α-FAtE: A new predictive score of response to atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma.

Atezolizumab plus bevacizumab (AB) and lenvatinib can be alternatively used as first-line systemic treatment of unresectable hepatocellular carcinoma (HCC). However, no direct comparison of the two regimens has been performed in randomized clinical trials, making the identification of baseline differential predictors of response of major relevance to tailor the best therapeutic option to each patient. Baseline clinical and laboratory characteristics of real-world AB-treated HCC patients were analyzed in uni- and multivariate analyses to find potential prognostic factors of overall survival (OS). Significant variables were incorporated in a composite score (α-FAtE) and it was tested for specificity and sensitivity in receiver operating characteristic (ROC) curve and in multivariate analysis for OS. The score was applied in uni- and multivariate analyses for OS of a comparable lenvatinib-treated HCC population. Finally, comparison between treatments was performed in patients with low and high α-FAtE scores and predictivity estimated by interaction analysis. Time-to-progression (TTP) was a secondary endpoint. OS of AB-treated HCC patients was statistically longer in those with α-fetoprotein <400 ng/mL (HR 0.62, p = .0407), alkaline phosphatase (ALP) <125 IU/L (HR 0.52, p = .0189) and eosinophil count ≥70/µL (HR 0.46, p = .0013). The α-FAtE score was generated by the sum of single points attributed to each variable among the above reported. In ROC curve analysis, superior sensitivity and specificity were achieved by the score compared to individual variables (AUC 0.794, p < .02). Patients with high score had longer OS (HR 0.44, p = .0009) and TTP (HR 0.34, p < .0001) compared to low score if treated with AB, but not with lenvatinib. Overall, AB was superior to lenvatinib in high score patients (HR 0.55, p = .0043) and inferior in low score ones (HR 1.75, p = .0227). At interaction test, low α-FAtE score resulted as negative predictive factor of response to AB (p = .0004). In conclusion, α-FAtE is a novel prognostic and predictive score of response to first-line AB for HCC patients that, if validated in prospective studies, could drive therapeutic choice between lenvatinib and AB.

Comparison of prognostic impact of atezolizumab plus bevacizumab versus lenvatinib in patients with intermediate-stage hepatocellular carcinoma.

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.

Impact of body mass index on the prognosis of unresectable HCC patients receiving first-line Lenvatinib or atezolizumab plus bevacizumab.

INTRODUCTION: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment. METHODS AND MATERIAL: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests. RESULTS: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis. CONCLUSION: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib.

Kinetics of the hepatitis B core-related antigen and treatment responses in chronic hepatitis B patients treated with tenofovir alafenamide.

AIM: An association between hepatitis B core-related antigen (HBcrAg) kinetics and hepatocarcinogenesis during nucleoside (t)id analog (NA) treatment has recently been reported. HBcrAg kinetics and factors associated with HBcrAg response during tenofovir alafenamide (TAF) administration remain unclear. In this multicenter retrospective study, we aimed to clarify the efficacy and safety of TAF in treatment-naïve patients with chronic hepatitis B, focusing on the reduction in HBcrAg levels. METHODS: Patients were treated with TAF monotherapy for 96 weeks, and the kinetics of HBcrAg during treatment and the factors associated with HBcrAg response (defined as a change in HBcrAg of -1 log IU/mL from baseline) were evaluated. RESULTS: The study population comprised 241 patients, 36.9% of whom were HBeAg-positive. The median baseline HBcrAg level was 4.7 log IU/mL. The median change in HBcrAg from baseline was -1.1 log IU/mL at 96 weeks after treatment. The HBcrAg response rate at 96 weeks was 56.6% (43/76). Multivariate analysis revealed high alanine transaminase level as an independent baseline factor associated with HBcrAg response at 96 weeks of treatment (p = 4.53 × 10-6). No correlation was found between the HBcrAg and hepatitis B surface antigen kinetics in patients treated with TAF monotherapy. CONCLUSIONS: In TAF monotherapy for patients with chronic hepatitis B, HBcrAg levels were significantly decreased and baseline alanine transaminase level is an important factor associated with HBcrAg reduction. As no correlation was found between HBcrAg and reduced hepatitis B surface antigen levels in this study, HBcrAg kinetics in addition to hepatitis B surface antigen may need to be monitored during TAF treatment.

