Background: Lenvatinib (Len) is a multikinase inhibitor targeting VEGFR 1-3, FGFR 1-4 and other kinases. Pembrolizumab (Pem) and nivolumab (Nivo) are antibodies inhibiting programmed cell death 1 (PD-1) and reactivate T-cell cytotoxic effect. Len plus PD-1 inhibitors have shown promising results in treating various solid tumors. The role of this combination in ICC is undefined. Methods: 14 ICC pts (median age 49 years, range 34-68; 7 males and 7 females) with treatment of enrolled in a single center, observational study of Len plus Pem/Nivo. Objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were measured according to RECIST 1.1. Next generation sequencing (NGS) with deep coverage on 450 cancer genes and whole exome sequencing were performed in 7 pts to detect all classes of genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI) status. Results: All 14 pts had > = 2 prior anticancer therapy with clinical stage IV. ORR was 21.4% with 3 pts achieved partial response (PR), DCR was 92.9% and clinical benefit rate (ORR + durable stable disease > = 5 months) was 64.3%. Median PFS was 5.9 months (95% CI: 4.2-6.2). The most common adverse events (AEs) included hypertension, aminotransferase elevation and fatigue. The grade-3 AEs were occurred at 14% while no grade-4 AE was observed. The most altered genes in the 7 sequenced tumors were IDH1 (3 pts), ARID1A (3 pts), PIK3CA (3 pts), TP53 (2 pts) and BAP1 (2 pts). 4 out of the 7 pts had high TMB ( > 12 mut/Mb) and all responded to Len plus Pem/Nivo with 2 PR. One pt with low TMB and FGFR2 mutation had a response of 27% decreased target lesion. Two low TMB pts were progressed, including one with FGFR2 rearrangement. A responder harbored a 399 bp deletion on MLH1, and was identified as MSI-H. More data will be presented. Conclusions: Our study preliminarily indicates that combining Len with PD-1 inhibitors results in promising efficacy in advanced ICC. High TMB from 450-gene NGS panel was strongly associated with a better therapeutic response.