Durvalumab plus bevacizumab, added to TACE, shows benefit for unresectable hepatocellular carcinoma

Dr Riccardo Lencioni - University of Pisa, Pisa, Italy

The study investigated patients with intermediate hepatocellular carcinoma, so we are talking about patients who are unsuitable for radical treatment options, including surgery or ablation, but had disease still confined to the liver. So, for this patient population for more than 20 years the standard of care has been trans arterial chemoembolisation, or TACE. However, PFS after TACE does not exceed 7-8 months so there is a large unmet need for this patient population.

What was the study design?

In the EMERALD-1 study we investigated the potential synergistic effect of TACE with checkpoint inhibitors and VEGF inhibitors. So the trial had three arms, arm A was TACE in combination with durvalumab, arm B was TACE plus durvalumab and bevacizumab, and arm C was the control arm and included TACE plus placebo. The primary endpoint was progression free survival for the combination of durvalumab and bevacizumab with TACE versus the control.

What were the results of the study?

The study met its primary endpoint and the combination of TACE, durvalumab and bevacizumab resulted in a statistically significant and clinically meaningful improvement in progression free survival with respect to TACE plus placebo. The median PFS was 8.2 months in the control arm, and this is one of the best reported results for TACE in a global phase III trial. This was improved to 15 months with the combination of durvalumab and bevacizumab.

Other secondary endpoints like TTP and objective response supported the outcome of the primary endpoint.

How can these results impact the treatment of hepatocellular carcinoma?

The results are definitely very compelling. I have yet to mention that the study is still ongoing because overall survival, which was a secondary endpoint, was immature. So we are waiting for more events to be able to perform the final analysis of OS.

However, the study has opened a new horizon, demonstrating for the first time that there could be a synergy between local regional therapies such as chemoembolisation, or potentially other forms of local intervention, and systemically active drugs with an immune based regimen. So we hope that with more and more data and with a proper allocation in treatment guidelines and recommendations this would be another very important step forward to improve the outcome for our patients with HCC.

What is next for this study?

Other trials are already ongoing and well on their way. Some of them attempt to combine the same association of durvalumab and bevacizumab with other forms of local regional therapy such as Y-90 radioembolisation instead of chemoembolisation. Other studies are investigating different forms of systemic therapies in combination with TACE. For instance, in EMERALD-3 the combination of durvalumab and tremelimumab plus or minus lenvatinib is investigated and other trials are also working on this immune-oncology based combination. So definitely more data will follow soon and in the near future we will have a 360 information on the potential with immune-oncology combinations to improve the prognosis of HCC across all stages, so in the early resectable, curable stage in the adjuvant setting, in the intermediate stage, as we discussed for EMERALD-1, as a combination strategy and, of course, as systemic standalone therapy for advanced stage.

So we are looking forward to a broader armamentarium and a management of the disease that becomes more and more multidisciplinary.

Is there anything else you would like to add?

I just wanted to mention that when you move from clinical trials to clinical practice there are some important points to consider. This is a patient population that has two diseases: one is the tumour and the other one is the underlying cirrhosis. So these are vulnerable, fragile patients that must be carefully selected. So in the study we selected patients in good general condition with preserved liver function. With endoscopy we excluded the patients at potential risk of bleeding.

So it is important once and if this combination will be approved for clinical practice to consider that an individual, careful, multidisciplinary assessment of each individual patient is truly extremely important to prevent undesirable adverse events and to achieve the best outcomes.