Background: In the United States (U.S.), lenvatinib monotherapy was approved in August 2018 for first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC) based on the pivotal trial, REFLECT. Treatment patterns in uHCC are evolving with recent approvals. The main objective of our real-world data (RWD) study was to assess treatment patterns and clinical effectiveness of lenvatinib among previously treated uHCC patients in U.S. clinical practices. Methods: A retrospective patient chart review study was conducted among U.S. adult patients (≥18 years) with uHCC and ECOG status of 0 or 1, who initiated lenvatinib monotherapy as second- or later-line systemic therapy between Aug 2018 and Sept 2019. Data were extracted from individual patients’ electronic health records and captured in electronic case report forms. Clinical outcomes assessed include provider-reported best response, progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated using Kaplan-Meier methods. For PFS, patients were censored at end of treatment or end of follow-up in case of ongoing treatment, while censoring occurred at end of follow-up for OS. Results: Of 164 patients, median age was 62 years, majority were male (72%), and most were Caucasian (56%) followed by African American (23%). The most common liver disease etiologies were alcohol-related (32%), hepatitis C (26%), non-alcoholic steatohepatitis (21%) and hepatitis B (15%). Only one-third (31%) had Child Pugh A cirrhosis, with nearly half (49%) having Child Pugh B cirrhosis. Most patients had Barcelona Clinic Liver Cancer Stage B (24%) or C (38%) disease. Median body weight was 77 kg, and the median starting dose of lenvatinib was 12 mg daily. Median duration of lenvatinib treatment was 6.9 months, with 43% of patients remaining on lenvatinib at end of follow-up. RECIST v1.1 was reported as the criteria used to assess response in 60% of patients. Provider-reported best response was complete response (CR):9%, partial response (PR):45% and stable disease (SD): 26%. Median PFS and median OS were estimated to be 12.5 months and 14.0 months respectively. At 6 and 12 months, landmark PFS was 71% and 52%, respectively and landmark OS was 84% and 58%, respectively. PFS and OS estimates were consistent in subgroup analyses among those who had received lenvatinib in the second-line (81%, n=133) or treated with lenvatinib post immunotherapy (66%, n=109) (Table). Conclusions: Results from this retrospective real-world study affirm the clinical effectiveness of lenvatinib monotherapy among previously treated uHCC patients, including those with prior immunotherapy.