Five years after IMbrave150 with clinical integration of atezolizumab plus bevacizumab in hepatocellular carcinoma

Five years after IMbrave150, atezolizumab plus bevacizumab (ate/bev) remains the first-line standard for unresectable hepatocellular carcinoma (uHCC). High response rates allow downstaging and curative conversion, enabling drug-free remission in some patients. Durable responses suggest potential for de-escalation, though discontinuation criteria need validation. In hepatitis B virus-related HCC, ate/bev appears safe across baseline viral loads when administered with concomitant antiviral therapy. Bleeding risk, particularly esophagogastric variceal hemorrhage, warrants baseline endoscopy and proactive management. Hypertension and proteinuria require close surveillance and early control to maintain bevacizumab use. Late bevacizumab interruption is acceptable, whereas early discontinuation is associated with poorer outcomes. After progression on ate/bev, evidence across cohorts favors tyrosine kinase inhibitor strategies such as lenvatinib over sorafenib. Cabozantinib and ramucirumab (for alpha-fetoprotein ≥400 ng/mL) are options and selected patients may benefit from immune checkpoint inhibitor-based combinations. Combining ate/bev with locoregional therapy (LRT) is promising. Phase III data with transarterial chemoembolization show improved progression-related endpoints. Early series suggest potential benefit with Yttrium-90 radioembolization, hepatic arterial infusion chemotherapy and radiotherapy, although high-level evidence is still lacking. Translational markers such as pre-existing immunity and transcriptomic models are promising but unvalidated. Adjuvant ate/bev has not demonstrated durable benefit. The neoadjuvant role and additional combination strategies require further exploration. Although ate/bev has improved outcomes in uHCC, key gaps remain, including biomarkers for regimen selection, de-escalation criteria, optimal sequencing, and integration with LRT or perioperative care. Prospective studies are needed to guide practice.