Unresectable hepatocellular carcinoma (uHCC) is a leading cause of cancer death. FDA-approved first-line systemic therapies include atezolizumab/bevacizumab (atezo/bev) and durvalumab/tremelimumab (durva/treme); however, there is a lack of comparative data.

We reviewed outcomes of patients with uHCC who initiated atezo/bev or durva/treme between 2017 and 2024, across six institutions. Overall survival (OS) and time to treatment discontinuation (TTD) were analyzed using the Kaplan-Meier and Cox models, adjusting for baseline characteristics.

452 uHCC pts were included. Median age: 68 years; 77% male; 81% white. Most common etiologies were viral hepatitis (38.9%) and metabolic dysfunction-associated steatohepatitis (19.5%). Disease progression was the primary reason for treatment discontinuation, atezo/bev (56%) and durva/treme (42%). Outcomes were not statistically significant (median OS [month, m]: 14.0 vs. 14.6 [p = 0.66]; median TTD [m]: 4.9 vs. 3.9 [p = 0.42] for atezo/bev vs. durva/treme). Outcomes were significantly different between Child-Pugh classes (CP: A, B7, B8/9, C) respectively, median OS(m): 19.0, 6.1, 5.1, 2.0 (p < 0.001); median TTD(m): 6.1, 2.3, 3.0, 1.3 (p < 0.001).

In this real-world study of uHCC, no significant difference in clinical outcomes was observed between atezo/bev and durva/treme in the first line setting. CP scores were a key prognostic variable with both regimens.

This study offers real-world comparative data on two first line regimens in uHCC. As multiple first-line regimen combinations emerge, assessment of differences in efficacy, safety, and patient selection outside of clinical trials remain an unmet need. These findings may help guide treatment decisions, particularly in settings where toxicity, comorbidities, or resource constraints influence regimen choice.