Advanced Hepatocellular Carcinoma: Systemic Therapy

Advanced Hepatocellular Carcinoma: overview

This algorithm covers systemic therapy for advanced hepatocellular carcinoma in patients with Child-Pugh A liver function, organized by line of therapy. The first-line branch is immunotherapy-based. Atezolizumab plus bevacizumab is the preferred regimen (IMbrave150), and durvalumab plus tremelimumab is shown as the dual-IO alternative (HIMALAYA). When immunotherapy is contraindicated, the chart directs to a tyrosine kinase inhibitor, lenvatinib or sorafenib, supported by REFLECT.

After progression, the second-line branch lists two tyrosine kinase inhibitors, regorafenib (RESORCE) and cabozantinib (CELESTIAL), plus a biomarker-selected option: ramucirumab for patients with high AFP (REACH-2). In the site's REACH-2 summary, ramucirumab significantly improved overall survival in patients with HCC and AFP of 400 ng/mL or higher after sorafenib. REACH-2 was the first phase III trial designed prospectively in a biomarker-selected HCC population, validating AFP as a predictive biomarker for VEGFR-2 inhibition and establishing a biomarker-selected standard for second-line treatment.

Trials behind this algorithm

• HIMALAYA Trial, Tremelimumab plus Durvalumab in Unresectable HCC Abou-Alfa GK et al, NEJM Evid, 2022; PMID: 38319892
• Resorce Trial Bruix J et al, Lancet, 2016, PMID: 27932229
• Celestial Trial, cabo vs pbo Abou-Alfa GK et al, NEJM, 2018, PMID: 29972759
• REACH-2 Zhu AX et al, Lancet Oncol, 2019; PMID: 30665869

Background reading: Hepatocellular carcinoma (HCC) board review notes.