Comparative analysis of the therapeutic outcomes of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma patients aged 80 years and older: Multicenter study.

AIM: Elderly patients are believed to have a reduced immune capacity, which may make immunotherapy less effective. The aim of this study was to compare the therapeutic outcome of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) for advanced hepatocellular carcinoma (HCC) in patients aged 80 years and older. METHODS: From March 2018 to July 2022, 170 and 92 elderly patients who received LEN and Atez/Bev as first-line treatment, respectively, were retrospectively analyzed. RESULTS: The median ages of the Atez/Bev and LEN groups were 83.0 (8.01-86.0) and 83.0 (82.0-86.0) years (p = 0.3), respectively. Men accounted for approximately 70% of the patients in both groups. The objective response rate was 35.9% in the LEN group and 33.7% in the Atez/Bev group (p = 0.8), whereas the disease control rates in the LEN and Atez/Bev groups were 62.9% and 63.0%, respectively (p = 1.0). The median progression-free survival (PFS) in the LEN and Atez/Bev groups was 6.3 and 7.2 months, respectively, which were not significantly different (p = 0.2). The median overall survival (OS) was 17.9 months in the LEN group and 14.0 months in the Atez/Bev group. This difference was not statistically significant (p = 0.7). In multivariate analyses, the choice of treatment (LEN vs. Atez/Bev) showed no association with PFS or OS. The Atez/Bev group had a significantly higher rate of postprogression treatment (59.0% vs. 35.7%, p = 0.01) and a lower rate of discontinuation due to adverse events (69 [40.6%] vs. 19 [20.7%], p < 0.001) compared to the LEN group. CONCLUSIONS: Atezolizumab plus bevacizumab showed comparable effectiveness to LEN in HCC patients aged 80 years and older. Given the results of postprogression treatment and discontinuation due to adverse events, Atez/Bev could serve as a first-line treatment even for elderly HCC patients.

Risk factors for hepatocellular carcinoma at baseline and 1 year after initiation of nucleos(t)ide analog therapy for chronic hepatitis B.

Nucleos(t)ide analogs (NAs) cannot completely suppress the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to identify the risk factors for HCC development in naïve CHB patients treated with current NA. Patients receiving NA (n = 905) were recruited retrospectively from the 17 hospitals of the Japanese Red Cross Liver Study Group. All treatment-naïve patients had been receiving current NA continuously for more than 1 year until the end of the follow-up. We analyzed the accuracy of predictive risk score using the area under receiver operating characteristic curve. The albumin-bilirubin (ALBI) score was significantly improved by NA therapy (-0.171 ± 0.396; p < 0.001 at Week 48). A total of 72 (8.0%) patients developed HCC over a median follow-up of 6.2 (1.03-15.7) years. An independent predictive factor of HCC development was older age, cirrhosis, lower platelet counts at baseline and ALBI score, and alpha-fetoprotein (AFP) at 1 year after NA therapy according to multivariate analysis. The accuracy was assessed using the PAGE-B, mPAGE-B, aMAP, APA-B, and REAL-B scores that included these factors. Discrimination was generally acceptable for these models. aMAP and REAL-B demonstrated high discrimination with 0.866/0.862 and 0.833/0.859 for 3- and 5-year prediction from the status of 1 year after NA therapy, respectively. Baseline age and platelet count, as well as ALBI and AFP one year after NA, were useful for stratifying carcinogenesis risk. The aMAP and REAL-B scores were validated with high accuracy in Japanese CHB patients.

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.

Comparison between Atezolizumab Plus Bevacizumab and Lenvatinib for Hepatocellular Carcinoma in Patients with Child-Pugh Class B in Real-World Clinical Settings.

