Atezolizumab-bevacizumab treatment increases survival in unresectable hepatocellular carcinoma

1. Combination treatment of atezolizumab and bevacizumab was shown to significantly increase overall survival and progression-free survival outcomes in patients with advanced unresectable hepatocellular carcinoma.

2. Patients treated with the combinatorial treatment of atezolizumab and bevacizumab were shown to experience serious toxic side effects.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Hepatocellular carcinoma is a leading cause of cancer-related death with most patients presenting with unresectable disease. First-line systemic treatment consists of sorafenib, which is a multikinase inhibitor. Currently, several immunotherapies targeting the PD-L1-PD-1 pathway are becoming of interest for patients with hepatocellular carcinoma such as atezolizumab and bevacizumab. This study determined the safety and efficacy of a combinatorial atezolizumab-bevacizumab treatment in patients with unresectable hepatocellular carcinoma. The participants were randomized to receive atezolizumab-bevacizumab or sorafenib treatment. The study determined the patients in the atezolizumab-bevacizumab group had a significantly higher overall survival and progression-free survival compared to the patients in the sorafenib group. However, patients in the treatment group did experience serious toxic side effects such as hypertension and pruritis, which were consistent with the known safety profiles of atezolizumab and bevacizumab. This randomized trial was limited by the study design as an open-label study. The study design resulted in the participants and the researchers knowing the treatment classification potentially introducing a bias in patient-related outcomes such as adverse effects and quality of life measurements. Another limitation of the study was the study population only included patients with preserved liver function. Nonetheless, this study was strengthened by the long-term patient follow-up and matched patient characteristics between both groups. For physicians, these findings highlighted an alternative treatment for patients with advanced unresectable hepatocellular carcinoma.

Click to read the study in NEJM

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In-Depth [randomized controlled trial]: This randomized control trial enrolled 501 patients in a multicenter study from 111 sites in 17 countries. The inclusion criteria included pubertal adolescents (12 to <18 years of age). Inclusion criteria included: participants 18 years of age or older; presence of locally advanced and/or unresectable hepatocellular carcinoma; and no previous systematic therapy for liver cancer. The exclusion criteria for the study included history of autoimmune disease; coinfection with hepatitis B or hepatitis C virus; and esophageal or gastric varices with bleeding or high risk of bleeding. The patients were randomized to the atezolizumab-bevacizumab or sorafenib treatment group in a 2:1 ratio. The coprimary outcomes were overall survival and progression-free survival. Overall survival was defined as the time from randomization to death from any cause. Progression-free survival was defined as the time from randomization to disease progression. Additionally, adverse outcomes within both treatment groups were recorded. At six months, the overall survival was significantly longer with atezolizumab-bevacizumab treatment (84.8%, 95% confidence interval [CI], 80.9 to 88.7) compared to sorafenib treatment (72.2%, 95% CI, 65.1 to 79.4). At 12 months, the overall survival was significantly longer with atezolizumab-bevacizumab treatment (67.2%, 95% confidence interval [CI], 61.3 to 73.1) compared to sorafenib treatment (54.6%, 95% CI, 45.2 to 64.0). The hazard ratio for death with atezolizumab-bevacizumab treatment compared to sorafenib treatment was 0.58 (95% CI, 0.42 to 0.79; P<0.001). Additionally, the progression-free survival was significantly longer with atezolizumab-bevacizumab treatment (median, 6.8 months, 95% CI 5.7 to 8.3) compared to sorafenib treatment (median, 4.3 months, 95% CI 4.0 to 5.6). The hazard ratio for disease progression or death was 0.59 (95% CI, 0.47 to 0.76; P<0.001). Furthermore, serious adverse events occurred more frequently in the atezolizumab-bevacizumab group (38.0%) compared to the sorafenib group (30.8%). The most common grade 3 or 4 event with atezolizumab-bevacizumab treatment was hypertension (15.2%), which is consistent with the known safety profile for bevacizumab. Taken together, administration of atezolizumab-bevacizumab treatment significantly increased overall survival and progression-free survival outcomes.

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