Hope for Long-Term Survival in Advanced Liver Cancer with Immunotherapy

For decades, advanced hepatocellular carcinoma (HCC), the most common type of liver cancer, carried a grim prognosis. However, the emergence of immune checkpoint inhibitors (ICIs) is changing that narrative, offering the potential for prolonged survival and, in some cases, even a cure. Recent analyses of clinical trials and real-world data suggest that up to 15% of patients with advanced HCC treated with combination immunotherapy may experience long-term survival, with a cure fraction estimated between 7 and 9%.

The Evolution of HCC Treatment

Hepatocellular carcinoma accounts for more than 90% of primary liver tumors.¹ Historically, treatment options for unresectable HCC were limited, with tyrosine kinase inhibitors (TKIs) serving as the standard of care. These therapies offered modest benefits, with a median progression-free survival of only 3-4 months.¹ However, the landscape began to shift with the introduction of ICIs, which harness the body’s own immune system to fight cancer.

Breakthrough Trials Demonstrate Superiority of ICIs

Several pivotal phase 3 trials, including HIMALAYA, CheckMate-9DW, and IMbrave150, have demonstrated the superiority of ICI-based combinations compared to TKIs in the first-line treatment of unresectable HCC.^2,3 These trials showed late separation of survival curves and plateaus, indicating a potential for durable benefit in a subset of patients. Specifically, the HIMALAYA trial led to the FDA approval of tremelimumab-actl with durvalumab in October 2022.¹

Mixture Cure Models Offer New Insights

To better quantify the potential for long-term survival and cure, researchers have applied mixture cure models (MCMs) to data from these trials and real-world cohorts. MCMs are a statistical approach that estimates both the proportion of long-term survivors and the fraction of patients who may be cured.⁴

• HIMALAYA Trial: MCM analysis estimated a 12.8% proportion of long-term survivors with durvalumab/tremelimumab, compared to 5.2% with sorafenib.⁴
• CheckMate-9DW Trial: MCMs identified 8.7% of long-term survivors with nivolumab-ipilimumab versus 4.1% with TKIs, and a cure fraction of 17.8% with ICI versus 3.5% with TKI.⁴
• Real-World Cohort: Analysis of 1,581 patients treated with atezolizumab-bevacizumab showed a long-term survivor proportion of 12.3% and a cure fraction of 7.9%.⁴

The Role of Liver Function

Research suggests that prolonged survival in advanced HCC depends not only on antitumor response but also on preserved liver function.⁴ This is particularly relevant, as the majority of HCC cases develop in patients with underlying cirrhosis. The analysis indicates that mortality rates decrease after the first year and converge towards background mortality linked to cirrhosis, suggesting that beyond the initial peak, liver damage, rather than tumor progression, becomes the primary determinant of survival.

Predictors of Prolonged Survival and Cure

Multivariate analysis has identified several factors associated with prolonged survival and cure:⁴

• Prolonged Survival: Albuminemia, bilirubinemia, and hepatitis C virus infection.
• Cure: Albuminemia and hepatitis C infection.

Future Directions

“Cancer control must therefore be associated with optimal management of the underlying liver disease,” concludes Professor Jean-Charles Nault.⁴ As immunotherapy continues to evolve, combining these treatments with strategies to improve liver health will be crucial for maximizing outcomes in patients with advanced HCC. Further research is needed to identify biomarkers that can predict which patients are most likely to benefit from ICI therapy and to develop strategies to overcome resistance.

Keywords: Hepatocellular Carcinoma, HCC, Immunotherapy, Immune Checkpoint Inhibitors, ICI, Liver Cancer, Treatment, Survival, Cure, Durvalumab, Tremelimumab, Nivolumab, Ipilimumab, Atezolizumab, Bevacizumab, Sorafenib, Lenvatinib.