INTRODUCTION: Systemic treatment is generally recommended for Child-Pugh (CP) A status patients with an unresectable hepatocellular carcinoma (uHCC). This study aimed to elucidate differences regarding therapeutic efficacy between lenvatinib (LEN), a multi-molecular target agent, and atezolizumab plus bevacizumab (Atez/Bev), a newly developed immune-combined therapeutic regimen for CP-B patients affected by uHCC. METHODS: From April 2018 to July 2022, 128 patients with uHCC treated with Atez/Bev (n = 29) or LEN (n = 99) as the initial systemic treatment were enrolled (median age 71 years; males 97; CP score 7:8:9 = 94:28:6; median albumin-bilirubin score -1.71). Therapeutic response was evaluated using RECIST, version 1.1. Clinical features and prognosis were retrospectively examined. RESULTS: There were no significant differences between the Atez/Bev and LEN groups in regard to best response (CR:PR:SD:PD = 0:5:12:7 vs. 5:22:25:20, p = 0.415), progression-free survival (PFS) (median 5.0 [95% CI: 2.4-7] vs. 5.5 [95% CI: 3.4-7.9] months, p = 0.332), or overall survival (OS) (5.8 [95% CI: 4.3-11] vs. 8.8 [95% CI: 6.1-12.9] months, p = 0.178). Adverse events (any grade/≥ grade 3) were observed in 72.4%/17.2% (n = 21/5) of patients treated with Atez/Bev and 78.8%/25.3% (n = 78/25) of those treated with LEN (p = 0.46/0.46). DISCUSSION: This retrospective study found no significant differences regarding PFS or OS between CP-B patients given Atez/Bev or LEN as initial systemic treatment for uHCC.

Nutritional Status Is Associated with Prognosis in Patients with Advanced Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab.

INTRODUCTION: This study investigated the relationship between nutritional status, as determined by the prognostic nutritional index (PNI), and outcomes in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/bev). METHODS: The study analyzed 485 HCC patients treated with Atez/bev. RESULTS: There were 342 patients with a low PNI (<47) and 143 patients with a high PNI (≥47). The median follow-up duration was 9.4 (6.0-14.3) months. Multivariate Cox hazards analysis showed that an α-fetoprotein level ≥100 ng/mL (hazard ratio (HR), 2.217; 95% confidence interval (CI), 1.588-3.095; p < 0.001), and PNI ≥47 (HR, 0.333; 95% CI, 0.212-0.525; p < 0.001) were independently associated with overall survival. Multivariate analysis showed that an α-fetoprotein level ≥100 ng/mL (HR, 1.690; 95% CI, 1.316-2.170; p < 0.001) and PNI ≥47 (HR, 0.696; 95% CI, 0.528-0.918; p = 0.010) were independently associated with progression-free survival. Cumulative overall and progression-free survival rates differed significantly by PNI (p < 0.001 and p < 0.002, respectively). In a subgroup analysis using inverse probability weighting adjustment in patients with albumin-bilirubin grade 1 (n = 173), univariate Cox hazards analysis showed that a PNI ≥47 (HR, 0.502; 95% CI, 0.260-0.991; p = 0.047) was significantly associated with overall survival. Spline curve analysis revealed that a PNI of approximately 34-48 is an appropriate cutoff for predicting good overall and progression-free survival. CONCLUSION: The PNI, a biomarker of nutritional status, can predict prognosis in patients with HCC treated with Atez/bev, even those who are considered to have a good prognosis due to good liver function.

Lenvatinib as Second-Line Treatment after Atezolizumab plus Bevacizumab for Unresectable Hepatocellular Carcinoma: Clinical Results Show Importance of Hepatic Reserve Function.

