The treatment landscape for advanced hepatocellular carcinoma (HCC) has evolved rapidly, with atezolizumab + bevacizumab, durvalumab + tremelimumab (STRIDE), and nivolumab + ipilimumab now established as first-line treatment options.¹ At the 13th APGCS, Professor Yau, Chung-Cheung Thomas, from Queen Mary Hospital, Hong Kong, discussed how treatment selection is increasingly driven by efficacy, durability, toxicity, and patient characteristics.²

Current first-line options fall broadly into two therapeutic strategies: immune checkpoint inhibitor (ICI) + vascular endothelial growth factor (VEGF) blockade and dual immune checkpoint blockade.¹ In HCC, the clinical value of ICI + VEGF blockade was established in IMbrave150, where atezolizumab + bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) vs. sorafenib, supporting its role as a global first-line standard of care for unresectable HCC.^1,3 Conversely, ICI + VEGF-blocking tyrosine kinase inhibitor (TKI) combinations have produced less consistent results, with CARES-310 demonstrating significant PFS and OS improvements, predominantly in an Asian population with hepatitis B virus infection.^2,4 These combinations have therefore not been established as the global first-line standard.¹ Prof. Yau also highlighted the generally greater toxicity with these combinations, including more grade ≥3 adverse events, treatment discontinuations, dose reductions, and hepatic toxicity associated with TKI metabolism.²

Dual checkpoint blockade offers an alternative strategy.¹ Nivolumab + ipilimumab uses repeated high-dose cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) exposure during induction, whereas the STRIDE regimen evaluated in HIMALAYA uses a single priming dose of tremelimumab followed by durvalumab maintenance.^5-7 In CheckMate 9DW, nivolumab + ipilimumab achieved an objective response rate (ORR) of 36% vs. 13% with lenvatinib or sorafenib, with durable responses approaching three years and a 3-year OS rate of approximately 38%.⁵ HIMALAYA similarly demonstrated long-term survival benefits with STRIDE vs. sorafenib.^6,7 Prof. Yau emphasized that while response kinetics are broadly comparable across approved regimens, deeper and more durable tumor regression may favor nivolumab + ipilimumab.²

Toxicity considerations heavily influence regimen selection.² Grade 3-4 adverse events were broadly similar between nivolumab + ipilimumab and atezolizumab + bevacizumab but lower with STRIDE.^3,5,7 Dual ICI regimens were associated predominantly with hepatic immune-related adverse events, whereas atezolizumab + bevacizumab was characterized mainly by hypertension, proteinuria, and bleeding risks.^3,5,7

Hepatic reserve is also a key consideration in treatment selection, influencing both treatment tolerance and eligibility for subsequent therapy.² As pivotal trials predominantly enrolled Child-Pugh A patients, data in poorer liver function remain limited.^3,5,7 Albumin-bilirubin (ALBI) grade provides additional prognostic stratification.² Atezolizumab + bevacizumab demonstrated a more consistent OS benefit in patients with ALBI grade 1 (though ALBI grade 2 patients may still benefit).⁸ Nivolumab + ipilimumab showed consistent OS benefit regardless of ALBI grade, while STRIDE demonstrated similar OS hazard ratios in ALBI grade 1 and 2/3 patients.^9,10

Anatomical features and comorbidity profiles further guide regimen selection.² Patients with main portal vein tumor thrombosis were included in IMbrave150 but excluded from CheckMate 9DW and HIMALAYA, supporting the use of atezolizumab + bevacizumab in this subgroup.^3,5 Conversely, recent variceal bleeding, untreated high-risk varices, or therapeutic dose anticoagulation may favor non-bevacizumab-based approaches.² For patients unsuitable for ICI because of autoimmune disease, previous severe immune-related toxicity, or transplant-related concerns, single-agent lenvatinib remains a preferred option.²

Planning beyond first-line failure requires evaluating mechanisms of action, Eastern Cooperative Oncology Group (ECOG) performance status, Child-Pugh class, prior treatment response, and safety profiles.² Real-world evidence supports the feasibility and potential survival benefit of sequential systemic therapy, underpinning the importance of preserving functional liver reserve.² Concurrently, locoregional therapies such as transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) remain central for selected patients, while novel strategies, including TIGIT/TIM-3 inhibitors, chimeric antigen receptor-T (CAR-T) cell therapies,  bispecific T-cell engagers (BiTEs), and cytokine-targeting therapies, continue to advance.²

Ultimately, first-line selection in advanced HCC is not defined by a single universal standard.² Treatment should be individualized according to tumor burden, hepatic reserve, bleeding risk, portal vein involvement, ICI suitability, and patient preference, with the goals of durable disease control, preserved liver function, and future treatment options.²