Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Unresectable hepatocellular carcinoma (uHCC) is defined as disease that is multinodular and unresponsive to locoregional therapies, diffusely infiltrative with bi-lobar involvement, or characterized by portal vein invasion and\/or extrahepatic spread, in patients who have preserved liver function and adequate performance status, in alignment with Barcelona Clinic Liver Cancer (BCLC) criteria.<\/p>\n\n\n\n
HCC is the sixth-leading cause of cancer-related death in the United States, with an estimated 41,630 new diagnoses and 29,840 deaths in 2024. Globally, HCC ranks as the sixth most common cancer and third in cancer-related mortality. The median age at diagnosis is 67 years, and incidence rates for males are 2 to 3 times greater than for females due to an imbalance in risk factors. The 5-year relative survival rate remains low, at 21.7%, highlighting the aggressive nature of HCC and the need for improvements in treatment.<\/p>\n\n\n\n
HCC is most commonly found in the context of liver cirrhosis and, in rare cases, in a healthy liver. Its prevalence has risen in recent years, particularly in Western nations, due to the increasing frequency of non-alcoholic fatty liver disease.<\/p>\n\n\n\n
Advances in next-generation sequencing (NGS) have greatly expanded understanding of the molecular drivers of hepatocarcinogenesis, revealing a heterogeneous landscape marked by recurrent somatic mutations, structural variations, and dysregulated signaling pathways. Among the most common genetic alterations in HCC are TERT promoter mutations, present in approximately 60% of tumors. Key dysregulated pathways \u2014 such as VEGF\/VEGFR and TGF-\u03b2 \u2014 are closely associated with uHCC, especially in the presence of macrovascular invasion or extrahepatic spread.<\/p>\n\n\n\n
The Barcelona Clinic Liver Cancer (BCLC) staging system is widely used to guide treatment selection based on tumor burden, liver function, and patient performance status. While curative options such as surgical resection, local ablation, and liver transplantation are available for patients with early-stage disease, those with intermediate (BCLC-B) or advanced-stage (BCLC-C) disease who are not candidates for transplantation require systemic therapy.<\/p>\n\n\n\n
Recent guidelines from the American Association for the Study of Liver Diseases (AASLD) strongly recommend systemic therapy for patients with preserved liver function (Child\u2013Turcotte\u2013Pugh class A or B7), an ECOG performance status of 0\u20131, and BCLC stage C disease.<\/p>\n\n\n\n
For many years, the only proven therapy for uHCC was sorafenib, a tyrosine kinase inhibitor. Sorafenib was approved in 2007 based on a survival benefit versus placebo. The Asia-Pacific phase 3 trial showed median overall survival (OS) of 6.5 months for sorafenib versus 4.2 months for placebo.<\/p>\n\n\n\n
The field was transformed when combination immunotherapy was shown to outperform sorafenib:<\/p>\n\n\n\n
The IMbrave150 trial (2020) evaluated atezolizumab (PD-L1 inhibitor) in combination with bevacizumab (VEGF inhibitor) compared to sorafenib in unresectable HCC. Overall survival was improved at 12 months (67.2% vs 54.6%), with an improvement in median PFS of 2.5 months (6.8 vs 4.3 months). Extended follow-up demonstrated a median overall survival of 19.2 months compared to 13.4 months in the sorafenib group. This established atezo\/bev as the new standard of care.<\/p>\n\n\n\n
The HIMALAYA trial demonstrated that the STRIDE regimen \u2014 comprising a single priming dose of tremelimumab (Imjudo) plus durvalumab (Imfinzi) followed by durvalumab alone \u2014 improved median OS compared with sorafenib (16.43 vs 13.77 months), achieving a 22% reduction in the risk of death. This was the first FDA approval demonstrating an improvement in survival for combination immunotherapies in HCC, and the first approved indication for tremelimumab.<\/p>\n\n\n\n
The FDA approved nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the first-line treatment of adult patients with unresectable or metastatic HCC in April 2025, supported by the phase 3 CheckMate 9DW trial. At a median follow-up of 35.2 months, patients who received nivolumab plus ipilimumab achieved a median OS of 23.7 months vs 20.6 months for those treated with sorafenib or lenvatinib, translating to a 21% reduction in the risk of death. The combination also yielded one of the highest objective response rates (ORRs) seen in first-line uHCC at 36%, compared with 13% with TKIs.<\/p>\n\n\n\n