Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). Its inhibition of VEGF signaling may lead to proteinuria due to endothelial dysfunction but the association between endothelial function and clinical outcomes has not been established. This study aimed to investigate vascular endothelial function in patients with HCC receiving atezolizumab plus bevacizumab, and to assess the correlation between reactive hyperemia index (RHI) and adverse renal outcomes.

This pilot prospective observational study included 20 patients with HCC who received atezolizumab plus bevacizumab. We used reactive hyperemia-peripheral arterial tonometry (RH-PAT) and evaluated vascular endothelial function on the basis of RHI. RHI, blood pressure, and proteinuria were recorded at baseline and at 3 and 6 months after initiation of atezolizumab plus bevacizumab treatment. Statistical analyses were performed to investigate the relationship of RHI to blood pressure and proteinuria.

Following initiation of atezolizumab plus bevacizumab treatment, systolic blood pressure and urine protein-creatinine ratio increased significantly, and RHI decreased. Patients with borderline or low baseline RHI had a higher incidence of grade ≥ 2 proteinuria than those with normal baseline RHI but not hypertension. A significant inverse correlation was found between RHI and urine protein-creatinine ratio.

Bevacizumab administration may cause endothelial dysfunction in patients with HCC. The vascular endothelial function status before and during atezolizumab plus bevacizumab treatment is associated with the risk of bevacizumab-induced proteinuria.

Proteinuria presents a challenging complication during systemic therapy for hepatocellular carcinoma (HCC). This study aims to identify risk factors for proteinuria in patients with HCC treated with atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic treatment.

A retrospective analysis was conducted on 622 consecutive patients with unresectable HCC who received Atezo/Bev or LEN as first-line systemic treatment between October 2013 and October 2022. Cumulative incidence of proteinuria was estimated using Kaplan-Meier curves and compared using log-rank tests. Risk factors for proteinuria were identified using Cox proportional-hazard models, along with propensity score-matched and subgroup analyses.

Among 367 patients treated with Atezo/Bev and 255 with LEN, the cumulative incidence of proteinuria at 12 months was 27.5%. In the multivariable analysis, Atezo/Bev treatment (adjusted HR [aHR]: 1.57; 95% CI: 1.03-2.42), diabetes (aHR: 1.64; 95% CI: 1.03-2.61), hypertension (aHR: 2.27; 95% CI: 1.04-4.97), Child-Pugh class B (aHR: 3.43; 95% CI: 1.34-8.78), macrovascular invasion (MVI; aHR: 1.58; 95% CI: 1.04-2.38), and an estimated glomerular filtration rate ≤60 mL/min/1.73 m2 (aHR: 3.21; 95% CI: 1.84-5.62) were identified as risk factors for proteinuria. A higher risk of proteinuria in Atezo/Bev patients compared with LEN was consistently observed in the PS-matched cohort, particularly pronounced in subgroups with MVI (HR: 2.84; 95% CI: 1.23-6.54) compared with those without MVI (HR: 1.31; 95% CI: 0.69-2.47).

Patients treated with Atezo/Bev as first-line systemic treatment for HCC exhibited a higher risk of proteinuria compared with those with LEN, particularly when accompanied by MVI.

Hepatocellular carcinoma (HCC) is the most prevalent cancer of the hepatobiliary tract and the third leading cause of cancer-related mortality worldwide. Atezolizumab and bevacizumab combination is currently considered among the front-line treatment modalities for advanced unresectable HCC. Most studies examining this combination were focused on evaluating its effectiveness. Despite numerous case reports documenting some side effects, there is a limited number of large-scale studies assessing these side effects. In this article, we comment on the case report by Park et al published recently, reporting a fatal intra-tumoral hemorrhage in a patient with HCC who received systemic therapy in the form of the combination of atezolizumab and bevacizumab.

Safety data for patients with hepatocellular carcinoma (HCC) treated with atezolizumab-bevacizumab in the real-world setting remain uncertain. Thus, the aim of this study was to evaluate the incidence of adverse events (AEs) in patients with HCC treated with atezolizumab-bevacizumab in the literature.

In this systematic review and meta-analysis, we searched PubMed for original studies reporting percentages of AEs in patients with HCC receiving atezolizumab-bevacizumab between 2020 to 2023, using the search terms "Atezolizumab/Bevacizumab", "HCC" and "Adverse events". We summarized the incidence of AEs and performed a meta-analysis in order to evaluate the incidence of AEs reported in the literature.

