Liver cancer, specifically hepatocellular carcinoma (HCC), remains a significant challenge in the field of oncology. For over two decades, researchers have been striving to find an effective systemic therapy for patients with unresectable HCC. A recent randomized trial has shed light on the potential benefits of transarterial chemoembolization (TACE) in combination with immunotherapy. This article will critically analyze the trial’s findings and their implications for the management of unresectable liver cancer.
The trial compared the efficacy of TACE alone versus TACE combined with durvalumab and bevacizumab. The results demonstrated a clear improvement in progression-free survival (PFS) with the addition of durvalumab and bevacizumab. Patients in the combination therapy group had a median PFS of 15.0 months, compared to 8.2 months in the TACE plus placebo group. Notably, the improvement in PFS was primarily driven by bevacizumab. Patients receiving durvalumab alone did not show a significant improvement in PFS.
Manageable Safety Profile
One crucial aspect of any therapeutic intervention is its safety profile. The trial reported that adverse events (AEs) occurred at a similar rate across all three treatment groups. However, patients in the durvalumab-bevacizumab arm experienced a higher incidence of grade 3/4 AEs possibly related to the study treatment. Although rates of fatal AEs did not differ significantly, it is essential to consider the potential risks associated with any treatment regimen.
The trial’s primary endpoint was PFS, but the debate persists regarding whether PFS is an adequate surrogate for overall survival (OS). Another analysis of randomized trials in advanced HCC suggested that the minimum threshold for surrogacy with PFS is a hazard ratio (HR) below 0.6. In the current trial, the absolute PFS difference translated into an HR of 0.77, raising questions about its surrogacy with OS. It is uncertain whether the observed improvement in PFS will translate into a meaningful benefit in terms of survival.
The Role of Bevacizumab
The study’s results have also illuminated the role of bevacizumab in advanced HCC. A recently conducted study found that atezolizumab in combination with bevacizumab is superior to single-agent sorafenib. However, monotherapy with an immune checkpoint inhibitor did not demonstrate significant efficacy. Researchers identified certain markers of response to bevacizumab, such as notch signaling activation. Notably, tumors lacking activation of notch signaling showed higher responsiveness to bevacizumab. These findings emphasize the importance of considering individual tumor characteristics when selecting therapeutic approaches.
Despite the limitations of PFS as a surrogate for survival, the current trial marks an important milestone by demonstrating an improvement beyond the activity of TACE alone. The addition of durvalumab and bevacizumab has the potential to become the new standard of care in the management of intermediate HCC. However, further investigations are warranted to evaluate its impact on overall survival and long-term outcomes. Additionally, it is essential to consider the feasibility and accessibility of upper GI endoscopy, as it may become a mandatory requirement for patients receiving the combination therapy.
The integration of transarterial chemoembolization with immunotherapy represents a promising approach in the treatment of unresectable liver cancer. The combination of durvalumab and bevacizumab has demonstrated a significant improvement in progression-free survival compared to TACE alone. However, the surrogacy of PFS with overall survival remains uncertain. Moreover, individual tumor characteristics, such as notch signaling activation, may play a crucial role in determining the response to bevacizumab. As we enter a new era in the management of unresectable HCC, continued research and clinical trials will provide valuable insights into optimizing treatment strategies and improving patient outcomes.
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