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Background: Atezolizumab plus bevacizumab (Atezo/Bev) is frequently selected as the primary systemic therapy for hepatocellular carcinoma (HCC)., Aims: To investigate the outcomes of patients with HCC treated with Atezo/Bev in a real-world setting based on whether they met the inclusion criteria for the phase 3 IMbrave150 trial., Methods: A total of 936 patients were enrolled. There were 404 patients who met the inclusion criteria of the phase 3 IMbrave150 trial (IMbrave150 group) and 532 who did not (non-IMbrave150 group)., Results: Median progression-free survival (PFS) in the IMbrave150 and non-IMbrave150 groups was 7.4 months and 5.6 months (p = 0.002). Multivariable analysis revealed that non-B, non-C HCC aetiology (hazard ratio [HR], 1.173), α-fetoprotein ≥100 ng/mL (HR, 1.472), Barcelona Clinic Liver Cancer stage ≥ C (HR, 1.318), and modified albumin-bilirubin (mALBI) grade 2b or 3 (HR, 1.476) are independently associated with PFS. Median overall survival (OS) in the IMbrave150 and non-Imbrave150 groups was 26.5 and 18.8 months (p < 0.001). Multivariable analysis revealed that Eastern Cooperative Oncology Group performance status ≥2 (HR, 1.986), α-fetoprotein ≥100 ng/mL (HR, 1.481), and mALBI grade 2b or 3 (HR, 2.037) are independently associated with OS. In subgroup analysis, there were no significant differences in PFS or OS between these groups among patients with mALBI grade 1 or 2a., Conclusions: Patients who are treated with Atezo/Bev and meet the inclusion criteria for the phase 3 IMbrave150 trial, as well as those who do not meet the inclusion criteria but have good liver function, have a good prognosis for survival., (© 2024 John Wiley & Sons Ltd.)

Background: In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors., Objective: This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting., Patients and Methods: The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea)., Results: Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13-0.90; p < 0.01] and immunotoxicity G < 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24-0.99; p = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43-0.95; p = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38-0.85; p = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65-0.95; p < 0.01), arterial hypertension G < 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52-0.87; p < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64-0.98; p = 0.03) as independent prognostic factors for progression-free survival., Conclusions: As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab., (© 2024. The Author(s).)

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.)

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. [ABSTRACT FROM AUTHOR]

Aim: This retrospective study compared the impact of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) on the liver function in patients with hepatocellular carcinoma. Methods: We included 526 patients who received Atez/Bev and 731 who received LEN March 2018 and July 2022 in this study. We conducted a 1:1 propensity‐score‐matched analysis and identified 324 patients in each group for inclusion in the present analysis. Nonlinear mixed‐effects regression models were employed, allowing for the evaluation and inclusion of cases where treatment was interrupted due to disease progression, adverse events, or loss to follow‐up. These models were used to compare the ALBI score between the Atez/Bev and LEN groups. Results: Following propensity score matching, the mean ALBI scores in the Atez/Bev and LEN groups were −2.41 ± 0.40 and −2.44 ± 0.42 at baseline, and −2.17 ± 0.56 and −2.19 ± 0.58 at 12 weeks, respectively. Although the ALBI score significantly worsened during treatment in both groups (p < 0.001), there was no significant difference in the rate of ALBI score deterioration between the groups (p = 0.06). Subgroup analyses showed that LEN‐treated patients with BCLC advanced stage (p = 0.02) and those who initially received the full dose (p < 0.001) had a significantly greater worsening of ALBI score compared to Atez/Bev. Conclusions: Using a nonlinear mixed‐effects regression approach, which allowed for the inclusion of cases with treatment interruption, we found no significant difference in the trend of liver function deterioration between the Atez/Bev and LEN groups. Caution should be exercised for LEN‐treated patients with BCLC advanced stage or those receiving the full dose of LEN. [ABSTRACT FROM AUTHOR]

