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Aim: We evaluated the safety and efficacy of vascular endothelial growth factor receptor (VEGFR)‐targeted peptide vaccines for the immunization of patients with unresectable hepatocellular carcinoma (HCC) who had responded to transarterial chemoembolization. Methods: Twenty‐two patients were randomized 1:1 to receive VEGFR‐targeted peptides or placebo. The primary end‐point was the safety assessment of the immunization. The secondary end‐points were evaluation of immunological responses and clinical outcomes. Results: No severe adverse events were induced by the study agents. Among the 12 patients in the vaccine group, a VEGFR1‐specific cytotoxic T lymphocyte (CTL) response was induced in eight (66.7%) patients and a VEGFR2‐specific CTL response was induced in 10 (83.3%). The median progression‐free survival (PFS) and overall survival (OS) rates were 4.8 and 52.0 months, respectively, in the vaccine group, and 2.7 and 21.8 months, respectively, in the placebo group. No statistically significant differences were found between the two groups (PFS p = 0.925, OS p = 0.190). When divided into two groups according to immunoreactivity, the median PFS of patients with and without a strong immune response to VEGFR1 were 7.4 and 2.7 months, and that to VEGFR2 were 10.6 and 2.7 months, respectively; there were significant differences according to the immune response. Conclusions: Immunotherapy with peptide vaccines targeting VEGFR1 and VEGFR2 was well tolerated with no serious adverse events. It also effectively induced peptide‐specific CTLs in patients with unresectable HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: We aimed to evaluate the impact of therapeutic modifications of atezolizumab (Atezo) plus bevacizumab (Bev) therapy (Atezo/Bev) in the case of intolerable adverse events on the prognosis of patients with unresectable hepatocellular carcinoma. Therapeutic modifications included the interruption or discontinuation of both Atezo and Bev, and the reduction, interruption, or discontinuation of Bev alone. Patients with therapeutic modifications other than the discontinuation of both Atezo and Bev had favorable overall survival and time to progression. In contrast, those with the discontinuation of both Atezo and Bev without other therapeutic modifications were associated with unfavorable overall survival and time to progression. Modified albumin–bilirubin grade 2b liver function at the initiation of Atezo/Bev or experience of immune-related adverse events could increase the risk of discontinuation of both Atezo and Bev without other therapeutic modifications. Avoiding the discontinuation of both Atezo and Bev without other therapeutic modifications may be the optimal management of unresectable hepatocellular carcinoma. We retrospectively evaluated the impact of therapeutic modifications of atezolizumab (Atezo) plus bevacizumab (Bev) therapy (Atezo/Bev), including the interruption or discontinuation of both Atezo and Bev, and the reduction or discontinuation of Bev, on the outcome of patients with unresectable hepatocellular carcinoma (uHCC) (median observation period: 9.40 months). One hundred uHCC from five hospitals were included. Therapeutic modifications without discontinuation of both Atezo and Bev (n = 46) were associated with favorable overall survival (median not reached; hazard ratio (HR): 0.23) and time to progression (median: 10.00 months; HR: 0.23) with no therapeutic modification defined as the reference. In contrast, the discontinuation of both Atezo and Bev without other therapeutic modifications (n = 20) was associated with unfavorable overall survival (median: 9.63 months; HR: 2.72) and time to progression (median: 2.53 months; HR: 2.78). Patients with modified albumin–bilirubin grade 2b liver function (n = 43) or immune-related adverse events (irAEs) (n = 31) discontinued both Atezo and Bev without other therapeutic modifications more frequently (30.2% and 35.5%, respectively) than those with modified albumin–bilirubin grade 1 (10.2%) and without irAEs (13.0%). Patients with objective response (n = 48) experienced irAEs more frequently (n = 21) than those without (n = 10) (p = 0.027). Avoiding the discontinuation of both Atezo and Bev without other therapeutic modifications may be the optimal management of uHCC. [ABSTRACT FROM AUTHOR]

