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Background & Aims: The study goal was to compare the outcomes of patients with intermediate-stage (Barcelona Clinic Liver Cancer [BCLC]-B) hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic therapy., Methods: A total of 358 patients with BCLC-B HCC treated with Atezo/Bev (n = 177) or LEN (n = 181) as first-line systemic therapy were included., Results: The median progression-free survival (PFS) times in the Atezo/Bev and LEN groups were 10.8 months (95% confidence interval [CI], 7.8-12.6) and 7.3 months (95% CI, 6.3-8.5), respectively (p = .019). In the propensity score-matched cohort, the median PFS times in the Atezo/Bev (n = 151) and LEN (n = 151) groups were 10.2 months (95% CI, 7.0-12.3) and 6.9 months (95% CI, 5.9-8.1), respectively (p = .020). Restricted mean survival times of PFS were significantly higher in the Atezo/Bev group than in the LEN group at landmarks of 12 and 18 months (p = .031 and .012, respectively). In a subgroup analysis of patients with HCC beyond the up-to-seven criteria, the median PFS times in the Atezo/Bev (n = 134) and LEN (n = 117) groups were 10.5 months (95% CI, 7.0-11.8) and 6.3 months (95% CI, 5.5-7.3), respectively (p = .044)., Conclusions: The use of Atezo/Bev as first-line systemic therapy in patients with BCLC-B HCC is expected to result in good PFS., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: This study aimed to investigate the safety and efficacy of lenvatinib in real-world settings, including patients excluded from the REFLECT trial, a phase III trial that compared lenvatinib with sorafenib., Patients and Methods: This multicenter, nonrandomized, open-label prospective study was conducted at 10 medical facilities in Japan (jRCTs031190017). Eligible patients had advanced hepatocellular carcinoma (HCC) and were suitable for lenvatinib therapy. The study included patients with high tumor burden (with >50% intrahepatic tumor volume, main portal vein invasion, or bile duct invasion), Child-Pugh B status, and receiving lenvatinib as second-line therapy following atezolizumab plus bevacizumab., Results: From December 2019 to September 2021, 59 patients were analyzed (47 and 12 patients with Child-Pugh A and B, respectively). In patients with Child-Pugh A, the frequency of aspartate aminotransferase elevation was high (72.7%) in the high-burden group. No other significant ad verse events (AE) were observed even in second-line treatment. However, patients with Child-Pugh B had high incidence of grade ≥3 AE (100.0%) and high discontinuation rates caused by AE (33.3%) compared with patients with Child-Pugh A (80.9% and 17.0%, respectively). Median progression-free survival was 6.4 and 2.5 months and median overall survival was 19.7 and 4.1 months in Child-Pugh A and B, respectively. Lenvatinib plasma concentration was higher in patients with Child-Pugh B on days 8 and 15 and correlated with dose modifications and lower relative dose intensity., Conclusions: Lenvatinib is safe and effective for advanced HCC in patients with Child-Pugh A, even with high tumor burden. However, it carries a higher risk of AE and may not provide adequate efficacy for patients with Child-Pugh B status., (©2023 American Association for Cancer Research.)

It was recently reported that hepatocellular carcinoma (HCC) patients with non-alcoholic steatohepatitis (NASH) are not responsive to immune-checkpoint inhibitor (ICI) treatment. The present study aimed to evaluate the therapeutic efficacy of lenvatinib in patients with non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC). Five hundred thirty u-HCC patients with Child-Pugh A were enrolled, and divided into the NAFLD/NASH (n = 103) and Viral/Alcohol (n = 427) groups. Clinical features were compared in a retrospective manner. Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P = 0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P = 0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated ALT (≥ 30 U/L) (HR 1.247, P = 0.029), modified ALBI grade 2b (HR 1.236, P = 0.047), elevated AFP (≥ 400 ng/mL) (HR 1.294, P = 0.014), and NAFLD/NASH etiology (HR 0.763, P = 0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.758, P = 0.092), whereas AFP (≥ 400 ng/mL) (HR 1.402, P = 0.009), BCLC C stage (HR 1.297, P = 0.035), later line use (HR 0.737, P = 0.014), and modified ALBI grade 2b (HR 1.875, P < 0.001) were significant. Lenvatinib can improve the prognosis of patients affected by u-HCC irrespective of HCC etiology or its line of treatment., (© 2021. The Author(s).)

