Change in Liver Function in Durvalumab Plus Tremelimumab Treatment for Unresectable Hepatocellular Carcinoma.

BACKGROUND/AIM: Maintaining liver function throughout the treatment of hepatocellular carcinoma (HCC) is crucial, yet the impact of durvalumab plus tremelimumab (DT) treatment on liver function is not well understood. This multicenter study aimed to examine the changes in liver function during DT treatment. PATIENTS AND METHODS: This nationwide multicenter study included 80 patients who received DT treatment for unresectable HCC. The primary outcome was changes in albumin-bilirubin (ALBI) scores at baseline, week 8, week 12, and at the time of progressive disease (PD). RESULTS: The median (interquartile range) ALBI scores at baseline, week 8, week 12, and the time of PD were -2.24 (-2.49 to -1.94), -2.13 (-2.51 to -1.86), -2.23 (-2.51 to - 1.77), and -2.06 (-2.53 to -1.72), respectively. No significant differences were observed at 8 weeks (p=0.06), at 12 weeks (p=0.4), and at PD (p=0.8) compared to baseline. Subgroup analyses were conducted for patients with an ALBI grade of 2 at baseline and for those who received DT treatment as a second-line or later treatment. No deterioration in liver function was observed at any time point in both analyses. CONCLUSION: DT treatment can maintain liver function throughout the treatment period. Maintaining liver function is crucial in managing HCC, and this is an advantage of using DT treatment as a first-line treatment for unresectable HCC.

Impact of Bevacizumab Being Skipped due to Adverse Events of Special Interest for Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab: An Exploratory Analysis of the Phase III IMbrave150 Study.

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs). Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs. A-2). PFS was evaluated per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated. Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 versus A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs. 9.7 months) per IRF-HCC mRECIST for group A-1 versus A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis. Discussion/Conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab.

Treatment response to durvalumab plus tremelimumab after progression with previous immune checkpoint inhibitor in unresectable hepatocellular carcinoma.

Although immune checkpoint inhibitors (ICI) are used for unresectable hepatocellular carcinoma (HCC), it is unclear whether sequential ICI treatment-durvalumab plus tremelimumab (DT) after progression on atezolizumab plus bevacizumab (AB)-is effective for HCC. In this nationwide multicenter study, we aimed to investigate the effect of DT treatment based on the timing of treatment. A total of 85 patients receiving DT treatment were enrolled. The primary endpoint is treatment response at week 8 among patients receiving first-line DT treatment, those receiving second-line or later treatment without prior AB therapy, and those receiving second-line or later treatment with prior AB therapy. Objective response rates (ORRs) in patients with first-line treatment, second-line treatment without AB, and second-line treatment with prior AB were 44%, 54%, and 5%, respectively (p < 0.001). Similarly, disease control rates (DCRs) were 69%, 91%, and 26%, respectively (p < 0.001). ORR and DCR were significantly lower in patients with prior AB treatment. Progression free survival (PFS) was significantly shortened in patients receiving second-line therapy following prior AB treatment and an adjusted hazard ratio (95% confidence interval) in those patients for PFS, using first-line therapy as a reference, was 2.35 (1.1-5.1, p = 0.03). In conclusion, the impact of DT sequencing following AB treatment was limited. However, even after second-line treatment, the treatment effect can be equivalent to that of first-line treatment in cases with no history of AB treatment. Thus, prior treatment history should be taken into account when initiating DT treatment.

Enhanced Liver Fibrosis Score for Diagnosing Liver Fibrosis in Chronic Hepatitis.

