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, Michel Ducreux, Tae-You Kim, Masatoshi Kudo, et al.

Bottom Line

The phase 3 IMbrave150 trial demonstrated that first-line combination therapy with atezolizumab and bevacizumab significantly improves overall survival and progression-free survival compared to sorafenib in patients with unresectable hepatocellular carcinoma.

Key Findings

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

2. At 12 months, the overall survival rate was 67.2% (95% CI, 61.3 to 73.1) in the atezolizumab-bevacizumab group versus 54.6% (95% CI, 45.2 to 64.0) in the sorafenib group.

3. Median progression-free survival was significantly longer with combination therapy than with sorafenib (6.8 months vs. 4.3 months; HR 0.59; 95% CI, 0.47 to 0.76; P<0.001).

4. The objective response rate by independent review was significantly higher in the combination group (27.3%) compared to the sorafenib group (11.9%) (P<0.001).

5. Grade 3 or 4 adverse events occurred in 38.0% of patients receiving atezolizumab-bevacizumab and 30.8% of those receiving sorafenib, with a manageable safety profile consistent with the known toxicities of the individual agents.

Study Design

Design

Phase 3 RCT

Open-Label

Sample

501

Patients

Duration

8.6 mo

Median

Setting

Multicenter, global

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

Intervention Atezolizumab 1200 mg plus bevacizumab 15 mg/kg IV every 3 weeks

Comparator Sorafenib 400 mg orally twice daily

Outcome Overall survival (OS) and progression-free survival (PFS) assessed by RECIST 1.1

Study Limitations

• The open-label design could introduce bias in investigator-assessed endpoints and adverse event reporting, though the progression-free survival endpoint was assessed by a blinded independent review facility.

• The study was restricted to patients with well-compensated liver function (Child-Pugh class A), limiting the generalizability of the findings to patients with more advanced cirrhosis (Child-Pugh B or C).

• Patients with untreated or incompletely treated esophageal or gastric varices at high risk for bleeding were excluded, meaning safety results cannot be definitively extrapolated to this higher-risk population.

• The median follow-up of 8.6 months at the time of the primary analysis was relatively short for characterizing long-term overall survival, although subsequent updates later confirmed the enduring survival benefit.

Clinical Significance

The IMbrave150 trial established a new first-line standard of care for unresectable hepatocellular carcinoma. By combining an immune checkpoint inhibitor (atezolizumab) with a VEGF inhibitor (bevacizumab), it demonstrated the first significant survival improvement over sorafenib in more than a decade. This marked a profound paradigm shift in the management of advanced HCC, proving the clinical viability and superiority of immunotherapy-based combination regimens in a disease historically refractory to systemic therapies.

Historical Context

For over a decade following the landmark SHARP trial in 2008, the multikinase inhibitor sorafenib was the sole approved first-line systemic therapy for advanced hepatocellular carcinoma. Numerous phase 3 trials attempting to unseat sorafenib with other targeted therapies or immunotherapy monotherapies (such as the CheckMate 459 trial for nivolumab) failed to show a statistically significant overall survival benefit. Concurrently, preclinical and early clinical data suggested that VEGF-mediated immunosuppression plays a major role in the tumor microenvironment of HCC, and that blocking VEGF could enhance T-cell infiltration and the efficacy of PD-L1 blockade. IMbrave150 successfully capitalized on this mechanistic synergy, becoming the first phase 3 trial to successfully displace sorafenib as the optimal first-line agent.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanistic rationale for combining a VEGF inhibitor (bevacizumab) with a PD-L1 inhibitor (atezolizumab) in the treatment of hepatocellular carcinoma?

Key Response

VEGF not only promotes angiogenesis but also creates an immunosuppressive tumor microenvironment by inhibiting dendritic cell maturation and increasing regulatory T cells. Bevacizumab normalizes the tumor vasculature and reverses this immunosuppression, enhancing the T-cell mediated anti-tumor activity of the immune checkpoint inhibitor atezolizumab.

