Multimodality Management of Advanced Liver Cancer - Episode 7

Optimal Sequencing of I/O Therapy in Liver Cancer


Ghassan K. Abou-Alfa, MD, MBA: Back to you Riccardo. I’ll tell you a story. I had a patient come to me, and the patient was totally eligible for an embolization. And I suggested the embolization. He said, “No, I want a checkpoint inhibitor. I want immunotherapy.” What I’m trying to relay here is, have you thought of any sequential use of these therapies between local and systemic? Are you seeing patients engaged more in regard to checkpoint inhibitors or TKIs [tyrosine kinase inhibitors]? Your thoughts?

Riccardo Lencioni, MD, FSIR, EBIR: Clearly the combination between locoregional therapies, particularly TACE [transarterial chemoembolization], with TKIs truly fail to provide a meaningful clinical benefit. There is a focus today on the potential synergistic effect between a local therapy, in particular chemoembolization, with checkpoint inhibitors. Why is that? Well, we know that all locoregional therapies induce an immune response, but usually this is not really able to translate into a meaningful effect. I’ve never seen let’s say an abscopal effect. I’ve never seen regression in a tumor that was not directly targeted with ablation or chemoembolization.

However, the tumor disruption, the increased antigen exposure, the enhanced T-cell activation, there is work that suggests that this immune effect induced by chemoembolization could then be amplified by checkpoint inhibitors, and there are several studies investigating which combination and which sequence is best.

Ghassan K. Abou-Alfa, MD, MBA: We’ll hold on that thought; I have 2 things that we still would like to spend a lot of time on with you. But before we go there, I’m going to ask, and I’ll start with Mike, TKI followed by checkpoint inhibitors or checkpoint followed by TKI? What’s the appropriate sequence?

Michael A. Morse, MD, MHS, FACP: I guess we have to get to this question at some point. Thanks for making me the first one. The simple answer is, our thinking around this is probably continuing to evolve. I, like most people, would have previously said, “Well, it depends on how they did on their original therapy.” But what we’re seeing is, it doesn’t actually translate regardless of how long you were on or how you tolerated your first-line TKI. You can still do well with the second-line TKI. For some patients, they do come in with an interest in immunotherapy, and so we certainly want to defer to them. In other people, the sense of changing mechanism is important. Changing the toxicity risks might be a more appropriate reference, but I’m not sure I can tell you that in a strong way of navigating this question.

Ghassan K. Abou-Alfa, MD, MBA: Well to be fair, probably none of us know. But to summarize and hash out what we just heard, the checkpoint inhibitors, no question, definitely have a substantial value in regard to treatment in HCC [hepatocellular carcinoma]. Two of them already are conditionally approved by the FDA, being pembrolizumab and nivolumab, with the understanding that it probably was more the duration of response rather than anything else because the response rate remained limited to the 15% range.

However, clearly, I think we all agreed that we were definitely, No. 1, surprised; No. 2, we’re trying to understand and explain the negative pembrolizumab versus placebo phase III data, and upcoming, we’re going to see the data. None of us know the data yet of nivolumab versus sorafenib. Nonetheless, despite what we just heard about potential explanation points as to why the trials could have been negative based on some statistical design issues, at the end of the day it didn’t work. If anything, it brings in a little bit of better understanding in regard to what’s critical about the anti—PD-1 [anti-programmed cell death protein 1], anti–PD-L1 [anti–programmed death-ligand 1] therapy? And what is the involvement of anti–CTLA-4 [anti–cytotoxic T-lymphocyte–associated protein 4]? And maybe the combination of those is going to be the critical component.

Day after day I’m seeing more that HCC is not like really an anti—PD-1, anti–PD-L1 disease. It’s more an anti–CTLA-4 disease. And I think Tim already suggested that in the discussion as well. Nonetheless, as also Catherine mentioned, the combinations are what we’re very intrigued by, and we have of course the atezolizumab-bevacizumab combination that we were very intrigued by, and we’re waiting for more data from the IMbrave trial. We have the atezolizumab-cabozantinib trial, and in addition to that we have the pembrolizumab-lenvatinib trial. And I would say there will be more to come. So between the durvalumab-tremelimumab, as well as the different combination of the TKIs plus checkpoint inhibitors, I think we have plenty to wait for to see.

Transcript Edited for Clarity