Background and aims: The enhanced liver fibrosis (ELF) score is a blood test that combines three markers linked to liver fibrosis. The utility of the ELF score has been demonstrated primarily in Western countries, but whether it is useful in areas with a high number of elderly people suffering from chronic liver disease has yet to be determined. Methods: This is a prospective study that included 373 consecutive patients who underwent a liver biopsy and had their ELF score measured on the same day. The diagnostic accuracy of the ELF score for liver fibrosis and the effect of age on the ELF score were investigated. Results: The median (interquartile) ELF scores in F0, F1, F2, F3, and F4 are 8.7 (8.2-9.2), 9.3 (8.8-10.0), 10.1 (9.4-10.7), 10.7 (9.9-11.2), and 12.0 (11.2-12.7), respectively. ELF scores increased with increasing liver fibrosis stage (p < 0.001). The diagnostic accuracy of the ELF score and FIB-4 for significant fibrosis (F2-4) and advanced fibrosis (F3-4) was comparable, but the ELF score had a higher diagnostic accuracy for cirrhosis (F4) than FIB-4. When patients were stratified by age of 60 years, the median ELF score did not differ by age in F2, F3, and F4. However, the median FIB-4 increased in patients with ≥60 years compared to those with <60 years in all fibrosis stages. Conclusions: ELF score has high diagnostic accuracy for liver fibrosis, regardless of age, and it could be used as a primary screening method.

Ramucirumab for advanced hepatocellular carcinoma in the current real world: a Japanese single-arm study post-REACH-2 (The R-evolution study).

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.

Multicenter Phase II Trial of Lenvatinib plus Hepatic Intra-Arterial Infusion Chemotherapy with Cisplatin for Advanced Hepatocellular Carcinoma: LEOPARD.

Introduction: Hepatic arterial infusion chemotherapy (HAIC) with cisplatin and lenvatinib exhibits strong antitumor effects against advanced hepatocellular carcinoma (HCC). Higher antitumor activity is expected for the combination treatment. The aim of this trial was to evaluate the efficacy and safety of lenvatinib in combination with HAIC using cisplatin in patients with advanced HCC. Methods: In this multicenter, open-labeled, single-arm, phase II trial, patients with advanced HCC categorized as Child-Pugh class A with no prior history of systemic therapy were enrolled. Patients received lenvatinib plus HAIC with cisplatin (lenvatinib: 12 mg once daily for patients ≥60 kg, 8 mg once daily for patients <60 kg; HAIC with cisplatin: 65 mg/m2, day 1, every 4-6 weeks, maximum of six cycles). The primary endpoint was the objective response rate (ORR) assessed using modified RECIST by the Independent Review Committee. The secondary endpoints were the ORR assessed using RECIST v1.1, progression-free survival, overall survival, and frequency of adverse events associated with the treatment. Results: A total of 36 patients were enrolled between September 2018 and March 2020. In the 34 evaluable patients, the ORR assessed by the Independent Review Committee using modified RECIST and RECIST v1.1 were 64.7% (95% confidence interval [CI]: 46.5-80.3%) and 45.7% (95% CI: 28.8-63.4%), respectively. The median progression-free survival and overall survival were 6.3 months (95% CI: 5.1-7.9 months) and 17.2 months (95% CI: 10.9 - not available, months), respectively. The main grade 3-4 adverse events were increased aspartate aminotransferase (34%), leukopenia (22%), increased alanine aminotransferase (19%), and hypertension (11%). Conclusion: Lenvatinib plus HAIC with cisplatin yielded a favorable ORR and overall survival and was well tolerated in patients with advanced HCC. Further evaluation of this regimen in a phase III trial is warranted.

Magnetic resonance elastography for the prediction of hepatocellular carcinoma in chronic hepatitis B.

Background and Aim: Magnetic resonance elastography (MRE) is used for the evaluation of liver fibrosis; however, it remains unclear whether MRE-based liver stiffness is associated with hepatocellular carcinoma (HCC) development, particularly in patients with chronic hepatitis B. Methods: A total of 504 patients with chronic hepatitis B receiving MRE were enrolled. The primary endpoint was the association between MRE-based liver stiffness and HCC. Results: In a cross-sectional analysis at the time of MRE measurement, the median (interquartile range) liver stiffness values in patients with presence or history of HCC and those without HCC were 3.68 (2.89-4.96) and 2.60 (2.22-3.45) kPa, respectively, and liver stiffness was significantly higher in patients with presence or history of HCC than in those without HCC (P < 0.001). In a longitudinal analysis of patients without HCC, the 1-, 3-, and 5-year cumulative incidence of HCC in patients with liver stiffness ≥3.6 kPa and those with liver stiffness <3.6 kPa were 3.8%, 7.0%, and 22.9%, and 0%, 0.9%, and 1.5%, respectively (P < 0.001). In the multivariable analysis, MRE-based liver stiffness (per 1 kPa) or liver stiffness ≥3.6 kPa was an independent factor for HCC development with an adjusted hazard ratio (aHR) of 1.61 (95% confidence interval [CI], 1.3-2.0) or aHR of 8.22 (95% CI, 2.1-31). Conclusion: MRE-based liver stiffness is associated with HCC risk in patients with chronic hepatitis B and may be used for the early prediction of HCC development and determination of indications for treatment.

