The New England Journal of Medicine MAY 14, 2020

Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma

Richard S. Finn, Shukui Qin, Masafumi Ikeda, Peter R. Galle, Masatoshi Kudo, et al.

Bottom Line

The IMbrave150 trial demonstrated that the combination of atezolizumab and bevacizumab significantly improves overall and progression-free survival compared to sorafenib in patients with untreated advanced hepatocellular carcinoma.

Key Findings

1. Atezolizumab plus bevacizumab significantly improved overall survival compared to sorafenib, with a hazard ratio for death of 0.58 (95% CI, 0.42 to 0.79; P<0.001).

2. The 12-month overall survival rate was 67.2% for the combination therapy group versus 54.6% for the sorafenib group.

3. Progression-free survival was also significantly better with the combination therapy (hazard ratio 0.59; 95% CI, 0.47 to 0.76; P<0.001), with a median progression-free survival of 6.8 months compared to 4.3 months for sorafenib.

4. Grade 3 or 4 adverse events were reported in 56.5% of patients receiving atezolizumab-bevacizumab and 55.1% of patients receiving sorafenib.

Study Design

Design

RCT

Open-Label

Sample

501

Patients

Duration

8.6 mo

Median

Setting

Multicenter, 17 countries

Population Patients with unresectable, locally advanced or metastatic, or recurrent hepatocellular carcinoma who had not received prior systemic therapy and had an ECOG performance status of 0 or 1 and Child-Pugh class A liver function.

Intervention Atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) intravenously every 3 weeks.

Comparator Sorafenib (400 mg) orally twice daily.

Outcome Overall survival and progression-free survival as assessed by an independent review facility according to RECIST 1.1.

Study Limitations

• The trial was open-label, which may introduce observer bias in assessing secondary endpoints.

• Patients with high-risk esophageal varices were required to undergo prophylactic endoscopic treatment before randomization, which might limit the generalizability of safety results regarding bleeding risk in real-world settings.

• The trial exclusively enrolled patients with Child-Pugh class A liver function, meaning the results cannot be extrapolated to patients with more advanced liver impairment (Child-Pugh B or C).

• The primary analysis was performed while survival data were still immature, requiring subsequent follow-up reports to confirm the durability of the observed benefits.

Clinical Significance

The results of IMbrave150 established atezolizumab plus bevacizumab as a new standard-of-care first-line therapy for unresectable hepatocellular carcinoma, replacing sorafenib which had been the singular standard for over a decade.

Historical Context

For over a decade following the SHARP trial, sorafenib served as the only systemic treatment with a proven survival benefit for advanced hepatocellular carcinoma; the IMbrave150 trial marked the first successful phase III study to demonstrate the superiority of an immune checkpoint inhibitor-based regimen in this setting.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How do the mechanisms of action for atezolizumab and bevacizumab work synergistically to overcome the unique immunosuppressive environment of hepatocellular carcinoma (HCC)?

Key Response

Atezolizumab is a PD-L1 inhibitor that restores T-cell mediated anti-tumor responses. Bevacizumab, by inhibiting VEGF, not only limits tumor angiogenesis but also reduces VEGF-mediated immunosuppression (such as decreasing the recruitment of regulatory T-cells and myeloid-derived suppressor cells), thereby enhancing T-cell infiltration into the tumor microenvironment.

Resident

What is the most critical screening requirement for a patient with advanced HCC before initiating the atezolizumab plus bevacizumab regimen, and why is it prioritized in this specific patient population?

Key Response

All patients must undergo an Esophagogastroduodenoscopy (EGD) within 6 months prior to starting treatment to evaluate and manage esophageal varices. This is critical because bevacizumab, a VEGF inhibitor, significantly increases the risk of major gastrointestinal hemorrhage, which can be fatal in patients with underlying portal hypertension common in cirrhosis.

