4594 Background: Lenvatinib (LEN) has been used in patients with unresectable hepatocellular carcinoma (u-HCC) and there is no established predictive biomarker. Previously it was reported that a plasma vascular endothelial growth factor (VEGF) concentration decrease at 8 weeks after starting sorafenib might predict favorable overall survival (OS) in patients with u-HCC (Tsuchiya, et al. Cancer, 2013). We aimed to investigate the value of changes in plasma VEGF at 8 weeks after LEN administration in patients with u-HCC. Methods: Forty-six patients with u-HCC who received LEN between April 2018 and August 2019 at our institution were enrolled. Plasma concentrations of VEGF and serum α-fetoprotein (AFP) levels were measured at baseline, 4 and 8 weeks after administration of LEN. A VEGF decrease was defined as > 5% decrease during 8 weeks after the beginning of LEN therapy. AFP response was defined as > 20% decrease during 8 weeks according to the previous reports. Results: Median overall survival (OS) was not reached and progression-free survival (PFS) was 5.9 months. Median observation period and treatment duration were 10.1 and 6.3 months. The objective response rate and disease control rate by mRECIST criteria were 43.5% and 82.6%. Median PFS in patients who had a VEGF decrease at week 8 (n = 29) was significantly longer than those who did not have a VEGF decrease (n = 17; 7.1 months vs 5.0 months; p = 0.014). AFP response was not associated with PFS. There were no significant differences in baseline VEGF, AFP, ALBI score, and extrahepatic metastasis between the patients with and without a VEGF decrease. A VEGF decrease was significantly associated with radiological objective response (p = 0.001) and 18 of 20 patients who achieved CR (n = 3) or PR (n = 17) had a VEGF response in LEN therapy. Conclusions: A decrease of plasma VEGF level at 8 weeks in patients with u-HCC on LEN was significantly associated with PFS. Changes in plasma VEGF could become a new biomarker for molecular targeted therapies including VEGF inhibitors in patients with unresectable HCC.