Impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on immunotherapy efficacy in advanced hepatocellular carcinoma.

Abstract

e16234 Background: Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are common medications used for managing hypertension and cardiovascular conditions. There is growing evidence that these medications may also modulate tumor microenvironment (TME), including in immune cell infiltration, angiogenesis, and fibrosis in certain lung, GI, and GU cancers. However, this has not been examined in hepatocellular carcinoma (HCC), where the renin-angiotensin system has been implicated in promoting tumor growth and immune evasion, offering a potential strategy to improve immunotherapy outcomes in advanced HCC. Methods: Patients with unresectable HCC who were treated with immune checkpoint inhibitors at UPMC Hillman Cancer Center between 2015-2024 were included in this retrospective analysis. Concurrent ACEi/ARB use was defined as any ongoing therapy while on immunotherapy regimen. Multivariate Cox proportional hazard model was used to evaluate progression free survival (PFS) and overall survival (OS). Results: A total of 293 patients were included in this analysis. Most common immunotherapy regimens used included atezolizumab/bevacizumab (n = 140, 48%), nivolumab (n = 75, 26%), and durvalumab/tremelimumab (n = 57, 19%). 64 (22%) were stage I/II at time of immunotherapy initiation, 121 (41%) were stage III, and 108 (37%) were stage IV. 141 patients (49%) had viral-associated HCC, 72 (25%) had alcohol-associated HCC, and 64 (26%) had no HCV/HBV exposure or significant alcohol use. 129 patients (44%) had concurrent ACEi/ARB use. Multivariate analysis adjusting for cancer stage and etiology showed concurrent ACEi/ARB use was associated with improved PFS (HR = 0.76, 95% CI 0.59-0.99, p = 0.039). No significant difference was seen in OS (HR = 0.81, 95% CI 0.59-1.1, p = 0.175). Subgroup analysis by etiology showed concurrent ACEi/ARB use was only associated with significantly improved PFS for patients with alcohol-associated HCC (HR 0.49, 95% CI 0.28-0.86, p = 0.014). Differences in PFS was not observed in viral-associated group (HR 0.79, 95% CI 0.54-1.1, p = 0.207) or non-viral/non-alcohol group (HR 1.0, 95% CI 0.57-1.6, p = 0.811). Conclusions: Our data suggests that patients with advanced HCC treated with immune checkpoint inhibitor therapy had improved PFS with concurrent use of ACEi/ARB medications within alcohol-associated HCC population specifically, potentially due to the differing tumor microenvironment of alcohol-associated HCC. Given the frequency of ACEi/ARB use, it will be important to validate this result in larger disease cohorts and/or prospective disease specific trials.