Background: Bevacizumab inhibits vascular endothelial growth factor-A (VEGF-A), though is known to increase bleeding risk as an adverse event (AE). This study examined whether atezolizumab/bevacizumab (Atez/Bev) for unresectable hepatocellular carcinoma (uHCC) can be used for patients with esophageal–gastric varices (EGV). Methods: From October 2020 to December 2022, 506 uHCC patients (median 74 years) underwent an upper gastrointestinal endoscopy examination were enrolled, after exclusion of those with portal vein tumor thrombus (PVTT). Patients with EGV (≧ F1) were defined as EGV positive, and the cohort was divided into non-EGV (n = 355) and EGV (n = 151). Before introducing Atez/Bev, endoscopic treatment was performed, when necessary. Prognosis was evaluated, retrospectively. Results: The EGV group had significantly worse hepatic function, lower platelet count, elevated alpha-fetoprotein, and lower rate of extrahepatic metastasis, and lower rate of first-line use (each P < 0.05) than the other. However, progression-free survival (PFS) was also not a significantly difference between the EGV and non-EGV groups in analyses with (PFS rate at 6/12/18 months: 60%/38%/30% vs. 65%/46%/34%, P = 0.29) or without inverse probability weighting adjustment [median: 10.6 months (95% CI 8.3–14.0) vs. 10.5 months (95% CI 7.8–13.7), P = 0.79]. As for AEs, diarrhea was more frequent in the EGV group (≧ G3: 2.0% vs. 0.3%, P = 0.036), while no significant difference was noted for EGV hemorrhage (≧ G3: 1.3% vs. 0.6%, P = 0.345). Of 28 patients who underwent endoscopic treatments before introducing Atez/Bev, none showed EGV-associated hemorrhage. Conclusions: Atez/Bev might be an effective therapeutic option in patients with EGV, when appropriate endoscopic treatment for EGV is performed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Atezolizumab plus bevacizumab (Atez/Bev) is the first-line treatment for unresectable advanced hepatocellular carcinoma (HCC). The tumor markers (TMs) for HCC include alpha-fetoprotein (AFP), fucosylated alpha-fetoprotein (AFP-L3), and des-gamma carboxyprothrombin (DCP). A TM score combining these markers has been reported to be useful in predicting HCC prognosis. This retrospective study aimed to evaluate the ability of this previously reported TM score involving AFP, AFP-L3, and DCP as TMs in predicting prognosis and therapeutic efficacy in HCC patients administered Atez/Bev as first-line treatment. The TM score was found to be effective in stratifying overall survival and progression-free survival in 371 patients with unresectable advanced HCC treated with Atez/Bev. The TM score proved to be a simple and useful prognostic marker and therapeutic efficacy indicator for advanced HCC patients administered Atez/Bev as first-line treatment. Aim: This study aimed to evaluate the ability of a previously reported tumor marker (TM) score involving alpha-fetoprotein (AFP), fucosylated AFP (AFP-L3), and des gamma-carboxy prothrombin (DCP) as TMs in predicting the prognosis and therapeutic efficacy in hepatocellular carcinoma (HCC) patients administered atezolizumab plus bevacizumab (Atez/Bev) as first-line treatment. Materials/Methods: The study period covered September 2020 to December 2022 and involved 371 HCC patients treated with Atez/Bev. The values of the TMs AFP, AFP-L3, and DCP were measured upon introducing Atez/Bev. Elevations in the values of AFP (≥100 ng/mL), AFP-L3 (≥10%), and DCP (≥100 mAU/mL) were considered to indicate a positive TM. The number of positive TMs was summed up and used as the TM score, as previously proposed. Hepatic reserve function was assessed using the modified albumin–bilirubin grade (mALBI). Predictive values for prognosis were evaluated retrospectively. Results: A TM score of 0 was shown in 81 HCC patients (21.8%), 1 in 110 (29.6%), 2 in 112 (29.9%), and 3 in 68 (18.3%). The median overall survival (OS) times for TM scores 0, 1, 2, and 3 were not applicable [NA] (95% CI NA-NA), 24.0 months (95% CI 17.8-NA), 16.7 months (95% CI 17.8-NA), and NA (95% CI 8.3-NA), respectively (p < 0.001). The median progression-free survival (PFS) times for TM scores 0, 1, 2, and 3 were 16.5 months (95% CI 8.0-not applicable [NA]), 13.8 months (95% CI 10.6–21.3), 7.7 months (95% CI 5.3–8.9), and 5.8 months (95% CI 3.0–7.6), respectively (p < 0.001). OS was well stratified in mALBI 1/2a and mALBI 2a/2b. PFS was well stratified in mALBI 2a/2b, but not in mALBI 1/2a. Conclusions: The TM score involving AFP, AFP-L3, and DCP as TMs was useful in predicting the prognosis and therapeutic efficacy in terms of OS and PFS in HCC patients administered Atez/Bev as first-line treatment. [ABSTRACT FROM AUTHOR]

