Ghassan K. Abou-Alfa, MD: Mark, earlier I asked you if you defer to treatment based on etiology. Based on the data from the lenvatinib-versus-sorafenib trial, is there anything, such as demographics or outcomes, that really comes to mind that you are curious about?

Mark H. O’Hara, MD: Looking at the data, and looking at the study, it’s sort of saying, “OK, they’re not inferior. They’re pretty much equivalent. Which group would I use lenvatinib in? Which patients would I use sorafenib for?” I don’t know if we have definitive data pointing one way or the other. For the patients in whom we might want a response in, maybe, by modified RECIST, they might use lenvatinib. Progression-free survival with no significant difference, and overall survival, I’m not sure how to interpret that data for patients with metastatic disease.

Ghassan K. Abou-Alfa, MD: Interestingly, there were some components. The group with hepatitis B was slightly different between the two. The AFP level was also slightly different between the two. But the secondary endpoints were really quite impressive, despite the noninferiority, which was really the best we could reach. By the way, the noninferiority was really all the way at the edge, regarding the hazard ratio. It was close to where the superiority would have kicked in. It was like a 0.01 or 0.02 difference between where the end of the noninferiority was and where the start of the superiority would be.

Manish, this study demonstrated amazing outcomes regarding progression-free survival and response, as we just spoke about, with lenvatinib. However, people will still wonder, “But it’s not inferior?” How do you interpret that?

Manish R. Sharma, MD: I think this is an example of a scenario where you have to dive a little bit deeper into the data. If you just read the headline, it’s not going to really give you the whole picture. When I first heard about this trial, I thought, “Why are we doing a noninferiority study with a drug that none of us are really thrilled with, sorafenib? Why are we trying to establish noninferiority to that?” When I looked deeper into the data, I saw, as you mentioned, a lot of superiority on the secondary endpoints. Lenvatinib outperformed sorafenib on all of these endpoints. The response rate, to me, was very telling. That’s something that is objective, right?

Whether we use modified RECIST or RECIST 1.1, in either case, lenvatinib significantly outperformed sorafenib. Shrinking tumors is always a good thing in oncology. Why it doesn’t translate into an overall survival benefit in this case, I think there are many theories about that. In this case, maybe we were close but didn’t quite make it to the superiority edge, right? We have a lot of therapies in hepatocellular carcinoma. This is going to affect survival going forward. I think this is very encouraging data. I am thrilled to have another option, assuming that lenvatinib does get FDA-approved. It has not, yet. All of us who’ve seen the data believe that they will be approved, and it would be great to have that other option. All of us, as medical oncologists, are going to have to become familiar with the drug. We are going to have to become comfortable with it. Sorafenib has had that 10-year lead. We’ve all learned how to use it, how to dose it, and how to adjust it. And so, I think there’s a comfort level there. Now, if lenvatinib comes to the scene, we have to kind of figure it out again.

Ghassan K. Abou-Alfa, MD: This is very important. If anything, however, just to carry on because there are some important points over here, it’s fascinating that the lenvatinib data did not necessarily pan out. We have to remember that the study was done with some components that had advantages for patients with hepatitis B. This could have influenced outcomes a little bit. We also have to remember that we didn’t have control over what the patients received afterwards.

But, again, I like what Mark said. At the end of the day, it was designed to be noninferior. It showed to be noninferior. We also saw a progression-free survival and response rates. Why not? This is great news for patients. This brings us to another important point: adverse events, or the tolerance of lenvatinib. Mark, do you have any thoughts on this, either from experience or based on your interpretation of the data?

Mark W. Karwal, MD: It’s pretty clear, from the data, that sorafenib’s going to blister your hands with some frequency. You don’t see that happen nearly as often with lenvatinib.

Ghassan K. Abou-Alfa, MD: That’s very important. If anything, what will be a common side effect? Is there anything that I would need to worry about with lenvatinib?

A. Ruth He, MD, PhD: High blood pressure.

Ghassan K. Abou-Alfa, MD: High blood pressure. OK, I know how to fix high blood pressure. Then we think about hand-foot syndrome. No doubt, that’s probably something we can control. But, you’re right. In the community, the perception is that people are not very receptive to this, regarding the management. And so, undoubtedly, the adverse events profile kind of plays a role here. At the end of the day, what’s fascinating is that the choice of therapy, based on the etiology being hepatitis B versus hepatitis C, is not there yet. And, if anything, these drugs could be used across the board, for everybody, without any specific limitations or concerns about who might benefit.

Mark W. Karwal, MD: One of the things with lenvatinib is that it can be taken with food. And it’s only taken once a day. Sorafenib is multiple pills, given twice a day, on an empty stomach—the classic 1 hour before and 2 hours after eating.

Ghassan K. Abou-Alfa, MD: Well, I presume that will be important. That’s why this is a rather practical component regarding the use of lenvatinib. Remember, patients may have problems eating. We’re going to make them starve further. I can understand your point.

Amit Singal, MD: Actually, I want to bring up 2 points. We have this concept of stage migration and transitioning. We often think of stage migration as progressive. You progress from locoregional therapy to systemic therapy, because that’s traditionally what we’ve been doing. I think the idea that you can have these objective response rates is interesting. You can actually have stage migration the other way. Theoretically, there are patients with large tumors in whom you can actually get objective response rates in. You may be able to do locoregional therapy in the future. I think this is interesting, as we start to see therapies giving higher objective response rates.

Ghassan K. Abou-Alfa, MD: I like what you have said. If anything, whenever I’m discussing all of this with a patient and their family, when they ask those questions, I say that everything remains on the table.

Transcript Edited for Clarity