Early mortality in atezolizumab/bevacizumab for HCC is associated with impaired liver function and alterations of systemic immunity.

Background & Aims: Atezolizumab/bevacizumab (atezo/bev) has revolutionized the standard of care for patients with unresectable hepatocellular carcinoma (HCC). However, only a subgroup of patients responds to atezo/bev and derives durable clinical benefit. This study aims to analyze the frequency and risk factors of early mortality (EM) in patients with HCC treated with atezo/bev. Methods: This study uses data from a large, European real-world cohort and flow cytometry-based immunophenotyping of patient's baseline PBMC. EM was defined as death from any cause within 90 days of treatment initiation. Logistic regression analysis was used to identify parameters associated with EM. Results: A total of 317 patients with unresectable HCC treated with first-line atezo/bev were included. EM rate in the cohort was 15.8%, with a median survival of 12.6 months. The proportion of patients with preserved liver function and BCLC stage B was significantly lower in the EM cohort. The strongest predictor of EM was advanced liver disease in univariate analysis, as reflected by surrogates of impaired liver function such as Child-Pugh score (CPS) B ( Conclusions: EM rate was 15.8% in patients with HCC treated with atezo/bev. Significant risk factors for early death involved impaired liver function, elevated biomarkers of inflammation and alterations of systemic immunity. Impact and implications: Although rare in clinical trial populations, early mortality (EM) is a significant concern following the initiation of immune checkpoint inhibitors in patients with hepatocellular carcinoma (HCC) in real-world cohorts, highlighting the need for adequate risk stratification and patient selection. Using data of a large, European real-world cohort as well as FACS-based immunophenotyping of baseline peripheral blood mononuclear cells, we comprehensively characterized the frequency, risk factors, and biomarkers associated with EM in atezo/bev-treated patients with HCC. We identified EM to represent a common event in patients with HCC after treatment initiation and demonstrated impaired liver function, elevated biomarkers of inflammation, and reduced lymphocyte frequencies and increased regulatory T cell activity to be associated with increased EM risk. These findings can help clinicians identify patients with HCC at high risk of EM, enabling adequate and informed decision-making regarding end-of-life care and palliative treatment.