Impact of immune-related adverse events in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

BACKGROUND AND AIM: Immune checkpoint inhibitors pose the risk of immune-related adverse events (irAEs). Recent data suggest that irAEs may be associated with a favorable prognosis. This study aimed to investigate and analyze the association between these adverse events and the clinical benefits in patients with unresectable hepatocellular carcinoma. METHODS: The study enrolled 130 patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab between November 2020 and January 2023 at a single center. The relationship between irAEs and both response rate and post-treatment outcomes was investigated. RESULTS: Out of the 130 patients, irAEs developed in 36 (27.7%) patients. The irAE group exhibited a significantly longer progression-free survival (PFS) than the non-irAE group, with a median PFS of 8.9 compared with 4.6 months (P < 0.01). No difference was found in the overall survival between the irAE and non-irAE groups. The irAE group demonstrated significantly higher disease control rate (DCR) than the non-irAE group (97.0% vs 65.5%, P < 0.01). The analysis by irAE severity revealed that the grade 1/2 group exhibited significantly longer PFS (7.9 vs 4.6 months, P = 0.007) and higher DCR (100% vs 65.5%, P < 0.01) than the non-irAE group. Furthermore, hypothyroidism correlated with a favorable PFS (8.9 vs 5.4 months, P = 0.02), DCR (100% vs 71.3%, P = 0.03), and overall response rate (58.3% vs 18.5%, P = 0.005). CONCLUSION: The presence of irAEs is associated with prolonged PFS and higher DCR. Specifically, mild irAEs (grade 1/2) and hypothyroidism displayed prolonged PFS and higher DCR.

Glycemic control target for liver and cardiovascular events risk in metabolic dysfunction-associated steatotic liver disease.

AIMS: Optimizing glycemic control may prevent liver-related events and major adverse cardiovascular events (MACE) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, the optimal hemoglobin A1c (HbA1c) threshold associated with a lower risk of complications, particularly liver-related events as well as MACE is unknown. METHODS: We investigated a nationwide population-based cohort and identified 633 279 patients with MASLD, with a mean follow-up of 4.2 years. Hemoglobin A1c levels were measured annually. The primary endpoint was the risk of liver-related events and MACE and to determine the optimal HbA1c level associated with the risk of complications. RESULTS: Mean HbA1c (per 1%) was associated with liver-related events (subdistribution hazard ratio [sHR] 1.26; 95% confidence interval [CI], 1.12-1.42) as well as MACE (sHR 1.36; 95% CI, 1.32-1.41) after adjustment for confounders. Multivariable sHR (95% CI) for HbA1c of <5.0%, 6.0%-6.9%, 7.0%-7.9%, 8.0%-8.9%, and ≥9.0% (reference, 5.0%-5.9%) were 14 (9.1-22), 1.70 (1.2-2.3), 3.32 (2.3-4.8), 3.81 (2.1-6.8), and 4.83 (2.4-9.6) for liver-related events, and 1.24 (0.8-1.8), 1.27 (1.2-1.4), 1.70 (1.5-2.0), 2.36 (1.9-2.9), and 4.17 (3.5-5.0) for MACE. An HbA1c level of 7% was selected as the optimal threshold for predicting complications (sHR 2.40 [1.8-3.2] for liver-related events and 1.98 [1.8-2.2] for MACE). CONCLUSION: The risk of liver-related events as well as MACE increased in a dose-dependent fashion with an increase in HbA1c levels, except for patients with HbA1c <5.0% for liver-related events. An HbA1c level of 7% was the optimal threshold associated with a lower risk of complications and may be utilized as a target for glycemic control in patients with MASLD.

