Second-Line Treatment Approaches for Advanced HCC

Tanios S. Bekaii-Saab, MD, FACP: I want to move on to the second line, and specifically think about our patients. Arndt, I’m going to have you open the discussion. Thinking about patients who now go primarily on frontline IO [immunotherapy], so atezolizumab plus bevacizumab. Then we move on to the second line, and most of the second-line data today available to us are post-sorafenib. How do we make sense of the second-line landscape?

Arndt Vogel, MD: That is a very good question. We discussed it also when we updated the ESMO [European Society for Medical Oncology] guideline. I’m not sure that we have read the text; we had 11 people, and we couldn’t agree on 1 statement. There were 2 options. Some of us, the minority, suggested that sorafenib and lenvatinib should become second line, and the other drugs, cabozantinib, regorafenib, and ramucirumab should be at third line. The majority of us thought we don’t really have the evidence to suggest that either drug should be preferred after IO therapy. Because we understand more and more about the mechanisms of action, but we don’t know which one is most important. We don’t know which one predicts resistance, so we thought we need to be more open, because just timing of the trial can’t decide whether we use it in our daily clinical practice. We cannot…that all drugs should be used. There was a minority report included saying lenvatinib and sorafenib should be preferred in second line. I do not agree with that, but it’s difficult because when you look at the efficacy data, they are very similar, there’s no drug that really stands out in response, or maybe lenvatinib, a little bit in response. Otherwise in PFS [progression-free survival] and overall survival, even if you look at first and second line, it’s all very similar.

Tanios S. Bekaii-Saab, MD, FACP: What’s your preferred strategy? What would be your first choice?

Arndt Vogel, MD: I’m driven by the money. I can’t decide by myself. In Germany we only have reimbursement for sorafenib in second line, and then we can use all other drugs after sorafenib. I’m driven by that. and I can’t use any other drug. If I could decide on my own, I probably would use more cabozantinib because personally I think cabozantinib is a very interesting drug, and we just discussed the COSMIC trial. I’m also interested in the third arm, sorafenib vs cabozantinib. That would also be my question to you. Do you think that this third arm could be of interest for our decision in the second-line setting?

Tanios S. Bekaii-Saab, MD, FACP: Interesting. Mark, any thoughts?

Mark Yarchoan, MD: Unfortunately, we have no data after atezolizumab plus bevacizumab. There’s a good argument to make that the second line after atezolizumab plus bevacizumab is more similar to the second line after sorafenib than a first-line setting. An agent that’s shown benefit in a post-VEGF setting may make a lot of sense. I agree cabozantinib is very reasonable in the second line after atezolizumab plus bevacizumab. That being said, a first-line TKI [tyrosine kinase inhibitor] like sorafenib or lenvatinib is also totally reasonable. We can’t say that one is better than the other. The one advantage of giving sorafenib in the second line is that it’s easier to give IPI NIVO [ipilimumab and nivolumab] in the third line because it’s approved post-sorafenib. And many of our patients now are making it not only to the second line, but third line, which is just amazing. The response rate to [ipilimumab and nivolumab] is approximately double that of PD-1 monotherapy at about 32%, so clearly CTLA-4 has activity in this tumor. It’s something that I like to integrate in some line of therapy for my patients. I’ve seen responses to [ipilimumab and nivolumab] in the post–PD-1 or PD-L1 setting.

Tanios S. Bekaii-Saab, MD, FACP: Rachna, would you rechallenge with IO therapy? If someone was pre-exposed to atezolizumab plus bevacizumab, skip a line, does it make sense? Should we study the question if it doesn’t make clinical sense?

Rachna Shroff, MD: There are a lot of preclinical and even early clinical data that do suggest that rechallenging, depending on what the combination was and the potential mechanisms for resistance, there could be a role. I agree with Mark, my preference is to do CTLA-4, PD-1 combination, but there are important trials right now that are looking at post-IO combination therapies with IO/IO or IO/TKI. Those are important trials to be running because at the end of the day, it’s like Mark is saying, we actually have patients who are able to go onto second- and third-line therapies. And to Arndt’s point, we don’t actually have a consensus on what we should be doing, but we know that these combination approaches are working. Investigating them in a prospective trial is actually really important. As you mentioned, there are global studies looking at these…has some studies. These are going to be important studies that hopefully will give us some help here.

Transcript Edited for Clarity