Background and Aim: This study aimed to elucidate the clinical importance of muscle volume loss (pre-sarcopenia) in patients receiving lenvatinib as treatment for unresectable hepatocellular carcinoma (u-HCC)., Methods: Of 437 u-HCC patients treated with lenvatinib at specific institutions in Japan between March 2018 and May 2020, 151 with available computed tomography imaging data from the time of lenvatinib introduction were enrolled. Pre-sarcopenia was diagnosed based on a previously reported cut-off value calculation formula [psoas muscle area at level of middle of third lumbar vertebra (cm 2 )/height (m) 2 ]. Clinical features and prognostic factors for overall survival (OS) with inverse probability weighting were investigated retrospectively for their relationship with pre-sarcopenia., Results: Cox hazard multivariate analysis showed alpha-fetoprotein (≥400 ng/mL) (hazard ratio [HR] 2.271, P < 0.001), Barcelona Clinic Liver Cancer stage (C and D) (HR 1.625, P = 0.018), and positive for pre-sarcopenia (HR 1.652, P = 0.042) to be significant prognostic factors. OS rates for the pre-sarcopenia group (n = 41) were worse than those for the non-pre-sarcopenia group (n = 110) (0.5-, 1-, and 1.5-year OS: 72.5%, 27.9%, and 7.0% vs 80.7%, 56.7%, and 46.1%, respectively; P < 0.001), as was progression-free survival (P = 0.025). Time to stopping lenvatinib or disease progression was better in the non-pre-sarcopenia group (0.5-, 1-, and 1.5-year OS: 48.0%, 24.5%, and 8.4% vs 20.0%, 10.3%, and 4.2%, respectively; P < 0.001). Also, the frequency of the adverse event appetite loss (any grade) was greater in the pre-sarcopenia group (43.9% vs 18.2%, P = 0.003)., Conclusion: Pre-sarcopenia was shown to be a significant prognostic factor in patients treated with lenvatinib for u-HCC., (© 2020 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background/aim: We assessed suitable factors indicating newly developed lenvatinib (LEN) treatment for unresectable hepatocellular carcinoma (u-HCC) by investigating real-world clinical features of patients., Materials/methods: One hundred fifty two u-HCC patients, who receive LEN treatment from March to December 2018, were enrolled. (Child-Pugh score [CPS] 5/6/7/8 = 76/61/13/2, modified albumin-bilirubin grade [mALBI] 1/2a/2b/3 = 53/35/60/4). Clinical features were evaluated retrospectively., Results: Overall-response rate (ORR)/disease control rate (DCR) at 1 month after starting LEN were 38.7%/86.0%, respectively. Estimated median time to progression (TTP) was 7.0 months, while median survival time was not reached within the observation period. CPS (≥7) and past history of tyrosine-kinase inhibitor (TKI) were not significant prognostic factors. mALBI ≥2b was an only significant prognostic factor (HR 4.632, 95%CI 1.649-13.02, P = 0.004) in Cox-hazard multivariate analysis. In patients with Child-Pugh A, c-index/Akaike's information criterion (AIC) of prognostic predictive value of mALBI were superior to CPS (0.682/135.6 vs 0.652/138.7), while those of stopping LEN also showed that mALBI was better (0.575/447.3 vs 0.562/447.8). Additional analysis of patients with good mALBI (1/2a) revealed that time to stopping LEN was significantly shorter in those with the adverse event (AE) of appetite loss (any grade) than those without (P = 0.006) and body mass index (BMI) was also lower in patients with that AE (20.3 ± 3.0 vs 23.6 ± 4.0kg/m 2 , P < 0.001), while patients with a hand-foot skin reaction (any grade) showed good ORR/DCR (59.1%/86.4%) and longer TTP as compared to patients without (P = 0.007)., Conclusion: Good hepatic function (mALBI 1/2a) is the best indication for LEN, while potential appetite loss in association with low BMI should be kept in mind in such cases., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background/aim: Presently, there are no therapeutic options for unresectable hepatocellular carcinoma (u-HCC) patients who are intolerant to sorafenib or regorafenib failure. There have been no reports with detailed clinical findings of lenvatinib (LEN), a newly developed first-line tyrosine kinase inhibitor (TKI), obtained in real-world practice. We aimed to elucidate the therapeutic efficacy of LEN., Materials/methods: From March to August 2018, 105 u-HCC patients were treated with LEN. Following exclusion of those who started with a reduced LEN dose and/or had a short observation period (<2 weeks), 77 patients (72.0 ± 8.9 years, 59 males, 8 mg/12 mg = 49/28, Liver Cancer Study Group of Japan 6th [LCSGJ]-TNM stage II/III/IVa/IVb = 8/28/4/37, and American Joint Committee on Cancer/Union for International Cancer Control 8th [AJCC/UICC]-TNM stage IB:II:IIIA:IIIB:IVA:IVB = 2:27:6:5:9:28) were divided into two groups (TKI naïve [n = 33] and