Peter Galle, MD: We have long been waiting for immunotherapy entering the stage in advanced-stage hepatocellular carcinoma. With IMbrave150, we indeed have the first clinical trial combining atezolizumab, an immuno-oncological agent, and bevacizumab, an antiangiogenic agent. It has been very clear that both overall survival and progression-free survival are improved, with very favorable hazard ratios of 0.58 and 0.59. Here we have a clear improvement of overall survival and, in fact, had additional significant objective response rate in the range of almost 30%, depending on how you are looking at it.

This was a major step forward in terms of efficacy, but also patient-reported outcomes were analyzed and gave clear data on the quality of life and physical functioning. It demonstrated that of all these aspects, there is a long maintenance of quality of life and the other aspects over time during treatment, particularly much longer in comparison with sorafenib. We have an efficacious new therapy improving outcome over what has been the standard in the past. This is the accepted discussion among all experts. I would say that this will become the next first line upon approval. There might be regulatory in different countries, but that will replace sorafenib as the first-line standard.

This is then having quite interesting sequelae, in that we do not have all the evidence for further-line therapies. Is then what used to be first line the new second line? And is the old second line the new third line? Or do we use those substances with a given rationale? For example, do you start with an I/O [immuno-oncology] therapy and continue with the TKI [tyrosine kinase inhibitor]? That is an open question. At this time it’s only expert opinion, but it is among the issues that needs to be clarified in the near future.

The combination of atezolizumab and bevacizumab is not only efficacious but also well tolerated, and it results in a maintained quality of life. The way this assessment was performed was by starting with a given number, for example, quality of life or role functioning, and then checking when this was deteriorating over time. Here it took up to a year for certain parameters to get worse in the treated group with the combo of ATEZO [atezolizumab] and BEVA [bevacizumab]. It was much shorter for sorafenib, meaning you are getting successfully treated but also maintaining your quality of life.

This is very relevant for the patient, and in the future I believe the aspect of patient-reported outcomes in general will play an increasingly important role, because it makes a lot of sense if you have a limited life span and we are still talking about a palliative situation. Then the quality of life for the remaining time you have is playing a really important role. Good for the patient.

It’s an interesting aspect, the rationale for the combination of an antioncogenic agent and an immuno-oncology agent. What have we learned? We have learned from the single-agent therapy that we do see in a percentage, between 10% and 20% or so, objective responses. But apparently the majority of the patients are not benefiting enough to get positive data in what has been produced as a phase 3 trial so far. We are looking for an appropriate combination partner improving and fostering the I/O impact. Apparently bevacizumab, which is tackling the VEGF ligand, not only is impacting angiogenesis—this is what it was produced for—but apparently has an immunomodulatory quality. It acts on the immune cells, antigen-presenting cells, and other cells, it seems, in combination with the I/O. Is this an additive effect? Is this synergy? This is something that needs to be investigated further. But it tells us a story, in the combination, we are able to move I/O therapy into the systemic therapy of HCC [hepatocellular carcinoma].

Kate Kelley, MD: The atezolizumab-plus-bevacizumab data from the IMbrave150 trial has really become the new de facto standard of care in the first line for fit patients. By that I mean patients who really met the eligibility criteria for that phase 3 trial. In a patient who has Child-Pugh class A liver function, with no evidence of esophageal or gastric varices on a recent endoscopy, who is not at high risk for bleeding on an endoscopy—no patients on anticoagulation or is otherwise a high risk for bleeding—we really should consider atezolizumab plus bevacizumab as a first-line standard. Those criteria are very important to keep in mind, particularly that of the endoscopy. We know that bevacizumab as monotherapy has a substantial bleeding risk in patients with Child-Pugh class B liver function and in patients who have had incompletely treated esophagogastric variceal disease. In patients who haven’t had a recent endoscopy or who have high-risk findings on an endoscopy, it is not validated as a safe or effective therapy to date.

Transcript Edited for Clarity