INTRODUCTION: Lack of an established methodology for post-progression systemic treatment following atezolizumab plus bevacizumab (Atez/Bev) administration is an important clinical issue. The present study aimed to elucidate the potential of lenvatinib as a second-line treatment option after Atez/Bev failure. METHODS: From 2020 to 2022, 101 patients who received lenvatinib as second-line treatment were enrolled (median 72 years, males 77, Child-Pugh A 82, BCLC-A:B:C:D = 1:35:61:4), while 29 treated with another molecular targeting agent (MTA) during the period as second-line treatment were enrolled as controls. The therapeutic efficacy of lenvatinib given as second-line treatment was retrospectively evaluated. RESULTS: Median progression-free survival/median overall survival for all patients was 4.4/15.7 months and for those with Child-Pugh A was 4.7 months/not-reached. When prognosis was compared with patients who received another MTA, there was no significant difference for PFS (3.5 months, p = 0.557) or OS (13.6 months, p = 0.992), and also no significant differences regarding clinical background factors. mRECIST findings showed that objective response and disease control rates in patients treated with lenvatinib were 23.9% and 70.4%, respectively (CR:PR:SD:PD = 3:14:33:21), while those shown by RECIST, ver. 1.1, were 15.4% and 66.2%, respectively (CR:PR:SD:PD = 1:10:36:24). Adverse events (any grade ≥10%) were appetite loss (26.7%) (grade 1:2:3 = 2:15:10), general fatigue (21.8%) (grade 1:2:3 = 3:13:6), protein in urine (16.8%) (grade 1:2:3 = 0:4:13), and hypertension (13.9%) (grade 1:2:3 = 1:8:5). CONCLUSION: Although lenvatinib treatment might not provide a pseudo-combination immunotherapy effect following Atez/Bev failure, lenvatinib when used as second-line treatment after Atez/Bev failure might be expected to be comparable as compared to its use as first-line treatment.

Role of the Prognostic Nutritional Index in Predicting Survival in Advanced Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab.

INTRODUCTION: The prognostic nutritional index (PNI) is a multiparametric score introduced by Onodera based on the blood levels of lymphocytes and albumin in patients with gastrointestinal neoplasms. Regarding hepatocellular carcinoma (HCC), its prognostic role has been shown in patients treated with sorafenib and lenvatinib. The aim of this real-world study was to investigate the association between clinical outcomes and PNI in patients being treated with atezolizumab plus bevacizumab. METHODS: The overall cohort of this multicentric study included 871 consecutive HCC patients from 5 countries treated with atezolizumab plus bevacizumab in first-line therapy. The PNI was calculated as follows: 10 × serum albumin concentration (g/dL) + 0.005 × peripheral lymphocyte count (number/mm3). RESULTS: Data regarding lymphocyte counts and albumin levels were available for 773 patients; therefore, these patients were included in the final analysis. The cut-off point of the PNI was determined to be 41 by receiver operating characteristic analysis. 268 patients (34.7%) were categorized as the PNI-low group, while the remaining 505 (65.3%) patients as the PNI-high group. At the univariate analysis, high PNI was associated with longer overall survival (OS) (22.5 vs. 10.1 months, HR 0.34, p <0.01) and progression-free survival (PFS) (8.7 vs. 5.8 months, HR 0.63, p <0.01) compared to patients with low PNI. At the multivariate analysis, high versus low PNI resulted as an independent prognostic factor for OS (HR 0.49, p <0.01) and PFS (HR 0.82, p = 0.01). There was no difference in objective response rate between the two groups (high 26.1% vs. low 19.8%, p = 0.09), while disease control rate was significantly higher in the PNI-high group (76.8% vs. 66.4%, p = 0.01). CONCLUSION: PNI is an independent prognostic factor for OS and PFS in HCC patients on first-line treatment with atezolizumab plus bevacizumab.

Multicenter retrospective study of initial treatment outcome and feasibility of initiating dose reduction of cabozantinib in unresectable hepatocellular carcinoma.

