Hepatocellular Carcinoma.

TLDR

Liver cancer, projected to exceed one million cases by 2025, is dominated by hepatocellular carcinoma (≈90 % of cases), whose main risk factors include hepatitis B and C viruses and increasingly non‑alcoholic steatohepatitis, yet only about 25 % harbor actionable mutations that remain underutilized clinically, and diagnosis still relies on invasive molecular testing. The study aims to evaluate how ongoing trials of combination therapies—checkpoint inhibitors with tyrosine‑kinase or anti‑VEGF agents, or dual immunotherapies—will reshape HCC treatment across all disease stages. Six systemic therapies approved from phase III trials (atezolizumab‑bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib, ramucirumab) plus three accelerated FDA approvals, and new trials are testing combinations of checkpoint inhibitors, tyrosine‑kinase inhibitors, anti‑VEGF agents, or dual immunotherapies.

Abstract

Liver cancer remains a global health challenge, with an estimated incidence of >1 million cases by 2025. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. Infection by hepatitis B virus and hepatitis C virus are the main risk factors for HCC development, although non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West. Moreover, non-alcoholic steatohepatitis-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, which are yet to be translated into the clinical practice. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The current major advancements have impacted the management of patients with advanced HCC. Six systemic therapies have been approved based on phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and three additional therapies have obtained accelerated FDA approval owing to evidence of efficacy. New trials are exploring combination therapies, including checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies, or even combinations of two immunotherapy regimens. The outcomes of these trials are expected to change the landscape of HCC management at all evolutionary stages.