Aim: Multiple studies have revealed the correlation between gut microbiome and the response to checkpoint inhibitors (CPIs) in patients with cancer, and oral administration of butyrate‐producing enterobacteria has been reported to enhance the efficacy of CPIs. However, the effects of enterobacteria on patients with hepatocellular carcinoma (HCC) are not well understood. Methods: In this retrospective multicenter study, we enrolled 747 patients with advanced HCC, treated with atezolizumab and bevacizumab combination therapy. Tumor response, survival, and adverse effects were compared between 99 patients who ingested drugs containing butyric acid‐producing enterobacteria (butyric acid group) and the remaining patients (control group). Results: Objective response and disease control rates in butyric acid group (29.7% and 77.8%, respectively) were higher than those in the control group (26.4% and 72.7%, respectively). However, the differences were not statistically significant (p = 0.543 and p = 0.222, respectively). No difference in median survival time was observed between the two groups (20.0 months and 21.4 months, respectively; p = 0.789), even after matching the backgrounds of the patients with propensity scores (p = 0.714). No adverse effects occurred upon the administration of butyrate‐producing bacteria. However, proteinuria (41.4% vs. 30.9%; p = 0.041), fever (17.2% vs. 10.2%, p = 0.036), and diarrhea (15.2% vs. 6.2%; p = 0.001) occurred more frequently in the butyric acid group. Conclusion: Butyrate‐producing bacteria does not enhance the efficacy of atezolizumab–bevacizumab combination therapy in patients with HCC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/Aim: There is no known report regarding the relationship of atezolizumab plus bevacizumab (Atez/Bev) treatment with muscle volume loss (MVL) in unresectable hepatocellular carcinoma (u-HCC) patients. This study aimed to elucidate the clinical relationship between MVL and Atez/Bev. Materials/Methods: From September 2020 to December 2021, 229 u-HCC patients treated with Atez/Bev and with muscle volume data obtained by computed tomography at the baseline available were analyzed (median age, 74 years; males, 186 (81.2%); ECOG PS 0/1, 221 (96.5%); HCV:HBV:alcohol:others = 81:33:40:75; Child-Pugh A, 212 (92.6%); modified albumin-bilirubin (mALBI) grade 1:2a:2b = 79:60:90; BCLC 0:A:B:C = 1:24:87:117; median observation period, 6.8 months). Japan Society of Hepatology criteria were used for definition of MVL and prognostic factors were retrospectively evaluated. Results: Multivariate Cox-hazard analysis of prognostic factors for progression-free survival (PFS) showed elevated alpha-fetoprotein (AFP) (≥100 ng/mL) (HR 1.848, 95% CI 1.264–2.702, p = 0.002), mALBI grade (≥2a) (HR 1.563, 95% CI 1.035–2.359, p = 0.034), and MVL (HR 1.479, 95% CI 1.020–2.144, p = 0.039) as significant factors. For overall survival (OS), significant factors included elevated AFP (≥100 ng/mL) (HR 3.564, 95% CI 1.856–6.844, p < 0.001), mALBI grade (≥2a) (HR 3.451, 95% CI 1.580–7.538, p = 0.002), and MVL (HR 2.119, 95% CI 1.150–3.904, p = 0.016). Patients with MVL (MVL group, n = 91) showed worse PFS than those without (non-MVL group, n = 138) (median PFS 5.3 vs. 7.6 months, p = 0.025), while the MVL group showed worse OS (p = 0.038), though neither reached the median survival time. Conclusion: MVL may be a clinical factor related to poor prognosis in patients receiving Atez/Bev treatment for u-HCC. [ABSTRACT FROM AUTHOR]

