FDA Approves Atezolizumab/Bevacizumab Combo for Unresectable, Metastatic HCC

By Michael Vlessides, /alert Contributor
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Patients with unresectable or metastatic hepatocellular carcinoma who have not received prior systemic therapy have a new treatment option in atezolizumab (Tecentriq; Genentech Inc.) plus bevacizumab (Avastin; Genentech, Inc.), which was approved by the FDA in late May. 

The administration’s approval of the drug combination was largely the product of the IMbrave150 study (NCT03434379), which the researchers said is the first phase III cancer immunotherapy study to show an improvement in overall survival and progression-free survival in people with unresectable or metastatic hepatocellular carcinoma compared with sorafenib. 

As part of that multicenter, international, open-label, randomized investigation, researchers studied 501 patients with locally advanced unresectable or metastatic hepatocellular carcinoma who had not received prior systemic therapy. 

Participants in the investigation were randomized (2:1) to receive either the combination of atezolizumab and bevacizumab, or sorafenib. Atezolizumab was administered intravenously, 1200 mg on day one of each 21-day cycle, while bevacizumab was also administered intravenously, at 15 mg/kg on day 1 of each 21-day cycle. Twice-daily oral sorafenib, on the other hand, was administered 400 mg on days 1-21 of each 21-day cycle. 

Patients received both treatments until disease progression or unacceptable toxicity. 

The investigation’s main efficacy outcome measures were overall survival and progression-free survival per RECIST 1.1 and assessment by independent review facility. Additional efficacy outcome measures included overall response rate.

The trial found that combination therapy reduced the risk of death (overall survival) by 42%, with a hazard ratio of 0.58 (p=0.0006). Indeed, while median overall survival was not reached in the combination-therapy patients, it was 13.2 months among their counterparts who received sorafenib. 

Similarly, atezolizumab plus bevacizumab was also found to reduce the risk of disease worsening or death by 41% compared with sorafenib. Here the estimated median progression-free survival was 6.8 months (95% confidence interval: 5.8-8.3) versus 4.3 months (95% CI: 4.0-5.6), respectively (HR 0.59; p<0.0001). 

Finally, objective response rate using RECIST 1.1 was 28% in patients who received atezolizumab-bevacizumab combination therapy, compared with 12% in the sorafenib group (p<0.0001). When using mRECIST, objective response rate was found to be 33% and 13%, respectively (p<0.0001).

The most common adverse reactions found in the study -- which were reported by at least 20% of the patients receiving atezolizumab plus bevacizumab -- were hypertension, fatigue, and proteinuria. Serious adverse reactions (grade 3-4) occurred in 38% of patients receiving combination therapy. The most frequent of these (≥2%) included bleeding in the gastrointestinal tract, infections, and fever. 

In the combination therapy, the recommended atezolizumab dose is 1200 mg, followed by 15 mg/kg bevacizumab on the same day every three weeks. If bevacizumab is discontinued, atezolizumab should be given either as 840 mg every two weeks, 1200 mg every three weeks, or 1680 mg every four weeks.

Approval of the combination therapy was lauded by Richard S. Finn, MD, of the David Geffen School of Medicine at UCLA. “The results of the IMbrave150 study are really transformative for patients with advanced liver cancer, one of the few cancers with a rising death rate and limited options in the first-line setting,” Dr. Finn said in a statement. 

“For the first-time we have a regimen that markedly improves survival over sorafenib, the standard of care for first-line hepatocellular carcinoma since 2007, and offers patients the opportunity for improved disease control with a favorable tolerability profile,” he added. 

The results of IMbrave150 were published in the New England Journal of Medicine on May 14, 2020.

 

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