Improving Outcomes in Unresectable Liver Cancer: A Breakthrough in Systemic Therapy

Over the past two decades, efforts to improve outcomes for patients with unresectable liver cancer have yielded promising results. A recent randomized trial has shown that the addition of durvalumab and bevacizumab to transarterial chemoembolization (TACE) has significantly increased median progression-free survival (PFS) compared to TACE alone. This breakthrough in systemic therapy offers new hope for patients with hepatocellular carcinoma (HCC) eligible for embolization.

The EMERALD-1 trial, conducted by Riccardo Lencioni, MD, and his team at the University of Pisa in Italy, involved 616 patients with unresectable HCC and no extrahepatic disease. The patients were randomized into three groups: durvalumab plus TACE followed by durvalumab and placebo, durvalumab plus TACE followed by durvalumab and bevacizumab, or placebo plus TACE followed by placebo. The primary endpoint of the study was PFS, with a key secondary outcome being comparison of PFS for durvalumab with TACE followed by durvalumab-placebo.

The addition of durvalumab and bevacizumab to TACE led to a median PFS of 15.0 months, compared to 8.2 months for patients who received TACE plus placebo. Interestingly, the improved outcomes were primarily driven by bevacizumab, as patients who received only durvalumab had a median PFS of 10.0 months, which was not statistically different from the placebo arm. Importantly, the rates of adverse events (AEs) were similar across all three treatment groups, with grade 3/4 AEs related to the study treatment occurring more frequently in the durvalumab-bevacizumab arm. However, rates of fatal AEs did not differ significantly across the treatment groups.

Implications and Limitations

The results of the EMERALD-1 trial highlight the potential of durvalumab plus bevacizumab plus TACE as a new standard of care for intermediate HCC. The combination therapy showed a significant improvement in PFS, suggesting a potential impact on overall survival. However, it is important to acknowledge that PFS may not be an adequate surrogate for survival, as previously debated. Recent analysis has shown that a hazard ratio below 0.6 is the minimum threshold for surrogacy with PFS, and the absolute PFS difference in this trial translated into an HR of 0.77. Further studies are needed to explore the correlation between PFS and overall survival in HCC.

Another interesting aspect raised by the results of this trial is the role of bevacizumab in advanced HCC. A recent study demonstrated that atezolizumab plus bevacizumab is superior to single-agent sorafenib, while monotherapy with an immune checkpoint inhibitor alone is not. Furthermore, Llovet and his team found that activation of notch signaling in “cold” tumors, which are less likely to respond to bevacizumab, is associated with resistance to the drug. On the other hand, absence of the signaling cascade indicates downregulation of NRP1, which is a marker of response to bevacizumab. These findings suggest that the efficacy of bevacizumab in HCC may be influenced by the immune microenvironment within the tumor.

The EMERALD-1 trial represents a significant breakthrough in systemic therapy for unresectable liver cancer. The addition of durvalumab and bevacizumab to TACE has demonstrated a substantial improvement in PFS compared to TACE alone. While the study has limitations, such as the uncertainty of PFS as a surrogate for survival, it offers new hope and raises important questions about the role of bevacizumab in advanced HCC. Further research and clinical trials will be crucial to unravel the full potential of immunotherapy and combination treatment strategies in improving outcomes for patients with HCC.

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