Aim: To investigate the possible correlation between the development of adverse events (AEs) and prognosis in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev). Methods: A total of 286 patients with unresectable HCC treated with Atez/Bev as first‐line systematic therapy were included. Results: Regarding treatment‐related AEs, decreased appetite of any grade, proteinuria of any grade, and fatigue of any grade were found with a frequency of ≥20%. Multivariate analysis adjusted for immune‐related liver injury, immune‐related endocrine dysfunction, proteinuria, fatigue, decreased appetite, hypertension, sex, age, Eastern Cooperative Oncology Group performance status, HCC etiology, HCC stage, Child–Pugh score, and α‐fetoprotein showed that hypertension of any grade (hazard ratio [HR], 0.527; 95% confidence interval [CI], 0.326–0.854; p = 0.009) and α‐fetoprotein ≥100 ng/ml (HR, 1.642; 95% CI, 1.111–2.427; p = 0.013) were independently associated with progression‐free survival. Multivariate analysis adjusted for the same AEs showed that fatigue (HR, 2.354; 95% CI, 1.299–4.510; p = 0.010) was independently associated with overall survival. Median progression‐free survival was 6.5 months (95% CI, 5.2–8.1) in patients without hypertension of any grade and 12.6 months (95% CI, 6.7–not available) in patients with hypertension of any grade (p = 0.035). The overall survival was significantly shorter in patients in whom treatment‐related fatigue of any grade was observed (p < 0.001). Regarding response rates, the disease control rate of patients who developed treatment‐related hypertension (94.2%) was significantly higher than those who did not (79.1%) (p = 0.009). Conclusions: Treatment‐related hypertension is associated with good outcomes in patients with HCC treated with Atez/Bev. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: Recently, the neo‐Glasgow prognostic score (GPS), a composite biomarker determined by the C‐reactive protein level and albumin–bilirubin grade, was developed to predict outcomes in hepatocellular carcinoma (HCC) patients who undergo hepatic resection. The present research investigated whether the neo‐GPS could predict prognosis in HCC patients treated with atezolizumab plus bevacizumab (Atez/Bev). Methods: A total of 421 patients with HCC who were treated with Atez/Bev were investigated. Results: Multivariate Cox hazards analysis showed that a GPS of 1 (hazard ratio (HR), 1.711; 95% confidence interval (CI), 1.106–2.646) and a GPS of 2 (HR, 4.643; 95% CI, 2.778–7.762) were independently associated with overall survival. Conversely, multivariate Cox hazards analysis showed that a neo‐GPS of 1 (HR, 3.038; 95% CI, 1.715–5.383) and a neo‐GPS of 2 (HR, 5.312; 95% CI, 2.853–9.890) were also independently associated with overall survival in this cohort. Additionally, cumulative overall survival rates differed significantly by GPS and neo‐GPS (p < 0.001). The neo‐GPS, compared with the GPS, had a lower Akaike information criterion (1207 vs. 1,211, respectively) and a higher c‐index (0.677 vs. 0.652, respectively) regarding to overall survival. In a subgroup analysis of patients considered to have a good prognosis as confirmed using a Child–Pugh score of 5 (p = 0.001), a neutrophil‐to‐lymphocyte ratio <3 (p = 0.001), or an α‐fetoprotein level < 100 ng/mL (p < 0.001), those with a high neo‐GPS (≥1) had a statistically poorer overall survival than those with a low neo‐GPS. Conclusions: The neo‐GPS can predict prognosis in advanced unresectable HCC patients treated with Atez/Bev. [ABSTRACT FROM AUTHOR]

