Post Conference Perspectives: Immunotherapy Combinations for Unresectable HCC - Episode 1

The Impact of Liver Pathobiology on HCC Treatment Approach


Ghassan K. Abou-Alfa, MD: Our understanding of liver cancer pathobiology is evolving fast, and thankfully the therapies that are applied to that better understanding of the biology of liver cancer are evolving very fast as well. At the moment, it’s most important that we do recognize that there are certain specific targets that ought to be attacked in regard to liver cancer. Most of those usually are taken care of by what we call tyrosine kinase inhibition. On the other hand, an important component is the role of immunotherapy or checkpoint inhibitors in liver cancer and how can they play a role in treatment of the disease.

Immunotherapy, which is a very hot item in many cancers, has no doubt been extremely helpful. It’s still relatively novel in regard to liver cancer, and we’re still not sure where to place it specifically. However, it appears that liver cancer would react positively to immunotherapy because of the immune status of the liver cancer disease to begin with. Interestingly though, despite all promises and expectations that a checkpoint inhibitor like an anti—PD-1 [anti–programmed cell death protein 1], for example, nivolumab or pembrolizumab, would be able to benefit patients more than a tyrosine kinase inhibitor would do or even a placebo, in liver cancer has not been proven. It tells us that the ultimate alterations that are needed for the checkpoint inhibitors to work in liver cancer are much more complex than a single agent. And that’s why the novel approach that we are witnessing at the moment is combination therapies for the disease.

The classic targets in regard to liver cancer are the same we use for other cancers for the checkpoint inhibitors, being anti—PD-1, anti–PD-L1 [anti–programmed death-ligand 1]. But at the same time, the novel thing that we are bringing into liver cancer, which also is happening in other cancers is, is there a role for enhancing the capabilities of immunotherapy that a treatment like an anti–PD-1 can contribute, or an anti–PD-L1 can contribute, being: an antiangiogenic therapy plus an anti–PD-L1; a tyrosine kinase inhibitor plus an anti–PD-1 or PD-L1; and thirdly, a checkpoint inhibitor, e.g., an anti–CTLA-4 [anti–cytotoxic T-lymphocyte–associated protein 4] plus anti–PD-L1. Time will tell.

The combination of the checkpoint inhibitors plus something else was first understood as being just like 1 basket, that whatever you add to a checkpoint inhibitor will get better results, and move on. But now we have a better understanding that the combination of a checkpoint inhibitor plus an antiangiogenic is 1 category by itself. The combination of checkpoint inhibitors plus a tyrosine kinase inhibitor is another category, and the checkpoint inhibitor plus a checkpoint inhibitor, like, for example, anti—PD-L1 plus anti–CTLA-4, is a third category. The question is, are these 3 kinds of differentiations the same or different? Time will tell.

Transcript Edited for Clarity