Detecting advanced liver fibrosis using ultrasound shear wave velocity measurement in the general population.

Background: Advanced fibrosis detection in the general population is an unmet need. Additionally, screening method for advanced fibrosis in the general population is not established. Thus, this study aimed to examine the use of shear wave measurement (SWM), which measures liver stiffness by ultrasound elastography as a screening tool for advanced fibrosis in health checkups that represents the general population. Methods: SWM was performed in all subjects. Magnetic resonance elastography (MRE) was performed in those with SWM shear wave velocity (Vs) ≥1.3 m/s to determinate advanced fibrosis. The diagnostic accuracy of SWM Vs for advanced fibrosis (determined by MRE of ≥3.62 kPa) was examined. This prospective study was registered with the University Hospital Medical Information Network clinical trial registry (UMIN000041609). Results: A total of 2,233 subjects were included. SWM Vs of 1.64 m/s was selected as the best threshold for advanced fibrosis. Using the threshold of SWM Vs at ≥1.64 m/s, subjects were narrowed down to 1.7%, and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for advanced fibrosis were 53.3%, 92.4%, 47.1%, and 94.0%, respectively, among these subjects. The multivariable analysis, after adjusting the age, sex, body mass index (BMI), hypertension, diabetes mellitus (DM), dyslipidemia, and alcohol use, revealed an SWM Vs of ≥1.64 m/s as the significant factor for advanced fibrosis with an odds ratio (95% confidence interval) of 14.5 (3.4-62; P<0.001). Conclusions: SWM has high diagnostic accuracy for advanced fibrosis (PPV 47.1%) and may be used as a screening tool for liver fibrosis in the general population.

Achievement of Complete Response and Drug-Free Status by Atezolizumab plus Bevacizumab Combined with or without Curative Conversion in Patients with Transarterial Chemoembolization-Unsuitable, Intermediate-Stage Hepatocellular Carcinoma: A Multicenter Proof-Of-Concept Study.

Introduction: Atezolizumab plus bevacizumab therapy is extremely effective in the treatment of intermediate-stage hepatocellular carcinoma (HCC), with a response rate of 44%, as reported in the IMbrave150 trial. When tumor shrinkage is obtained, achieving complete response (CR) is possible in many cases using curative conversion with resection, ablation, or superselective transarterial chemoembolization (TACE) with curative intent. This concept, i.e., curative conversion by combining systemic therapy and locoregional therapy, has not been reported before. This multicenter proof-of-concept study was conducted to show the value of curative conversion in immunotherapy-treated intermediate-stage HCC meeting TACE-unsuitable criteria. Methods: This study included 110 consecutive Child-Pugh A patients who received atezolizumab plus bevacizumab as first-line treatment for unresectable and TACE-unsuitable intermediate-stage HCC at seven centers in Japan. CR rate, drug-free rate, time to CR, change in liver function, efficacy in positron emission tomography (PET)-positive HCC, progression-free survival (PFS), and overall survival (OS) were assessed in patients who achieved CR using resection, ablation, superselective TACE with curative intent following atezolizumab plus bevacizumab or atezolizumab plus bevacizumab alone. Results: Clinical or pathological CR was achieved in 38 patients (35%) (median observation period: 21.2 months). The modalities of curative conversion in 35 patients were as follows: resection, 7; ablation, 13; and superselective TACE, 15. Three patients achieved clinical CR with atezolizumab plus bevacizumab therapy alone. Among the 38 CR patients, 25 achieved drug-free status. PFS was not reached, and 3 patients experienced recurrence after reaching CR. Regarding OS, there were no deaths in any of the CR patients. The albumin-bilirubin score did not deteriorate after locoregional therapy or resection. Of seven PET-positive patients who achieved CR with atezolizumab plus bevacizumab followed by curative conversion, five achieved drug-free status. Conclusion: The achievement of CR rate by curative conversion in patients treated with atezolizumab plus bevacizumab as the preceding therapy for unresectable and TACE-unsuitable intermediate-stage HCC was 35%. Overall, 23% of patients achieved drug-free status and no recurrence was observed from this patient subgroup with CR and drug-free status. Thus, achieving CR and/or drug-free status should be a therapeutic goal for patients with intermediate-stage HCC without vascular invasion or extrahepatic spread.