Aim: This study compared the efficacy and safety of atezolizumab and bevacizumab (Atez/Bev) in patients with viral and non‐viral infection in clinical settings. Methods: We conducted the retrospective cohort study of 323 BCLC stage B or C hepatocellular carcinoma (HCC) patients with Child‐Pugh class A, and a performance status of 0 or 1 who started Atez/Bev from September 2020 to December 2021 at 22 institutions in Japan. Patients with viral infection was defined as those who were either serum anti‐HCV‐ Ab or HBs‐Ag‐positive, while patients with non‐viral infection was defined as those who were both serum anti‐HCV Ab‐ and HBs‐Ag‐negative. We constructed a propensity‐score‐matched cohort to minimize the risk of observable potential confounders. Results: Propensity score matching produced 126 matched pairs for patients with viral versus non‐viral infection. After matching, the significant differences in baseline demographic features did not exist between the two groups. The objective response rate was 20.6% and 24.6% in viral‐ and non‐viral‐related HCC patients, respectively, without a significant difference (p = 0.55). The disease control rate was not also significantly different (68.3% vs 69.0%, p = 1.00). The median progression‐free survival was 7.0 months (95% confidence interval [CI] 6.0–9.6) and 6.2 months (95% CI 5.1–7.8) in patients with viral and non‐viral infection, and the 12‐month survival rates were 65.5% (95% CI 50.8–76.8) and 71.7% (95% CI 57.3–81.9) in those with viral and non‐viral infection, respectively, which were not significantly different (p = 0.33, p = 0.38). No significant difference in treatment‐related adverse events was found between the two groups. Conclusions: Our etiology‐based study demonstrated that Atez/Bev showed good efficacy and safety for HCC patient with non‐viral infection as well as those with viral infection. [ABSTRACT FROM AUTHOR]

Introduction: We previously reported 2 cases of esophageal varices rupture during atezolizumab and bevacizumab (Atez/Bev) treatment, in which the spleen volume gradually increased. The aim of this retrospective study is to compare the chronological change in spleen volume of patients treated with Atez/Bev and lenvatinib (LEN). Methods: Seventy-two patients (Atez/Bev group, n = 26; LEN group, n = 46) were included in this retrospective study. The splenic parenchyma area was measured based on CT imaging. We used mixed-effect regression models with random intercepts to test the difference in the rate of change in spleen volume between the Atez/Bev and LEN groups. Results: The median age of the Atez/Bev and LEN groups was 74.0 (71.0–82.0) and 72.0 (67.5–76.0), respectively. About 80% patients were male. The mALBI grade was classified as 1, 2a, 2b, and 3 in 10 (38.5%), 6 (23.1%), 10 (38.5%), and zero (0.0%) patients, respectively, in the Atez/Bev group and 21 (45.7%), 9 (19.6%), 15 (32.6%), and 1 (2.2%) patient in the LEN group (p = 0.9). The median baseline neutrophil-to-lymphocyte ratio (NLR) was 2.61 (1.80–3.41) in the Atez/Bev group and 2.71 (1.76–3.67) in the LEN group (p = 1.0). The median baseline spleen volume was 185 (132–246) cm3 in the Atez/Bev group and 231 (150–355) cm3 in the LEN group. The spleen volume gradually increased during Atez/Bev treatment (2.41 cm3 per week), while it was mostly consistent during LEN treatment (0.32 cm3 per week). Among patients with mALBI grade 2b or 3, the spleen volume increased in the Atez/Bev group (2.99 cm3 per week) and slightly decreased in the LEN group (0.82 cm3 per week), without statistical significance (p = 0.07). Among patients with a baseline NLR of >2.68, the spleen volume increased at a rate of 2.57 cm3 per week in the Atez/Bev group and decreased at a rate of 1.18 cm3 per week in the LEN group. The difference in the slope of the two groups was statistically significant (p = 0.04). Discussion/Conclusion: Atez/Bev treatment could result in an increased spleen volume. Caution is required when managing patients treated with Atez/Bev, especially those with a high NLR. [ABSTRACT FROM AUTHOR]

