Supplementary Material for: REal life study of LEnVAtiNib therapy for HepAtocellular carcinoma: RELEVANT study

Introduction: In the REFLECT trial, lenvatinib was found to be non-inferior compared to sorafenib in terms of Overall Survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world, and to identify clinical factors that could be significantly associated with survival outcomes. Methods: The study population derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included Western and Eastern populations from 23 centres in five countries. Results: We included 1325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3 and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH related aetiology was independently associated with good prognosis. Median progression free survival was 6.3 months. Multivariate analysis for Progression Free survival revealed that NAFLD/NASH, BCLC, NLR and AST as independent prognostic factors for progression free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited that the appearance of decreased appetite Grade ≥ 2 versus Grade 0-1 as an independent prognostic factor for worse Progression Free Survival. 924 patients on 1325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over two-months from the beginning of second line treatment. From first line therapy the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months) and best supportive care (10.8 months). Conclusions: Our study confirms in a large and global population of patients with advanced HCC not candidate to locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.