A total of 30 studies (3,867 patients) were included. The analysis revealed heterogeneity in AE reporting, with arterial hypertension, proteinuria, and fatigue being the most frequently reported AEs whereas incidence of bleeding was reported in 66.7% of the studies and rare immune-related AEs were reported in 26.7% of the studies. The meta-analysis revealed pooled incidence rates of 79% for any grade AEs: 56% for grade 1/2 and 30% for grade ≥3. While the pooled rates of hypertension, anorexia, bleeding, pruritus, rash, and thyroid dysfunction were similar to those reported in the IMbrave150 trial, higher rates were observed in the literature for proteinuria, fatigue, ALT and AST elevations and gastrointestinal perforation. For grade ≥3 AEs, the percentages were consistent with the IMbrave150 trial, except for lower incidences of arterial hypertension and thrombosis in the literature. The exposure-adjusted incidence rates for proteinuria (55.7%), hypertension (45.3%) and fatigue (33.6%) were high. Heterogeneity was observed in the analysis of AEs across articles within the same cohorts of patients.

We observed a significant variability in AE reporting for atezolizumab-bevacizumab treatment in HCC in the literature, underscoring the need for standardized reporting practices.

Considering the demonstrated safety of atezolizumab-bevacizumab in randomized-controlled trials, this meta-analysis offers valuable insights into reported occurrences of adverse events. Our study highlights significant heterogeneity among studies, underscoring the need to improve adverse event recording. Understanding the incidence and severity of treatment-related adverse events beyond clinical trials is essential for prompt intervention and may help in preventing treatment discontinuation and complications, potentially leading to better outcomes without significantly compromising quality of life due to adverse events.

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death worldwide. surgery, transarterial chemoembolization (TACE), systemic therapy, local ablation therapy, radiotherapy, and targeted drug therapy with agents such as sorafenib. However, the tumor microenvironment of liver cancer has a strong immunosuppressive effect. Therefore, new treatments for liver cancer are still necessary. Immune checkpoint molecules, such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4), along with high levels of immunosuppressive cytokines, induce T cell inhibition and are key mechanisms of immune escape in HCC. Recently, immunotherapy based on immune checkpoint inhibitors (ICIs) as monotherapy or in combination with tyrosine kinase inhibitors, anti-angiogenesis drugs, chemotherapy agents, and topical therapies has offered great promise in the treatment of liver cancer. In this review, we discuss the latest advances in ICIs combined with targeted drugs (targeted-immune combination) and other targeted-immune combination regimens for the treatment of patients with advanced HCC (aHCC) or unresectable HCC (uHCC), and provide an outlook on future prospects. The literature reviewed spans the last five years and includes studies identified using keywords such as "hepatocellular carcinoma," "immune checkpoint inhibitors," "targeted therapy," "combination therapy," and "immunotherapy".

Real-world data regarding treatment with atezolizumab plus bevacizumab in high-risk patients with advanced HCC are lacking. In this multicenter retrospective cohort study, a total of 215 patients with advanced HCC received atezolizumab plus bevacizumab treatment at four tertiary hospitals. High-risk patients were those with grade Vp4 portal vein thrombus, bile duct invasion, or more than 50% liver infiltration. In total, 98 (45.6%) were the high-risk population, 186 (86.5%) were considered to be Child-Pugh class A, and 128 (59.5%) had previously received neoadjuvant or concomitant radiation treatment. Median overall survival (OS) was 11.25 months (95% CI, 9.50-13.10), and the median progression-free survival (PFS) was 8.00 months (95% CI, 6.82-9.18). In the high-risk population, the median OS was 10 months (95% CI, 8.19-11.82) and the median PFS was 6.50 months (95% CI, 3.93-9.08). In the high-risk population, multivariate analysis indicated that radiation therapy and lower ALBI grade were associated with better OS and PFS. A total of 177 (82.3%) patients experienced adverse events of any grade, the most common being proteinuria (23.7%). Atezolizumab plus bevacizumab treatment showed consistent efficacy and tolerability in both the total and high-risk population. Radiation therapy combined with atezolizumab plus bevacizumab treatment might be helpful to improve PFS and OS in high-risk populations.

The treatment efficiency and predictors of atezolizumab plus bevacizumab therapy for unresectable hepatocellular carcinoma in real-world practice have not been established. This study aimed to assess the efficacy and safety of atezolizumab plus bevacizumab and to investigate predictors of progression-free survival and overall survival. Patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab therapy in 19 hospitals were enrolled before treatment and observed prospectively. The outcomes of 222 patients in this cohort were analyzed. The objective response rate and disease control rate were 22.0% and 70.6%, respectively, whereas the median progression-free survival was 5.7 months. Independent risk factors for shortened progression-free survival were younger age (<75 years; 3.9 months vs. 8.6 months), higher number of intrahepatic tumors (≥5; 4.0 months vs. 7.9 months), macrovascular invasion (2.3 months vs. 6.7 months), and higher neutrophil-to-lymphocyte ratio (≥3.03; 3.0 months vs. 7.8 months). The median overall survival was not reached; however, independent risk factors for shortened overall survival were absence of hyperlipidemia, higher number of intrahepatic tumors (≥5), macrovascular invasion, higher α-fetoprotein level (≥400 ng/mL), worse Child-Pugh score (≥6), and higher neutrophil-to-lymphocyte ratio (≥3.03). Severe adverse events (grade ≥3) were observed in 96 patients (36.0%), with proteinuria being the most frequent. In conclusion, patients with older age, lower number of intrahepatic tumors, absent macrovascular invasion, and lower neutrophil-to-lymphocyte ratio are expected to have better progression-free survival with atezolizumab plus bevacizumab therapy for unresectable hepatocellular carcinoma.