Background/Aim: A comparison of therapeutic efficacy between atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib treatment given as first‐line therapy for unresectable hepatocellular carcinoma (u‐HCC) in regard to progression‐free survival (PFS) overall survival (OS) has not been reported. We aimed to elucidate which of those given as initial treatment for u‐HCC has greater prognostic impact on PFS and OS of affected patients, retrospectively. Materials/Methods: From 2020 to January 2022, 251 u‐HCC (Child–Pugh A, ECOG PS 0/1, BCLC‐B/C) treated were enrolled (Atez/Bev‐group, n = 194; lenvatinib‐group, n = 57). PFS and OS were analyzed following adjustment based on inverse probability weighting (IPW). Results: There was a greater number of patients with macro‐vascular invasion in Atez/Bev‐group (22.7% vs. 8.8%, p = 0.022). In lenvatinib‐group, the frequencies of appetite loss (38.6% vs. 19.6%, p = 0.002), hypothyroidism (21.1% vs. 6.7%, p = 0.004), hand foot skin reaction (19.3% vs. 1.0%, p < 0.001), and diarrhea (10.5% vs. 4.6%, p = 0.012) were greater, while that of general fatigue was lower (22.8% vs. 26.3%, p = 0.008). Comparisons of therapeutic best response using modified response evaluation criteria in solid tumors (mRECIST) did not show significant differences between the present groups (Atez/Bev vs. lenvatinib: CR/PR/SD/PD = 6.1%/39.1%/39.1%/15.6% vs. 0%/48.0%/38.0%/14.0%, p = 0.285). In patients of discontinuation of treatments, 48.2% switched to lenvatinib, 10.6% continued beyond PD, 8.2% received another systemic treatment, 5.9% underwent transcatheter arterial chemoembolization (TACE), 3.5% received hepatic arterial infusion chemotherapy (HAIC), and 1.2% underwent surgical resection in Atez/Bev‐group, while 42.2% switched to Atez/Bev, 4.4% continued beyond PD, 4.4% received another systemic treatment, 2.2% nivolumab, 6.7% received TACE, and 2.2% received HAIC in lenvatinib‐group. Following adjustment with inverse probability weighting (IPW), Atez/Bev‐group showed better PFS (0.5−/1−/1.5‐years: 56.6%/31.6%/non‐estimable vs. 48.6%/20.4%/11.2%, p < 0.0001) and OS rates (0.5−/1−/1.5‐years: 89.6%/67.2%/58.1% vs. 77.8%/66.2%/52.7%, p = 0.002). Conclusion: The present study showed that u‐HCC patients who received Atez/Bev as a first‐line treatment may have a better prognosis than those who received lenvatinib. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Aim: The safety and efficacy of atezolizumab plus bevacizumab (Atez/Bev) in elderly patients with unresectable hepatocellular carcinoma (HCC) have not been sufficiently investigated. Methods: A total of 317 patients with HCC treated with Atez/Bev were studied. We compared the survival and frequency of adverse events in elderly versus non‐elderly patients with HCC who were treated with Atez/Bev using an analysis of inverse probability weighting (IPW). Results: Univariate analysis adjusted with IPW showed that being elderly is not associated with worse overall or progression‐free survival (hazard ratio [HR], 1.239; 95% confidence interval [CI], 0.640–2.399; p = 0.526 and HR, 1.256; 95% CI, 0.871–1.811; p = 0.223, respectively). Regarding treatment‐related adverse events, any grade of fatigue, proteinuria, decreased appetite, hypertension, and liver injury occurred in ≥10% of patients. There were no significant differences in treatment‐related adverse events between the elderly and non‐elderly groups. In a subgroup analysis of elderly patients aged 75–79, 80–84, or ≥ 85 years, there were no significant differences in cumulative overall or progression‐free survival among these age groups (p = 0.960 and 0.566, respectively). In addition, there were no significant differences in treatment‐related adverse events among these three age groups, except for proteinuria of any grade. In a subgroup analysis of patients treated with Atez/Bev as first‐line systemic therapy, there were no significant differences in cumulative overall or progression‐free survival between the elderly and non‐elderly groups (p = 0.728 and 0.805, respectively). Conclusions: Atez/Bev can be used efficaciously and safely in spite of age in patients with unresectable HCC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

