Pierce K.H. Chow, PhD, MBBS, on Hepatocellular Carcinoma: New Data From the IMbrave050 Trial of Atezolizumab, Bevacizumab, and Active Surveillance

The IMbrave050 study is a phase three global study of atezolizumab plus bevacizumab used as adjuvant therapy versus active surveillance in patients who have undergone curative surgical resection and also ablation. The premise of this study is that there was no previous adjuvant therapy that was validated for HCC. And because of that, recurrence rates in HCC are very high, particularly among patients with larger tumors, multiple tumors, vascular invasion, and of course poor tumor differentiation. And so for this trial, we specifically enrolled patients with these poor cancer characteristics in a randomized controlled manner. So four to 12 weeks after surgical resection or ablation, they're randomized to receive either atezolizumab and bevacizumab as adjuvant or to the surveillance arm, the caveat being that if they are on the surveillance arm and they do have a recurrence, they are permitted to cross over to the atezolizumab plus bevacizumab arm, and this was run across the entire world. At the point of randomization, the patients are very well distributed between the two groups. Most of the patients were men. They were around 60 years old. More than 80% of them were from Asian ethnicity, and more than 70% of them were enrolled from Asia outside of Japan. More than 60% had evidence of vascular invasion, and more than 40% of them had poor tumor differentiation. The primary endpoint of the study was recurrence-free survival as assessed by independent review facility, and we adopted a hierarchical analysis approach. So the first interim analysis was triggered when 253 recurrence-free survival events were encountered. And at this first interim analysis, the IMbrave050 met its primary endpoint and became a positive trial and had a hazard ratio of 0.73 and a P value of 0.012. And this was achieved at the median follow up of 17.4 months, and at that time, recurrence-free survival was 78% for patients on atezolizumab plus bevacizumab versus 65% for patients on active surveillance. And when we look at the recurrence rates, it was particularly impressive because patients on atezolizumab and bevacizumab had a one third or 33% decrease in recurrence rate. So at landmark analysis at 12 months, this was 34% versus 20% for the two arms respectively. The adverse events were not different from what we saw in 150, the earlier trial for this therapy. The duration of treatment for patients on the 050 was significantly longer than that for the earlier 150 trial, which was for advanced HCC. So in the 050, for example, patients on atezolizumab had a median duration of treatment of 11.1 months and for bevacizumab it was 11 months. But in spite of this very much longer duration of treatment, we do not see an increase in adverse events for 050 compared to the earlier study. The most important adverse events which were encountered were proteinuria, hypertension, decrease in platelet counts, and also derangements of liver function. So in conclusion, this is the first trial historically to be positive for adjuvant therapy in the phase three setting, and this applied to patients across the major clinical subgroups. The adverse events were as we expected for this drug and the disease. And atezolizumab plus bevacizumab may become the standard of care for patients in terms of adjuvant therapy after curative resection or ablation and may also change clinical indications for surgical resection.