Impact of ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) on outcomes in hepatocellular carcinoma treated with atezolizumab–bevacizumab.

Abstract

4117 Background: Immune checkpoint inhibitor–based combinations (ICIs), including atezolizumab–bevacizumab (AB), have dramatically changed the therapeutic landscape of unresectable hepatocellular carcinoma (HCC), improving survival and response rates of patients, although outcomes remain heterogeneous. Concomitant medications may modulate immunotherapy efficacy through systemic and tumor microenvironment–mediated effects. Inhibition of the renin–angiotensin system (RAS) has been suggested to potentiate the effects of immunotherapy in various solid tumors by acting on angiogenesis, fibrosis, and immune modulation. However, the clinical impact of RAS inhibition in HCC patients receiving ICIs remains controversial, with retrospective studies suggesting possible improved outcomes. Methods: Patients with unresectable HCC treated from 2023 to 2025 with AB in Italy were included in this retrospective multicenter analysis from the ARTE database. Patients receiving concomitant ACEi/ARB at AB initiation were compared with non-exposed individuals. OS and PFS were estimated by Kaplan–Meier method and analyzed using Cox proportional hazards models. ORR and DCR were analyzed using logistic regression. To address baseline imbalances, a propensity score adjustment for potentially confounding characteristics (age, ECOG PS, viral etiology, alcoholic liver disease, cirrhosis, diabetes, obesity, cardiovascular events, decompensated cirrhosis, ALBI score, vascular/biliary invasion, previous locoregional treatments, metastatic disease and alpha-fetoprotein levels) was performed. Results: A total of 538 patients were included in our analysis, of whom 36% were receiving ACE-i/ARBs and 64% were not. ACEi/ARB use was associated with worse OS (HR 1.23; 95% CI: 0.97-1.57, p = 0.092), and a trend toward lower DCR (OR 0.63, 95% CI 0.39–1.02; p = 0.06). No significant associations were observed for PFS or ORR. After propensity score adjustment to balance baseline confounders, the magnitude of the OS difference was attenuated: median OS was 17.0 months in ACEi/ARB users versus 19.4 months in non-users (HR 1.14 (95% CI: 0.86-1.51; p = 0.358)), suggesting that the unadjusted signal was partly driven by baseline imbalance. Conclusions: In this large multicentric cohort of HCC patients treated with AB, concomitant ACEi/ARB therapy did not improve clinical outcomes and was possibly associated with a negative survival trend. Further studies will be needed to assess the potential effect of concomitant medications and RAS inhibitors on HCC, given their widespread use and the burden of comorbidities related to this specific tumor.