AIM: Cabozantinib (CAB), a multiple kinase inhibitor, has been approved for use in patients with previously treated unresectable hepatocellular carcinoma (uHCC). However, real-world clinical data are lacking, particularly clinical data regarding dose modifications of CAB. We analyzed the clinical outcomes of CAB in uHCC and compared treatment outcomes between the full- and reduced-dose groups. METHODS: This multicenter, observational study included patients with uHCC who were treated with CAB from March 2021 to April 2022. Patient characteristics, efficacy, and safety were compared between the full- and reduced-dose groups. RESULTS: Twenty-six patients from eight institutes were analyzed. Cabozantinib was administered as a third-line or later treatment in 25 (96.2%) patients and postimmunotherapy in 21 (80.5%) patients. There were 15 patients in the full-dose group (60 mg CAB) and 11 in the reduced-dose group (40 or 20 mg CAB). The objective response rate (ORR) and disease control rate (DCR) were not significantly different between the two groups. The ORR was 6.7% for the full-dose group and 9.1% for the reduced-dose group, and the DCR was 53.4% and 81.8%, respectively. Progression-free survival analysis showed no significant differences between the two groups. The incidence of decreased appetite, fatigue, and diarrhea, and the rate of discontinuation and dose reduction, was significantly higher in the full-dose group. CONCLUSIONS: Our study suggests that the efficacy and safety of CAB in real-world clinical practice are comparable to those of the phase III trial (CELESTIAL), and that dose reduction of CAB may be a safer treatment option.

Geriatric nutritional risk index as an easy-to-use assessment tool for nutritional status in hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

AIM: The present study focused on Geriatric Nutritional Risk Index (GNRI), which is based on bodyweight and serum albumin, and known as an easy-to-use nutritional assessment tool in clinical settings, to elucidate the prognostic predictive ability of GNRI in patients treated with atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC). METHODS: A total of 525 HCC patients treated with Atez/Bev, based on their classification of unsuitable status for curative treatments and/or transarterial catheter chemoembolization, were enrolled (Child-Pugh A:B:C = 484:40:1, Barcelona Clinic Liver Cancer stage 0:A:B:C:D = 7:25:192:283:18). Prognosis was evaluated retrospectively using GNRI. RESULTS: Atez/Bev was used in 338 of the present cohort as first-line systemic chemotherapy (64.4%). Median progression-free survival based on GNRI indicating normal, mild decline, moderate decline, and severe decline was 8.3, 6.7, 5.3, and 2.4 months, respectively, whereas median overall survival was 21.4, 17.0, 11.5. and 7.3 months, respectively (both p < 0.001). The concordance index (c-index) values of GNRI for predicting prognosis (progression-free survival/overall survival) were superior to those of Child-Pugh class and albumin-bilirubin grade (0.574/0.632 vs. 0.527/0.570 vs. 0.565/0.629). As a subanalysis, muscle volume loss was observed in 37.5% of 256 patients with computed tomography data available. Along with GNRI decline, frequency of muscle volume loss became progressively larger (normal vs. mild vs. moderate vs. severe = 17.6% vs. 29.2% vs. 41.2% vs. 57.9%, p < 0.001), and a GNRI value of 97.8 was predictive of its occurrence (AUC 0.715, 95% CI 0.649-0.781; specificity/sensitivity = 0.644/0.688). CONCLUSION: These findings indicate that GNRI is an effective nutritional prognostic tool for predicting prognosis and muscle volume loss complication in HCC patients treated with Atez/Bev.

Association of proton pump inhibitor and antibiotic use with the clinical outcomes of hepatocellular carcinoma patients receiving atezolizumab and bevacizumab: A multicenter analysis.

AIM: This retrospective study aimed to investigate the impact of proton pump inhibitor treatment (PPI) and antibiotic treatment on the therapeutic outcomes of hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/Bev). METHODS: The present study included a total of 441 HCC patients who were treated with Atez/Bev in 20 Japanese institutions from September 2020 to April 2022. We adopted the inverse probability of treatment weight to adjust for imbalance in the baseline characteristics of patients with and without PPI treatment as well as patients with and without antibiotic treatment. RESULTS: The progression-free survival (PFS) and overall survival (OS) of patients with and without PPI treatment did not differ to a statistically significant extent. In the weighted cohort, the difference in PFS and OS between the patients with and without PPI did not reach statistical significance (median PFS, 7.0 vs. 6.5 months, p = 0.07; 1-year survival rate 66.3% and 73.8%, p = 0.9). The PFS and OS in patients with antibiotic treatment were worse in comparison to patients without antibiotic treatment (median PFS, 3.8 vs. 7.0 months, p = 0.007; 1-year survival rate 58.8% and 70.3%, p = 0.01). In the weighted cohort, the PFS and OS of the two groups did not differ to a statistically significant extent (median PFS, 3.8 vs. 6.7 months, p = 0.2; 1-year survival rate, 61.8% and 71.0%, p = 0.6). CONCLUSIONS: The therapeutic outcomes of Atez/Bev in HCC patients did not differ between patients with and without PPI treatment or between patients with and without antibiotic treatment.