TKI experienced [n = 44], including 11 with regorafenib history). Therapeutic response was evaluated using mRECIST. Clinical data were retrospectively evaluated., Results: There were significant differences in age (74.6 ± 11.2 vs 70.0 ± 5.9 years, P = 0.040), LCSGJ-TNM (II:III:IVa:IVb = 8:12:1:12 vs 0:16:3:25, P = 0.006), and AJCC/UICC-TNM (IB:II:IIIA:IIIB:IVA:IVB = 2:17:1:1:4:8 vs 0:10:5:4:5:20, P = 0.028), while hepatic reserve function, adverse event (AE) profiles, and progression-free survival (89.7%/80.4% vs 90.5%/80.1%, P = 0.499) and overall survival (96.7%/96.7% vs 100%/92.3%, P = 0.769) after 4 and 12 weeks were not significantly different between the TKI-naïve and TKI-experienced groups. Overall response rate and disease control rate at 4 weeks (n = 52) were 38.5% and 80.8%, respectively, and 32.4% and 70.3%, respectively, at 12 weeks (n = 37). A significant decline in log10 AFP from the baseline to 4 weeks after introducing LEN was observed in patients with PR and SD (2.047 ± 1.148 vs 1.796 ± 1.179, P < 0.001)., Conclusion: Regardless of past TKI therapy, therapeutic response and AEs after introducing LEN were similar. LEN may be an important treatment for the present unmet need regarding TKI treatment against u-HCC., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background/aim: Lenvatinib (LEN) has been developed for the treatment of unresectable hepatocellular carcinoma (u-HCC). We aimed to elucidate the relative change in hepatic reserve function early following LEN treatment in affected patients., Materials/methods: From March 2018 to April 2019, 123 u-HCC patients (median age 71 years; male:female ratio 95:28; Child-Pugh score 5:6:7 = 65:50:8; modified albumin-bilirubin [mALBI] grade 1:2a:2b:3 = 44:28:50:1, Barcelona Clinic Liver Cancer stage A:B:C = 1:49:73) were enrolled. Relative changes in hepatic reserve function at 2 and 4 weeks after starting LEN were retrospectively evaluated., Results: The median survival was 11.3 months. The Child-Pugh score declined from the start to 4 weeks after commencing LEN (score 5:6:7:8:9:≥10 = 65:50:8:0:0:0 vs. 50:39:22:8:0:4, p < 0.001). A comparison among ALBI scores at the start of LEN and those at 2 and 4 weeks revealed significant relative changes (-2.36 ± 0.45 to -2.20 ± 0.49 at 2 weeks, -2.15 ± 0.50 at 4 weeks, p < 0.001, Bonferroni method), while there was no significant difference between those at 2 and 4 weeks (p= 0.210, Bonferroni method). Assessments of relative changes of ALBI score in patients divided by mALBI grade 1, 2a, and 2b or more showed a significant decline in score regardless of grade (-2.82 ± 0.17 to -2.53 ± 0.34, p < 0.001; -2.46 ± 0.10 to -2.31 ± 0.33, p = 0.017; and -1.90 ± 0.26 to -1.75 ± 0.42, p= 0.009, respectively)., Conclusion: Decline in hepatic function is common in the early stage (≤4 weeks, especially within 2 weeks) after introducing LEN. It is important to introduce molecular targeting agent drugs for u-HCC in patients with better hepatic function, who show transarterial catheter chemoembolization failure, as much as possible, along with consideration of the negative influence of LEN on the early response of hepatic function., (© 2019 S. Karger AG, Basel.)

Sorafenib, a multi-kinase inhibitor, inhibits tumor angiogenesis and is the first-line systemic therapy for patients with advanced hepatocellular carcinoma (HCC). However, due to its limited effects and frequent occurrence of side effects, biomarkers are needed to predict the effects of sorafenib. We considered the possibility of using TIE-2-expressing monocytes (TEMs) to predict the response in sorafenib-treated patients with advanced HCC. TEMs serve as a diagnostic marker of HCC and are related to angiogenesis. We analyzed 25 advanced HCC patients and prospectively evaluated TEMs before (Pre TEMs) and at 1 month after initial therapy (T1m TEMs). The radiologic response was evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Median survival time (MST) was significantly longer in the partial response/stable disease (PR/SD) group (21.8 months) than in the PD group (8.7 months). ΔTEMs (changes of T1m TEMs compared to Pre TEMs) were significantly lower in the PR/SD group than in the PD group. MST of the ΔTEMs low group (14.2 months) was significantly longer than that of the high group (8.7 months). Univariate and multivariate Cox regression analyses showed that ΔTEMs [hazard ratio (HR) = 8.53, 95% confidence interval (CI) = 1.51-48.16, p = 0.015] and Child-Pugh class (HR = 5.59, 95% CI = 1.06-29.63, p = 0.043) were independently associated with overall survival. Our results suggest that ΔTEMs could serve as a biomarker for predicting radiologic response and overall survival in sorafenib-treated patients with advanced HCC., (© 2017 UICC.)