An 81‐year‐old man initially underwent right hepatic lobectomy for liver cancer and was pathologically diagnosed with combined hepatocellular and cholangiocarcinoma (CHC). At 13 months after resection, multiple lymph node metastases were observed. We started atezolizumab plus bevacizumab (Atez/Bev), achieving a 7.5‐month progression‐free survival. Atez/Bev might exhibit efficacy for CHC patients. [ABSTRACT FROM AUTHOR]

Aim: The present study focused on the association of early bevacizumab (Bev) interruption with the clinical outcome of atezolizumab plus bevacizumab. Methods: This retrospective study included 239 patients with advanced hepatocellular carcinoma receiving atezolizumab/Bev from September 2020 to June 2021 at 16 different institutions in Japan. We conducted a 9‐week landmark analysis to investigate the association of Bev interruption due to adverse events with the therapeutic efficacy. Results: The median age was 73.0 (68.0–80.0) years old, with 195 (81.6%) men. The objective response rate was significantly higher in patients without Bev interruption than in those with it (34.5% vs. 17.3%, p = 0.038). The median progression‐free survival (PFS) was 6.5 months (95% confidence interval [CI] 4.5–9.7) and 9.0 months (95% CI 7.1–not applicable) in patients with and without Bev interruption, respectively, with statistical significance (p = 0.021). The 12‐month overall survival (OS) rates in patients with and without Bev interruption were 49.4% (CI 27.7%–67.9%) and 82.2% (95% CI 70.3%–89.6%), respectively, showing a significant difference (p = 0.004). The presence of Bev interruption was a significant factor associated with the PFS (p = 0.021) and OS (p = 0.008). A multivariate analysis showed that modified albumin–bilirubin 2b (p < 0.001) and later‐line treatment (p = 0.018) were unfavorable factors associated with Bev interruption. Liver injury, appetite loss, protein urea, and ascites or hepatic edema were more frequently found in patients with Bev interruption than in those without it. Conclusions: Early Bev interruption was an unfavorable factor associated with the PFS and OS. Good liver function and treatment settings may be associated with maintaining Bev treatment. [ABSTRACT FROM AUTHOR]

Background/Aim: Although systemic therapy is recommended for patients with multiple intermediate stage unresectable hepatocellular carcinoma (u‐HCC) classified as beyond the up‐to‐7 criteria (UT‐7 out/multiple) as a transcatheter arterial chemoembolization (TACE) unsuitable condition, few reports have examined the therapeutic efficacy of atezolizumab plus bevacizumab combination therapy (Atez/Bev) in such cases. This study aimed to elucidate the therapeutic response of Atez/Bev in u‐HCC patients classified as UT‐7 out/multiple. Material/Methods: From September 2020 to September 2021, 95 u‐HCC Japanese patients classified as UT‐7 out/multiple/Child‐Pugh A were enrolled from 21 institutions (median age 76 years, males 73, Child‐Pugh 5:6 = 68:27, TNM stage II:III = 17:78). Therapeutic response was retrospectively evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1 and modified RECIST (mRECIST). Results: Atez/Bev was given as first‐line treatment to 52 (54.7%). Objective response rate (ORR)/disease control rate (DCR) at six weeks of RECIST and mRECIST were 17.7%/84.7% and 42.5%/86.2%, respectively. Median PFS was 8.0 months (median observation period: 6.0 months). Child‐Pugh A/modified Albumin‐bilirubin grade (mALBI) 1 and 2a at baseline, 3, 6, and 9 weeks, were 100%/69.4%, 89.8%/57.3%, 94.8%/65.3%, and 91.4%/60.0%, respectively. Among adverse events (any‐grade, >10%) during the present observation period, general fatigue was most frequent (23.2%), followed by urine protein (21.1%), appetite loss (20.0%), and hypertension (13.7%). Conclusion: Atez/Bev treatment showed favorable therapeutic response with less influence on hepatic function, suggesting it as a useful therapeutic option for patients with such condition. [ABSTRACT FROM AUTHOR]