3%) MLH1,PMS2 20(48.8%) MLH1,PMS2,MSH6 1(2.4%) MSH2,MSH6 7(17.1%) MSH6 1(2.4%) PMS2 4(9.8%) Resectable at Diagnosis No 27(58.7%) Yes 19(41.3%)