Atezolizumab and Bevacizumab Combination Therapy Opens the Path to Curative-Intent Conversion Surgery in Patients with Advanced Hepatocellular Carcinoma
Background
The treatment landscape for patients with advanced hepatocellular carcinoma (HCC) has long been severely limited. Patients whose tumors invade the main blood vessels within the liver or have metastasized to other organs outside the liver, or those with prominent systemic symptoms due to cancer, are typically classified as BCLC Stage C according to the Barcelona Clinic Liver Cancer (BCLC) staging system. For patients at this stage, surgical resection has traditionally been considered an impractical option. Due to the anatomical characteristics of the liver, vascular invasion is associated with an extremely high recurrence rate after surgery and can cause a rapid decline in liver function, posing a significant risk to the patient's life.
Sorafenib, a multi-targeted therapy that has long served as the only first-line standard treatment for advanced HCC, only modestly extended survival without significantly reducing tumor size. Given the nature of HCC, where complete tumor removal is the only way to ensure long-term survival, the emergence of a treatment capable of converting non-surgical candidates into operable patients has long been a major aspiration in the field. In the absence of a potent drug combination suitable for patients with poor general condition, it was difficult to expect curative opportunities through downstaging.
Key Findings
This long-standing limitation has seen a dramatic shift with the advent of immunotherapy. Recent studies published in The Lancet demonstrate that the combination of the immune checkpoint inhibitor atezolizumab and the anti-vascular endothelial growth factor (VEGF) agent bevacizumab can induce downstaging in patients with advanced HCC, making curative-intent conversion surgery possible. In the phase III IMbrave150 trial, the atezolizumab and bevacizumab combination therapy group showed significantly superior clinical outcomes compared to the sorafenib group. Specifically, the objective response rate (ORR) in the combination therapy group reached 30%, which is approximately three times higher than the 11% observed in the sorafenib group, indicating a substantial tumor shrinkage effect.
The median overall survival (OS) in the combination therapy group was 19.2 months, compared to 13.4 months in the sorafenib group, representing a 34% reduction in the risk of death. The progression-free survival (PFS) was also 6.9 months, surpassing the 4.3 months achieved with sorafenib. These high response rates and rapid tumor reduction have led to the disappearance of vascular invasion or a significant reduction in tumor volume in a considerable number of patients who initially had vascular invasion. Medical teams conducted multidisciplinary team (MDT) evaluations to precisely assess the patient's liver function and remaining liver volume, and selected patients who became operable for successful R0 resection. This marks the establishment of a new clinical pathway, starting with systemic drug therapy and ultimately achieving surgical cure.
Significance and Outlook
The results of this study are of great significance in shifting the treatment paradigm for advanced HCC from monotherapy with systemic drugs to an active combination therapy aimed at achieving surgical cure. By offering curative opportunities to patients who were previously only treated for life extension, the study has broadened the door to long-term survival. The academic community is now showing momentum to revise HCC treatment guidelines, and many hospitals are accelerating the development of integrated multidisciplinary treatment systems involving surgery, oncology, and radiology.
However, not all patients with advanced HCC can fully benefit from this conversion surgery. Research on genetic biomarkers capable of accurately identifying patients who respond strongly to systemic therapy is still insufficient. Additionally, the risk of complications such as liver damage or bleeding during surgery after drug administration must be carefully managed. In the future, clinical practice should conduct follow-up randomized controlled trials to further ensure safety, particularly regarding the optimal duration of drug administration and the timing of adjuvant therapy after surgery.
The management of advanced hepatocellular carcinoma, defined by the presence of vascular invasion, extrahepatic spread, and cancer-related symptoms according to the Barcelona Clinic Liver Cancer staging system,1 has evolved since 2020 with the emergence of immunotherapy. Sorafenib remained as the single option showing a survival benefit2 until the publication of the positive results of the IMbrave 150 trial,3 which demonstrated superiority of the combination of atezolizumab and bevacizumab compared with sorafenib.
In clinical practice, conversion surgery provides a concrete new treatment pathway for patients who were previously considered inoperable. For example, imagine a middle-aged patient who had given up on liver resection due to severe portal vein invasion and was receiving palliative care. Suppose this patient began treatment with the combination of atezolizumab and bevacizumab and, after four cycles, the tumor thrombus in the invaded blood vessel was significantly reduced. At this stage, a multidisciplinary evaluation would assess the preservation of liver function and the volume of the right lobe to determine the feasibility of surgery. If the tumor resection is successfully completed, the patient would gain the real benefit of curative treatment, returning to a disease-free life rather than merely extending survival.
From the pharmaceutical industry perspective, the development of various combination therapies, including other targeted therapies or transarterial chemoembolization, is expected to become more active. Healthcare institutions are also gaining momentum to move beyond simple surgical interventions and develop high-value, personalized treatment programs that integrate precision diagnostics and multidisciplinary collaboration.