Recent updates from the IMbrave150 study, which led to the FDA approval of frontline atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma [HCC].
Richard S. Finn, MD: Now, there have been several attempts to beat sorafenib over the past decade. In reality, nothing has succeeded until we recently saw data from the IMbrave150 study, which looked at the combination of atezolizumab and bevacizumab vs sorafenib for this advanced liver cancer population.
Like all studies in advanced liver cancer, this study took patients who were in Child-Pugh stage A, and they had either Barcelona Clinic Liver Cancer [BCLC] stage C or BCLC stage B, intermediate, that progressed on TACE [transarterial chemoembolization]. This was an open-label study, and it was based on some scientific data that demonstrated that targeting VEGF with drugs like bevacizumab can potentiate the effect of a PD-L1 inhibitory antibody such as atezolizumab. We know that bevacizumab has been around for some time. It was initially approved in colon cancer in combination with chemotherapy, and since that time, it has had several other indications. Initially, its primary mechanism of action, which we know as a monoclonal, is against VEGF, but by modifying VEGF, we change the vasculature and potentiate chemotherapy effects.
However, our understanding has now evolved such that, by changing the vasculature, we also change the inflammatory milieu around a tumor into one that can be procytotoxic, and then by removing the brakes on the immune system by blocking checkpoint PD-L1, we can get synergy. This was initially seen in a large phase 1b expansion study in liver cancer of about 100 patients in which they saw an objective response rate of 36% and an [adverse] effect profile that was fairly consistent with the known mechanisms of bevacizumab and the known mechanisms of atezolizumab. Interestingly enough, because of the concern about bevacizumab and bleeding, bevacizumab had not been evaluated intensely in liver cancer.
Going back to 2008, our group [the Geffen School of Medicine at the University of California, Los Angeles] and others had done preclinical work that showed that bevacizumab might have activity in liver cancer because of its potent VEGF activity. We know that liver cancer is a hypervascular tumor. Studies looking at patients with advanced liver cancer did not show a robust response rate, but there was interesting progression-free survival data. There was a concern about bleeding. We conducted a study looking at bevacizumab in combination with chemoembolization, and it did not have any safety signals. It showed that we could block the intense VEGF increase after chemoembolization and prevent neovascularization. As it was a single agent, we did not see much more activity with bevacizumab until the combination data with atezolizumab and bevacizumab.
The IMbrave150 study took patients who had a Child-Pugh score A, as mentioned. All of them had a screening endoscopy within 6 months of coming on trial, and they were randomized, open label 2:1 to bevacizumab and atezolizumab vs bevacizumab alone. The results of this study were recently published in The New England Journal of Medicine, and this led to the FDA approval earlier [in 2020]. This study was well balanced between both arms. As the study was stopped at the first interim analysis, the median follow-up was about 8 and a half months.
We saw that, looking at the coprimary end point of overall survival, there was a 42% decrease in the risk of death. The median survival with sorafenib was about 13.2 months, and with atezolizumab and bevacizumab, we have not yet reached the median at the time of the primary analysis. If we look at the benchmark of 12-month survival, about 67% of patients were alive at 1 year with atezolizumab and bevacizumab, and this was 54.6% with sorafenib. The hazard ratio of 0.58 in the frontline setting has not been seen with any drugs vs an active control.
The coprimary end point of progression-free survival was also markedly improved from 4.3 months to 6.8 months with a hazard ratio of 0.59. When we look at the subgroups by overall survival or progression-free survival, we generally see a trend that supports all clinical subgroups benefitting from the addition of atezolizumab and bevacizumab. Obviously, not all of them are powered to show statistical significance, but the overall trend is reassuring.
Transcript edited for clarity.