IMbrave150: Efficacy and Safety of Atezolizumab plus Bevacizumab versus Sorafenib in Patients with Barcelona Clinic Liver Cancer Stage B Unresectable Hepatocellular Carcinoma: An Exploratory Analysis of the Phase III Study.

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis reports efficacy and safety results in patients with baseline Barcelona Clinic Liver Cancer (BCLC) stage B disease. Methods: Patients with systemic treatment-naive unresectable HCC and Child-Pugh class A liver function were randomized 2:1 to receive 1,200 mg of atezolizumab plus 15 mg/kg of bevacizumab or 400 mg of sorafenib. Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 in the BCLC stage B subgroup. Patients in this analysis had BCLC stage B disease at baseline per electronic case report form. Secondary efficacy endpoints included the objective response rate (ORR) and change in the sum of longest diameters (SLD) of target lesions from baseline per IRF RECIST 1.1 and modified RECIST (mRECIST) for HCC. Results: Of 501 enrolled patients, 74 (15%) had BCLC stage B disease at baseline (atezolizumab + bevacizumab, n = 49; sorafenib, n = 24). For this group, median follow-up was 19.7 months. A trend toward improved OS and PFS per IRF RECIST 1.1 was observed with atezolizumab + bevacizumab versus sorafenib (OS: hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.29, 1.34; PFS: HR: 0.64; 95% CI: 0.36, 1.12). ORRs per IRF RECIST 1.1 and HCC mRECIST were 43% and 50% with atezolizumab + bevacizumab and 26% and 30% with sorafenib, respectively. Percentage change in SLD of target lesions from baseline per IRF RECIST 1.1 and HCC mRECIST showed durable responses with atezolizumab + bevacizumab treatment. Safety data were consistent with known profiles of atezolizumab and bevacizumab, as seen in the overall study population. Discussion/Conclusion: Efficacy benefits were observed with atezolizumab + bevacizumab in patients with baseline BCLC stage B disease, consistent with the intention-to-treat population.

Switching from entecavir to tenofovir alafenamide for maintaining complete virological response in chronic hepatitis B.

Background and Aim: Hepatocellular carcinoma development can be decreased by achieving and maintaining complete virological response (CVR) in chronic hepatitis B. However, it is unclear whether switching from entecavir (ETV) to tenofovir alafenamide (TAF) could achieve and maintain CVR in patients with low-level viremia (LLV; HBV DNA ≤ 3.3 log IU/mL) or occasional detectable HBV DNA during ETV treatment. Therefore, we aimed to examine whether the switching from ETV to TAF is effective in achieving CVR in patients with LLV or occasional detectable HBV DNA. Methods: This study comprised 45 patients who switched from ETV to TAF. All patients received ETV and TAF for >2 years, and the HBV DNA levels were measured every 3 months. Maintaining undetectable HBV DNA during 2-year period is defined as CVR. The primary endpoint is the CVR rate during ETV and TAF treatment. Results: The CVR rate for each of the 2 years of ETV and TAF therapy was 33.3% (15/45) and 68.9% (31/45, P < 0.01), respectively, and the CVR rate increased by switching from ETV to TAF. In patients with occasional detectable HBV DNA during ETV treatment (22 patients), 15 achieved CVR and 7 maintained occasional detectable HBV DNA. In patients with LLV during ETV treatment (eight patients), three achieved CVR and five had occasional detectable HBV DNA. Conclusion: Switching from ETV to TAF increases the CVR rate in patients with LLV or occasional detectable HBV DNA and could be an alternative treatment option.

Pemigatinib treatment for intrahepatic cholangiocarcinoma with FGFR2 fusion detected by a liquid comprehensive genomic profiling test.

The liquid CGP was useful for detecting FGFR2 fusion and the patient experienced typical side effects (nail disorders, hyperphosphatemia, and taste disorders) of pemigatinib that required treatment.

Effects on survival of the adverse event of atezolizumab plus bevacizumab for hepatocellular carcinoma: a multicenter study by the Japan Red Cross Liver Study Group.