Advanced hepatocellular carcinoma (HCC) remains a highly lethal malignancy, although several systemic therapeutic options are available, including sorafenib (SFN), which has been one of the standard treatment agents for almost a decade. As early prediction of response to SFN remains challenging, biomarkers that enable early prediction using a clinically feasible method are needed. Here, we report that the serum secretory form of clusterin (sCLU) protein and its related predictive index are potential beneficial biomarkers for early prediction of SFN response. Using high‐throughput screening and subsequent multivariate analysis in the derivation cohort, we found that changes in the concentrations of CLU, vascular cell adhesion molecule‐1 (VCAM1), and α‐fetoprotein were significantly associated with response to SFN. Furthermore, we confirmed that an increase in CLU serum level 1 month after treatment initiation was significantly associated with shorter progression‐free survival. In addition, "NR‐index," which comprises these proteins, was evaluated as a tool for accurately predicting the efficacy of SFN and confirmed in the validation cohort. We also established SFN‐resistant HepG2 cells (HepG2‐SR) and found that sCLU significantly increased in HepG2‐SR cells compared with normal HepG2 cells, and confirmed that HepG2‐SR cells treated with SFN were resistant to apoptosis. The mechanism underlying activation of sCLU expression in acquired SFN resistance involves aberrant signaling and expression of Akt, mammalian target of rapamycin (mTOR), and a nutrient‐related transcription factor, sterol regulatory element binding protein 1c (SREBP‐1c). Furthermore, the PI3K and mTOR inhibitor BEZ235 markedly decreased sCLU expression in HepG2‐SR cells. Conclusion: These results suggest that measurement of sCLU serum levels and the sCLU‐related NR‐index are promising clinical tools for the early prediction of SFN response in HCC. Additionally, sCLU‐overexpressing HCC might be susceptible to mTOR inhibition. [ABSTRACT FROM AUTHOR]

Aims: We aimed to assess the optimal management of first or later‐line lenvatinib therapy (LEN) for patients with unresectable hepatocellular carcinoma (uHCC), by clarifying the difference of degree between relative dose intensity (RDI) to achieve objective response (OR) and disease control (DC) by aiming at stable disease (SD), taking dose modifications into consideration. Methods: One hundred uHCC patients who received LEN in first‐ or later‐line settings, between April 2018 and December 2020 in our hospital were analyzed retrospectively. The factors associated with overall survival (OS), time to progression (TTP), OR and DC were assessed. The optimal cut‐off values of RDI 4 weeks after initiation of LEN (RDI during cycle 1) and total RDI (RDI during all cycles) to predict achievement of OR and DC by aiming at SD were determined by receiver operator curve analysis. Results: Achievement of OR and SD were favorable factors for OS (HR, 0.080 and 0.20) and TTP (HR, 0.052 and 0.073), with progressive disease defined as the reference. RDI ≥ 0.8 during cycle 1 and RDI ≥ 0.4 during cycle 1 contributed to achievement of OR (odds ratio, 3.28) and DC (odds ratio, 4.85), respectively. Experience of dose interruption was associated with a favorable TTP (HR, 0.58). The therapeutic line of LEN did not contribute to OS, TTP or best response. Conclusions: To achieve OR and SD for a favorable outcome of first‐ or later‐line LEN, high and moderate early‐phase RDI are required, respectively. The degree of RDI during LEN and tolerance need compatible by dose modifications. [ABSTRACT FROM AUTHOR]

While sorafenib ( SFN) is the established worldwide standard therapeutic agent for advanced hepatocellular carcinoma ( HCC), hepatic arterial infusion chemotherapy ( HAIC) is also considered a favorable treatment for some advanced HCCs. This study aimed to evaluate each treatment and provide an optimal therapeutic choice for advanced HCCs. We analyzed 72 patients treated with SFN and 128 patients receiving HAIC. Both treatment groups were analyzed for prognostic and disease progression factors, and matched pair analysis was performed using the propensity score matching method. The preferable status of intrahepatic lesions, that is, no lesions or only a single (<3 cm) intrahepetic lesion, was positively associated with good prognosis and negatively associated with disease progression in the SFN group. Maximum tumor size (>5 cm) and low albumin (≤3.4 g/dL) were poor prognostic and disease progression factors in the HAIC group. Analysis of 53 patients selected from each of the SFN and HAIC groups based on the propensity score matching method showed no significant differences in survival or disease progression between the two matched subgroups. On the other hand, progression-free survival ( PFS) in the HAIC-matched subgroup was significantly longer than in the SFN-matched subgroup, particularly in patients with portal vein invasion ( PVI) and/or without extrahepatic spread ( EHS). The treatment efficacy of HAIC is similar to that of SFN regarding survival and disease progression. Longer PFS might be expected for HAIC compared with SFN, particularly in patients with PVI and/or without EHS. [ABSTRACT FROM AUTHOR]