Important article: “Liver Cancer Treatment Landscape Shifts Rapidly, but Best Sequencing Still Unclear — Real-world analysis shows liver function drives survival; only 20% reach second-line therapy,” from MedPage Today (12/30/2025).
Summary: Real-World HCC Treatment Shows Liver Function Drives Outcomes More Than Drug Choice
Immunotherapy-based combinations have rapidly supplanted tyrosine kinase inhibitors as first-line treatment for advanced hepatocellular carcinoma (HCC) in U.S. practice, but real-world outcomes remain primarily determined by baseline liver function and comorbidity burden, not by the specific systemic regimen used.
In a large analysis of over 4,000 HCC patients treated between 2011 and 2023 using the Flatiron Health database, atezolizumab–bevacizumab and durvalumab–tremelimumab replaced sorafenib as the most common first-line therapies. However, after adjustment for liver reserve and comorbidities, overall survival did not differ significantly by first-line regimen. Median overall survival was 8.1 months, and median progression-free survival was 3.9 months. While atezolizumab–bevacizumab modestly improved PFS versus sorafenib, this did not translate into an overall survival advantage.
Markers of hepatic reserve were the strongest predictors of mortality. Patients with poor liver function (ALBI grade 3) had more than double the risk of death compared with those with preserved function, and higher comorbidity burden further worsened outcomes. Critically, only about 21% of patients received second-line systemic therapy, reflecting rapid clinical deterioration or hepatic decompensation that often prevents treatment sequencing in routine care.
The findings highlight a significant gap between clinical trial populations and real-world patients, many of whom begin systemic therapy with more advanced liver dysfunction. They also help explain discrepancies with prior claims-based studies that suggested superior survival with immunotherapy combinations but lacked detailed liver function data.
Overall, the study underscores that preserving liver function and identifying patients earlier may be more impactful than drug selection alone, and that optimal sequencing strategies remain unclear given how few patients are able to reach second-line therapy in real-world practice.