This study aimed to describe the real-world efficacy and safety of the combination therapy of atezolizumab and bevacizumab (Atezo/Bev) for unresectable hepatocellular carcinoma (HCC). This retrospective analysis of a multicenter registry cohort included 268 patients treated with Atezo/Bev. The incidence of adverse events (AE) and its impact on overall survival (OS) and progression-free survival (PFS) were analyzed. Of the 268 patients, 230 (85.8%) experienced AE. The median OS and PFS in the whole cohort were 462 and 239 days, respectively. The OS and PFS were not different in terms of AE, but they were significantly shorter in patients with increased bilirubin level and those with increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Regarding increased bilirubin level, the hazard ratios (HRs) were 2.61 (95% confidence interval [CI]: 1.04-6.58, P = 0.042) and 2.85 (95% CI: 1.37-5.93, P = 0.005) for OS and PFS, respectively. Regarding increased AST or ALT, the HRs were 6.68 (95% CI: 3.22-13.84, P < 0.001) and 3.54 (95% CI: 1.83-6.86, P < 0.001) for OS and PFS, respectively. Contrarily, the OS was significantly longer in patients with proteinuria (HR: 0.46 [95% CI: 0.23-0.92], P = 0.027). Multivariate analysis confirmed that proteinuria (HR: 0.53 [95% CI: 0.25-0.98], P = 0.044) and increased AST or ALT (HR: 6.679 [95% CI: 3.223-13.84], P = 0.003) were independent risk factors for a shorter OS. Furthermore, analysis limited to cases who completed at least 4 cycles confirmed that increased AST or ALT and proteinuria were negative and positive factors for OS, respectively. In the real-world setting, increased AST or ALT and bilirubin level during Atezo/Bev treatment were found to have a negative impact on PFS and OS, whereas proteinuria had a positive impact on OS.

Clinical Utility of Comprehensive Genomic Profiling in Patients with Unresectable Hepatocellular Carcinoma.

The molecular mechanism of hepatocellular carcinoma (HCC) is partially demonstrated. Moreover, in the patients receiving multiple molecular-targeted therapies, the gene alternations are still unknown. Six molecular-targeted therapies of unresectable HCC (uHCC) and comprehensive genomic profiling (CGP) have been approved in clinical practice. Hence, the utility of CGP in patients with uHCC treated with multiple molecular-targeted agents is investigated. The data of the patients with uHCC who received CGP tests were collected, retrospectively, between February 2021 and May 2022. Gene alterations detected by foundation testing, excluding variants of unknown significance, were reported in all nine patients. The samples for CGP were derived from liver tumor biopsy (n = 2), surgical specimens of bone metastases (n = 2), and blood (n = 5). The median number of systemic therapies was four. Seven patients were candidates eligible for clinical trials. One patient with a high tumor mutation burden (TMB) could receive pembrolizumab after CGP. This study presented genomic alternations after receiving multiple molecular-targeted therapies. However, further investigation needs to be conducted to develop personalized therapies and invent newer agents for treating HCC.

Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2021 version (5th JSH-HCC Guidelines).

The fifth version of the Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine and partly to the Grading of Recommendations Assessment, Development and Evaluation system, which was published in October 2021 in Japanese. In addition to surveillance-diagnostic and treatment algorithms, a new algorithm for systemic therapy has been created, as multiple drugs for hepatocellular carcinoma can be currently selected. Here, new or revised algorithms and evidence on which the recommendations are based are described.

Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: Final results of a multicenter phase II study.