Cabozantinib was found to be effective as a second- or third-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) in the phase 3 CELESTIAL trial. So far, as immunotherapy has substituted molecular target agents as the primary systemic therapy for advanced HCC, cabozantinib is extensively used in the latest real-world clinical practice in a greatly different position than that shown by the CELESTIAL trial. In the current analysis, we examined the safety and effectiveness of cabozantinib administration in real-life settings for patients with advanced HCC.

We retrospectively obtained data from patients with advanced HCC who received cabozantinib in three institutions in Japan between 14 September 2018 and 30 November 2021.

During the study period, 23 patients with advanced HCC received cabozantinib. Our cohort included 21.7% of patients with Child-Pugh class B, and 52.2% of patients in fourth line or later. The median progression-free survival of patients given cabozantinib was 3.7 months. Regarding patients with Child-Pugh class B or administration in fourth line or later, the discontinuation rate due to adverse events in patients who initialized at 40 or 20 mg was lower than those who initialized at 60 mg (42.9% versus 75.0%). Patients who were able to continue treatment with cabozantinib for more than 3 months were more likely to undergo dose reduction than those who did not (85.7% versus 25.0%).

Cabozantinib has recently been administered to a diverse range of patients, including those who were not enrolled in the CELESTIAL trial. Deliberate dose reduction could potentially offer clinical benefits to patients with impaired liver function. Furthermore, managing adverse events by reducing the dose could play a crucial role in extending the duration of treatment with cabozantinib. The preprint version of this work is available on https://www.researchsquare.com/article/rs-2655181/v1 .

This retrospective multicenter study analyzed 244 patients with unresectable hepatocellular carcinoma treated with lenvatinib (LEN) and atezolizumab + bevacizumab (Atezo + Bev) to examine the characteristics, treatment courses, and prognoses. The cases of patients who could achieve HCC downstaging from Barcelona Clinic Liver Cancer (BCLC) stage B or C to A or zero indicated the need for conversion therapy. The patients' prognoses with and without conversion therapy were compared. Of the 244 patients, 12 (4.9%) underwent conversion therapy, six out of 131 (4.6%) were treated with LEN, and six out of 113 (5.3%) were treated with Atezo + Bev. Eleven patients (91.7%) with a modified albumin bilirubin (mALBI) grade 1 or 2a and BCLC-B stage showed significantly higher rates of transition during conversion therapy (p < 0.05). The patients undergoing conversion therapy had a significantly longer median overall survival rate than those receiving chemotherapy alone (1208 [1064-NA] vs. 569 [466-704] days, p < 0.01). A comparison of the patients who achieved a partial response with and without conversion was evaluated using propensity score matching to reduce the confounding factors, showing a significant survival benefit in the conversion group (1208 [1064-NA] vs. 665 days, p < 0.01). Among the patients with u-HCC who were treated with LEN and Atezo + Bev, those with mALBI 1 + 2a and BCLC-B were likely to achieve conversion therapy with downstaging.

Hepatocellular carcinoma (HCC) is one of the most common leading causes of cancer death worldwide. As most patients are diagnosed with advanced disease, systemic therapy remains the backbone of treatment. In recent years, we have witnessed the transformation of advanced HCC treatment landscapes from single-agent targeted therapies to immunotherapy combinations, with atezolizumab plus bevacizumab becoming the new first-line standard of care with an increase in overall survival, progression-free survival, and objective response rate compared to sorafenib, and a positive impact on quality of life. Although the efficacy and safety of this combination have been confirmed regardless of ethnicity, age, and etiology, only a subgroup of patients seems to benefit the most from this treatment. Currently, predictive serum and tissue biomarkers to select patients who are most likely to respond to atezolizumab plus bevacizumab are lacking. Moreover, the optimal subsequent therapy for patients who progress on first-line atezolizumab plus bevacizumab remains unknown, clinical trials are ongoing, and real-world data are needed to determine the most effective treatment sequence. Importantly, careful evaluation of bleeding risk and preservation of adequate liver function are fundamental to improve patients' prognosis, especially when subsequent treatments are administered.

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.

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).

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).

The use of Atezo/Bev as first-line systemic therapy in patients with HCC is expected to prolong survival.