Impact of first-line systemic therapy with atezolizumab plus bevacizumab in patients with hepatocellular carcinoma.

BACKGROUND AND AIM: The study goal was to compare the outcomes of patients with unresectable hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) as either first- or later-line systemic therapy. METHODS: A total of 430 patients with HCC treated with Atezo/Bev at 22 institutions in Japan were included. Patients treated with Atezo/Bev as first-line therapy for HCC were defined as the first-line group (n = 268) while those treated with Atezo/Bev as second- or later-line therapy were defined as the later-line group (n = 162). RESULTS: The median progression-free survival times in the first- and later-line groups were 7.7 months (95% confidence interval [CI], 6.7-9.2) and 6.2 months (95% CI, 5.0-7.7) (P = 0.021). Regarding treatment-related adverse events, hypertension of any grade was more common in the first-line group than in the later-line group (P = 0.025). Analysis adjusted by inverse probability weighting, including patient and HCC characteristics, showed that the later-line group (hazard ratio, 1.304; 95% CI, 1.006-1.690; P = 0.045) was significantly associated with progression-free survival. In patients with Barcelona Clinic Liver Cancer stage B, the median progression-free survival times in the first- and later-line groups were 10.5 months (95% CI, 6.8-13.8) and 6.8 months (95% CI, 5.0-9.4) (P = 0.021). Among patients with a history of lenvatinib therapy, the median progression-free survival times in the first- and later-line groups were 7.7 months (95% CI, 6.3-9.2) and 6.2 months (95% CI, 5.0-7.7) (P = 0.022). CONCLUSION: The use of Atezo/Bev as first-line systemic therapy in patients with HCC is expected to prolong survival.

Efficacy of hepatitis C virus eradication after curative treatment for hepatocellular carcinoma in patients with advanced hepatocellular carcinoma and decreased hepatic functional reserve: A nationwide, multicentre study by the Japanese Red Cross Liver Study Group.

Improvements in the hepatocellular carcinoma (HCC) recurrence rate and survival have been frequently reported following virus eradication after hepatitis C virus (HCV)-related HCC cure. However, the efficacy of direct-acting antiviral (DAA) therapy in patients who included those with advanced HCC and decreased hepatic functional reserve is unknown. A comparative examination was retrospectively conducted of 141 patients with hepatitis C who started DAA therapy within 1 year after undergoing curative HCC treatment and showed a sustained viral response (SVR) and 327 patients who underwent curative treatment for HCV-related HCC and did not subsequently receive antiviral therapy. Whether DAA therapy was given was identified as an independent factor related to both HCC recurrence and survival. Both the recurrence and survival rates improved significantly with DAA therapy in Child-Pugh (CP)-A, whereas no difference in the recurrence rate was seen with DAA therapy in CP-B. However, the survival rate was significantly higher in the DAA group in this class. Similarly, dividing the patients by the Milan criteria showed significant improvements in the recurrence rate and survival with DAA therapy in patients within the Milan criteria. Patients with HCC beyond the Milan criteria showed no difference in recurrence rates, but the DAA group tended to have higher survival rates. Thus, DAA after curative therapy for HCC can be expected to improve survival in patients with advanced HCC or decreased hepatic functional reserve. HCV should be aggressively eradicated in all patients eligible for curative treatment of HCC.

