Comparative Effectiveness and Safety of Atezolizumab–Bevacizumab and Durvalumab–Tremelimumab as First‐Line Systemic Therapy for Hepatocellular Carcinoma: A Real‐World Study

Background and Aims Atezolizumab plus bevacizumab (Atezo/Bev) and durvalumab plus tremelimumab (Durva/Treme) are established first‐line therapies for advanced hepatocellular carcinoma (HCC). However, direct comparisons between these regimens remain limited. This study aimed to evaluate their comparative effectiveness and safety. Methods We conducted a retrospective cohort study within the TriNetX Global Collaborative Network, including adults with HCC who initiated Atezo/Bev or Durva/Treme as first‐line systemic therapy between October 1, 2022, and October 31, 2025. Outcomes were defined using standardized diagnostic, procedural, and medication codes. Propensity score matching (1:1) was applied to minimize baseline differences between groups. Results Among 3362 eligible patients, 765 matched pairs were included in the final analysis. Over a median follow‐up of 14.8 months for Atezo/Bev and 17.5 months for Durva/Treme, overall survival was comparable between the regimens (median 14.6 vs. 17.3 months; aHR 0.96; 95% CI 0.83–1.12). Safety outcomes were broadly similar, including gastrointestinal bleeding (aHR 0.88; 95% CI 0.68–1.13) and non‐gastrointestinal bleeding (aHR 1.06; 95% CI 0.60–1.89). Treatment‐requiring immune‐related adverse events (irAEs) occurred significantly less frequently with Atezo/Bev (aHR 0.61; 95% CI 0.48–0.77), with curve separation evident early after treatment initiation. Incident hypertension was numerically more frequent with Atezo/Bev but was not statistically significant (aHR 1.24; 95% CI 0.87–1.76). Conclusions Atezo/Bev and Durva/Treme demonstrated similar overall survival in patients with HCC, with largely comparable safety profiles. The lower rate of treatment‐requiring irAEs observed with Atezo/Bev may assist clinicians in tailoring regimen selection for individuals with advanced HCC.