Resident

Before initiating atezolizumab plus bevacizumab in a patient with cirrhosis and newly diagnosed unresectable HCC, what specific screening procedure must be performed and why?

Key Response

Patients must undergo an upper endoscopy (EGD) within 6 months prior to starting therapy to evaluate for esophageal varices. Bevacizumab carries a significant risk of severe bleeding, and untreated varices are a major contraindication; any high-risk varices must be treated per standard of care before initiating the regimen.

Fellow

The IMbrave150 trial excluded patients with Child-Pugh B or C cirrhosis. How should we approach first-line systemic therapy for an unresectable HCC patient who presents with Child-Pugh B cirrhosis, and what alternative data exists for these patients?

Key Response

The safety and efficacy of atezolizumab and bevacizumab are unproven in Child-Pugh B/C patients, who have a higher risk of hepatic decompensation and bleeding. Fellows must weigh off-label use versus alternative tyrosine kinase inhibitors or single-agent immunotherapy, recognizing that systemic therapy in Child-Pugh B is generally considered borderline, often prioritizing best supportive care or early-phase clinical trials.

Attending

With the shift from TKIs to atezolizumab and bevacizumab as the first-line standard, how does the paradigm of toxicity monitoring change in your clinic, particularly regarding the delayed recognition of overlapping toxicities like hepatitis?

Key Response

Attending physicians must navigate the transition from managing classic TKI toxicities like hand-foot syndrome to monitoring for immune-related adverse events such as autoimmune hepatitis. This can be difficult to distinguish from progression of underlying viral hepatitis or drug-induced liver injury, requiring a fundamental restructuring of clinic workflows and multidisciplinary coordination with hepatology.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The IMbrave150 trial utilized co-primary endpoints of overall survival and progression-free survival evaluated by an independent review facility. What are the statistical challenges and alpha-spending implications of using co-primary endpoints in an unblinded oncology trial?

Key Response

Using co-primary endpoints requires splitting the alpha, typically utilizing a graphical approach to strongly control the family-wise error rate at 0.05. Furthermore, in an open-label trial, progression-free survival is subject to investigator bias, making an independent review facility using RECIST v1.1 and HCC-specific modified RECIST critical to ensure validity.

Journal Editor

Given that IMbrave150 was an open-label trial, how might the lack of blinding introduce ascertainment bias or impact the assessment of patient-reported outcomes, and did the trial design adequately mitigate this?

Key Response

Open-label designs can bias subjective outcomes, including adverse event reporting and quality of life metrics. A rigorous peer reviewer would scrutinize whether the delayed time to deterioration in quality of life observed with the combination was influenced by patients knowing they received the novel therapy, despite the use of independent central review for radiographic endpoints.

Guideline Committee

Based on the IMbrave150 results, what strength of recommendation and level of evidence should be assigned to atezolizumab plus bevacizumab for first-line treatment of unresectable HCC, and how does this relegate sorafenib or lenvatinib in the updated treatment algorithms?

Key Response

This trial provided high-quality Category 1 evidence demonstrating an overall survival benefit, prompting NCCN and AASLD to update guidelines to recommend atezolizumab plus bevacizumab as the preferred first-line regimen for Child-Pugh A patients. Sorafenib and lenvatinib were subsequently downgraded to alternative first-line options for patients with contraindications to immunotherapy or anti-VEGF agents.

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

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

2018

REFLECT Trial

n = 954 · Lancet

Tested

Lenvatinib

Population

Patients with untreated advanced hepatocellular carcinoma

Comparator

Sorafenib 400mg twice daily

Endpoint

Overall survival

Key result: Lenvatinib was non-inferior to sorafenib in overall survival with significant improvements in progression-free survival.

2022

HIMALAYA Trial

n = 1171 · NEJM Evid

Tested

Tremelimumab plus Durvalumab

Population

Patients with unresectable hepatocellular carcinoma

Comparator

Sorafenib

Endpoint

Overall survival

Key result: The STRIDE dual immunotherapy regimen significantly improved overall survival compared to sorafenib, reaching a median of 16.4 months versus 13.8 months.

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