Optimal threshold of alpha-fetoprotein response in patients with unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Alpha-fetoprotein (AFP) response (relative decline in AFP) is associated with imaging response evaluated by response evaluation criteria in solid tumors ver1.1 (RECIST) and survival in treatment for hepatocellular carcinoma (HCC). However, the optimal threshold of AFP response is still unknown, especially in atezolizumab and bevacizumab (Atez/Bev) treatment. In this prospective multicenter study, we aimed to investigate an optimal threshold of AFP response in Atez/Bev treatment. Out of 284 patients with unresectable HCC who were treated with Atez/Bev, 91 patients with AFP ≥ 10 ng/ml were enrolled in the multicenter study. We investigated the relationship between various AFP response thresholds (relative decline ≥ 20%, ≥ 50%, and ≥ 75%) and treatment response and progression-free survival (PFS). An AFP relative decrease of ≥ 50% was associated with an overall response rate (ORR) with an odds ratio (95% confidence interval [CI]) of 5.7 (1.9-17). Disease control rate (DCR) was associated with an AFP relative decrease of ≥ 20%, with a 100% positive predictive value and a 52.0% sensitivity. AFP relative decreases of ≥ 50% and ≥ 20% were significantly associated with PFS with a hazard ratio (HR) of 5.60 (95% CI: 1.6-19, p = 0.006) and a HR of 4.44 (95% CI: 1.9-10, p < 0.001), respectively. AFP response of ≥ 50% and ≥ 20% were related to ORR and DCR, respectively, and both of these responses were also associated with PFS. AFP can be used as a real-time monitor during Atez/Bev treatment and is helpful for treatment optimization.

Clinical Predictor of Urinary Protein as Adverse Event Associated with Atezolizumab plus Bevacizumab Treatment for Unresectable Hepatocellular Carcinoma.

INTRODUCTION: Adverse events (AEs) of urinary protein from monoclonal antibodies against vascular endothelial growth factor are factors that often inhibit systemic therapy for unresectable hepatocellular carcinoma (uHCC). This study aimed to elucidate risk factors of urinary protein in the early period (<12 weeks) of atezolizumab plus bevacizumab treatment (Atez/Bev). METHODS: From 2020 to June 2022, 193 uHCC patients treated with Atez/Bev at our affiliated hospitals were enrolled (median 73 years, 158 males, 183 Child-Pugh A, BCLC-0:A:B:C = 1:7:73:112). AEs related to urinary protein (≥G2) within 12 weeks were defined as significant, and related clinical features were analyzed retrospectively. RESULTS: In analyses of risk factors of urinary protein-related AEs during the first 12 weeks after starting Atez/Bev using a logistic regression method, univariate analysis showed positive for hypertension (odds ratio [OR] 3.54, 95% CI: 1.28-9.80, p = 0.015) and baseline urinary protein and urine creatinine ratio (UPC: ≥0.16) (OR: 2.52, 95% CI: 1.09-5.83, p = 0.031) as pretreatment clinical factors, while elevation of urinary protein in the early period (baseline to 3 weeks) with delta UPC per 3 weeks (ΔUPC/3W) (≥0.23) (OR: 15.80, 95% CI: 6.15-40.50, p < 0.001) was a clinical factor after starting treatment. Multivariate analysis of only baseline clinical factors revealed positive for history of hypertension as the only predictive factor (OR: 3.20, 95% CI: 1.14-8.95, p = 0.027), while only ΔUPC/3W (≥0.23) (OR: 14.40, 95% CI: 4.91-42.00, p < 0.001) were noted in multivariate analysis including ΔUPC/3W. Predictive factors for ΔUPC/3W (≥0.23) were hypertension (OR: 3.50, 95% CI: 1.23-99.90, p = 0.019) and UPC (≥0.16) (OR: 6.12, 95% CI: 2.61-14.30, p < 0.001) in multiple analysis. DISCUSSION/CONCLUSION: Urinary protein-related AEs are frequently observed during Atez/Bev treatment in uHCC patients with elevated ΔUPC/3W (≥0.23), and ΔUPC/3W (≥0.23) is often seen in patients with hypertension and/or UPC (≥0.16).