AIM: Cabozantinib showed a favorable benefit-risk profile in Japanese patients with advanced hepatocellular carcinoma (HCC) in an open-label, phase II study (NCT03586973). This analysis presents cumulative data to final database lock. METHODS: Patients with previously treated, advanced HCC received cabozantinib 60 mg/day. Progression-free survival (PFS) and tumor response rates in prior-sorafenib and sorafenib-naïve cohorts were assessed by independent radiology committee (IRC) and an investigator. Liver function was evaluated by albumin-bilirubin (ALBI) score. RESULTS: Median cabozantinib exposure was 5.6 months. In the prior-sorafenib cohort (n = 20), median PFS was 7.4 months per IRC assessment and 5.6 months per investigator assessment. In the sorafenib-naïve cohort (n = 14), median PFS was 3.6 and 4.4 months per IRC and investigator assessment, respectively. Six-month PFS rate per IRC and investigator assessment in the prior-sorafenib cohort was 59.8% and 49.5%, respectively, and in the sorafenib-naïve cohort was 16.7% and 35.7%, respectively. Disease control rate by both IRC and investigator assessment was 85.0% in the prior-sorafenib cohort and 64.3% in the sorafenib-naïve cohort. Median overall survival (Kaplan-Meier estimate) was 19.3 and 9.9 months in the prior-sorafenib and sorafenib-naïve cohort, respectively. Mean ALBI score remained relatively constant in patients able to continue treatment. The most frequent adverse events were palmar-plantar erythrodysesthesia syndrome, diarrhea, hypertension, and decreased appetite. No new safety concerns were identified. CONCLUSIONS: Cabozantinib showed efficacy and a manageable safety profile in Japanese patients with advanced HCC.

Effect of fatty liver and fibrosis on hepatocellular carcinoma development in patients with chronic hepatitis B who received nucleic acid analog therapy.

The number of patients with fatty liver has been increasing worldwide; however, the significance of fatty liver in patients with chronic hepatitis B who are receiving nucleic acid analog (NA) therapy remains unclear. Thus, we aimed to determine whether fatty liver affects the development of hepatocellular carcinoma (HCC) in patients receiving NA therapy. This study included 445 patients who received NA therapy, and the development of HCC was investigated. The primary outcome was the association between fatty liver and HCC development. During a mean follow-up period of 7.4 years, 46 patients (10.3%) developed HCC. No significant difference in the cumulative incidence of HCC was observed between patients with fatty liver and those without (p = 0.17). Multivariable analysis for age, gender, platelet count, alanine aminotransferase level at 1 year following NA therapy, and fatty liver revealed that the presence of fatty liver was not a significant factor for HCC development (hazard ratio [HR]: 0.96, 95% confidence interval [CI]: 0.5-1.9). In another multivariable analysis for advanced fibrosis, gender, and fatty liver, advanced fibrosis was found to be a significant factor for HCC development (HR: 9.50, 95% CI: 5.1-18) but not fatty liver (HR: 0.90, 95% CI: 0.5-1.7). In conclusion, in patients with chronic hepatitis B who received NA therapy, advanced fibrosis was found to be an important risk factor for HCC development but not fatty liver, suggesting the importance of providing treatment before the progression of liver fibrosis regardless of the presence of fatty liver.

Alanine aminotransferase levels as therapeutic targets after nucleotide/nucleoside analog therapy in patient with chronic hepatitis B.

AIM: Alanine aminotransferase (ALT) is a criterion for the introduction of nucleotide/nucleoside analog (NA), and ALT levels are decreased by NA treatment. However, the association between post-treatment ALT levels and hepatocellular carcinoma (HCC) risk remains unclear. To fill this gap, we aimed to establish a target value of ALT level during NA treatment. METHODS: In total, 413 patients with chronic hepatitis B who received entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate were enrolled. The subsequent development of HCC was examined and a target value of ALT level during NA treatment as a risk marker for HCC was evaluated. RESULTS: The median follow-up duration was 5.1 years, during which time 27 patients (8.6%) developed HCC. ALT level at the start of treatment was not associated with HCC development (p = 0.08). When stratified by ALT at 1 year after NA initiation, the cumulative 3- and 5-year rates of HCC for patients with ALT ≥21 IU/L were 11.5% and 18.1%, and those with ALT <21 IU/L was 2.3% and 6.5%, respectively. Patients with ALT <21 IU/L had a significantly lower risk of HCC development compared with patients with ALT ≥21 IU/L (p = 0.002). In multivariable analysis adjusting age, sex, and platelet counts, ALT ≥21 IU/L was an independent risk factor of HCC development with hazard ratio of 4.5 (95% confidence interval: 1.01-20.4). CONCLUSIONS: ALT <21 IU/L at 1 year after NA initiation has a lower risk of HCC and could be used as a target value for NA treatment.