Fellow

The IMbrave150 trial primarily enrolled patients with Child-Pugh Class A liver function. What are the clinical and evidence-based concerns when considering this regimen for a patient with Child-Pugh Class B cirrhosis?

Key Response

Safety and efficacy in Child-Pugh B patients remain uncertain as they were excluded from the trial. These patients have a higher baseline risk of variceal bleeding and decompensation; clinicians must weigh the potential survival benefit against the lack of robust data and the increased risk of bevacizumab-induced complications in the setting of more advanced liver dysfunction.

Attending

With atezolizumab plus bevacizumab now established as a first-line standard of care, how does this shift our interpretation of previous second-line data for agents like regorafenib or cabozantinib?

Key Response

Most existing second-line data (e.g., RESORCE, CELESTIAL trials) were established following progression on sorafenib. It is currently unknown if the survival benefit of these multi-kinase inhibitors (MKIs) is preserved when sequenced after immunotherapy-based combinations, necessitating a re-evaluation of the optimal therapeutic sequence and the role of 'traditional' 1L agents like lenvatinib in the modern landscape.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The IMbrave150 study utilized a co-primary endpoint design of Overall Survival (OS) and Progression-Free Survival (PFS) by Independent Review Facility (IRF) using RECIST 1.1. What are the statistical and methodological implications of using PFS as a co-primary endpoint in an open-label trial compared to OS?

Key Response

While OS is the gold standard, it requires longer follow-up and can be confounded by subsequent lines of therapy. PFS provides a more direct measure of the treatment's effect but is susceptible to assessment bias in open-label trials. The use of IRF/blinded central review is a critical methodological safeguard used in IMbrave150 to mitigate this bias and ensure the validity of the PFS benefit.

Journal Editor

Given the geographic distribution of the IMbrave150 trial, how might the high prevalence of Hepatitis B Virus (HBV) etiology in the study population impact the global generalizability of the hazard ratios for OS and PFS?

Key Response

Nearly 50% of the cohort had HBV-related HCC, which is common in Asia but less so in Western populations where NASH and HCV predominate. Since the immune microenvironment and sorafenib responsiveness can differ by etiology, a reviewer would scrutinize whether the treatment effect is consistent across subgroups or if the magnitude of benefit is driven disproportionately by the HBV-positive cohort.

Guideline Committee

How do the results of IMbrave150 alter the strength of recommendation for sorafenib in the current AASLD or ESMO guidelines, and what specific contraindications must be highlighted in the new preference for the combination therapy?

Key Response

Atezo/Bev is now recommended as the preferred first-line therapy (Level 1, A) for patients with Child-Pugh A and ECOG 0-1. However, guidelines must explicitly retain sorafenib or lenvatinib as the recommended choice for patients with contraindications to immunotherapy (e.g., autoimmune disease) or those with unmanaged varices/high bleeding risk where bevacizumab is unsafe.

Clinical Landscape

Noteworthy Related Trials

2008

SHARP Trial

n = 602 · NEJM

Tested

Sorafenib 400mg twice daily

Population

Patients with advanced hepatocellular carcinoma

Comparator

Placebo

Endpoint

Overall survival and time to symptomatic progression

Key result: Sorafenib significantly improved median overall survival compared to placebo (10.7 vs 7.9 months).

2018

REFLECT Trial

n = 954 · Lancet

Tested

Lenvatinib

Population

Patients with unresectable hepatocellular carcinoma

Comparator

Sorafenib

Endpoint

Overall survival

Key result: Lenvatinib was non-inferior to sorafenib in terms of overall survival and showed significant improvements in progression-free survival and objective response rate.

2020

CHECKMATE-459 Trial

n = 743 · Lancet Oncol

Tested

Nivolumab

Population

Patients with advanced hepatocellular carcinoma

Comparator

Sorafenib

Endpoint

Overall survival

Key result: Nivolumab did not reach statistical significance for overall survival compared to sorafenib despite a higher objective response rate.

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