Therapeutic efficacy of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma in patients with Child-Pugh class A or B liver function in real-world clinical practice.

BACKGROUND/AIM: Atezolizumab plus bevacizumab (Atez/Bev) treatment is recommended for unresechepatocellular carcinoma (u-HCC) patients classified as Child-Pugh A (CP-A). This study aimed to elucidate the prognosis of patients treated with Atez/Bev, especially CP-A and -B cases. MATERIALS/METHODS: From September 2020 to March 2022, 457 u-HCC patients treated with Atez/Bev were enrolled (median age 74 years, male:female = 368:89, CP-A:CP-B = 427:30, Child-Pugh score [CPS] 5:6:7:8:9 = 271:156:21:8:1). Therapeutic response was evaluated using RECIST ver.1.1. Clinical features and prognosis were retrospectively evaluated. RESULTS: There were no significant differences between CP-A and -B patients in regard to best response (CR:PR:SD:PD = 16:91:194:81 vs. 0:7:13:8, p = 0.739; objective response rate/disease control rate = 28.0%/78.8% vs. 25.0%/71.4%). Analysis performed using inverse probability weighting adjustments of clinical factors other than those related to hepatic reserve function with a p value < 0.10 for comparisons between patients with CP-A and -B showed that the progression-free survival (PFS) rate for CP-A cases was better (6-/12-/18-month: 58.2%/36.1%/27.8% vs. 49.6%/8.7%/non-estimable [NE], p < 0.001), as was overall survival (OS) rate (6-/12-/18-month: 89.9%/71.7%/51.4% versus 63.6%/18.4%/NE; p < 0.001). Median PFS (mPFS) and median OS (mOS) for the CPS-5 were 9.5 months/NE, and 5.1/14.0 months for the CPS-6 (both p < 0.001). Furthermore, for modified albumin-bilirubin grade (mALBI)-1/2a/2b, mPFS was 9.4/8.5/5.3 months (p < 0.001) and mOS was NE/17.8/13.4 months (p < 0.001). CONCLUSION: Better hepatic function, such as mALBI grade 1 or 2a are thought to indicate a better condition for obtaining sufficient prognosis with Atez/Bev treatment for u-HCC patients, whereas for CP-B patients, who mainly shown an mALBI grade of 2b or 3, Atez/Bev might have less therapeutic efficacy.

Time-course changes in liver functional reserve after successful sofosbuvir/velpatasvir treatment in patients with decompensated cirrhosis.

AIM: Direct-acting antivirals (DAAs) are currently available even for patients with decompensated cirrhosis. Reportedly, hepatic functional reserve improved in the short term after achievement of sustained virologic response (SVR). We aimed to clarify the outcomes after achievement of SVR in patients with decompensated cirrhosis who were treated by DAAs in real-world clinical practice. METHODS: A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted in 86 patients with decompensated cirrhosis, who were evaluated for 48 weeks post-treatment. RESULTS: The cohort included 8 patients with Child-Pugh class A, 56 with B, and 22 with C. The proportion of Child-Pugh class A patients increased from 9.1% at baseline to 44.1% at 48 weeks post-treatment, while that of class B and C patients decreased from 66.2% to 35.1% and from 24.7% to 14.3%, respectively. Among the patients with Child-Pugh class B and C, univariate analysis identified low total bilirubin, Child-Pugh score, Child-Pugh class B, ALBI score, and high serum albumin as factors associated with improvement to Child-Pugh class A. The optimal cut-off value of the factors for predicting improvement to Child-Pugh class A were 1.4 mg/dl for total bilirubin, 2.9 g/dl for serum albumin, 8 points for Child-Pugh score, and -1.88 for ALBI score. CONCLUSION: Achievement of SVR with sofosbuvir/velpatasvir improved the liver functional reserve at 12 weeks post-treatment and maintained the stable effects until 48 weeks post-treatment in patients with decompensated cirrhosis. Specifically, the patients with less advanced conditions had the likelihood of improving to Child-Pugh class A at 48 weeks post-treatment.