Hepatocellular Carcinoma: Practical Implications of Emerging Data - Episode 11

Selecting Second-Line Therapy for HCC

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Richard S. Finn, MD: Tony, what’s your thought about TKIs after atezolizumab/bevacizumab? I mean, are we going to first-line TKI, which would be sorafenib/lenvatinib, and then second-line TKI? Or is this step zero, and then we have first-line, second-line? What are your thoughts?

Tanios S. Bekaii-Saab, MD, FACP: No, it’s not step zero. It’s step one and it displaces your first-line sorafenib, so I’m not going to put sorafenib after it. It’s gone. Lenvatinib has not proven to be any better than sorafenib, so I’m not going to waste my purpose or my time thinking about this. My life has become simpler. I have a good first-line, atezolizumab/bevacizumab for most patients. My second-line is going to be the same second-line I struggle to use, plus simplified--I mean, I think regorafenib or cabozantinib. There’s nothing to say that lenvatinib is going to be better than regorafenib or cabozantinib in that setting. And very few patients will make it to the third-line. I think ramucirumab, in my viewpoint, is a goner at this stage. When bevacizumab fails, I’m not sure ramucirumab on its own is going to salvage it. I’d rather have a dirty multi-kinase inhibitor such as regorafenib or cabozantinib. Both of them have good targets that essentially revert back the resistance to VEGF or the resistance, actually, with regorafenib. You hit so many different targets, you can also argue that you hit more targets than we know, including some of the targets--like CSF1R and others, that are relevant to IO. The future is probably to enhance activity through combinatorial strategies across multiple lines. I mean, one thing we’ve seen--and we see that in lots of different malignancies. But specifically this one is that one agent--I don’t care which one you look at, whether it’s lenvatinib, whether it’s sorafenib, whether it’s nivolumab, whether it’s pembrolizumab, cabozantinib, I mean, you name it. One agent pulls a little bit of an advantage. Two agents are pulling much more of an advantage. So it sounds to me that ultimately, the questions in the second-line will have to focus similar to the first-line on combinations. But right now, in clinic, my life has become a little simpler for now until we get the results of all these other studies and then figure out what to do with them, it’s atezolizumab/bevacizumab, then it’s regorafenib or cabozantinib.

Richard S. Finn, MD: There’s six of us on the panel here, and you get six different opinions. But Amit, how do you think about it?

Amit Singal, MD: I think somewhat like Tony, but a little bit differently in different aspects. I agree obviously with atezolizumab/bevacizumab, with IMbrave150, I think all of us agree that atezolizumab/bevacizumab is a game changer. It’s going to be the standard first-line therapy for the vast majority of patients. In the second-line, I personally am putting everything in one big box. I am personally saying that you can choose sorafenib, lenvatinib, cabozantinib, and regorafenib. I do agree that ram, I don’t think that that has a major role now with atezolizumab/bevacizumab in the frontline. I personally am putting ram on the back burner. But the other four, I’m putting in one big box in the second-line setting, with the caveat that resource required sorafenib tolerance. And so maybe, I guess, regorafenib would be third-line for me if somebody goes on sorafenib to select those who can tolerate regorafenib. But I personally--otherwise, I’m not just throwing away sorafenib. I am still keeping that in that second-line box.

Tanios S. Bekaii-Saab, MD, FACP: You have to decide between those four. You have the patient in front of you. And you have those four, and you’re saying--and I don’t disagree. They’re probably somewhat in the same range. The question is, how do you pick one versus the other. I think you need to argue that sorafenib is probably the weakest link. So that’s easy; that goes. Ramucirumab goes. Lenvatinib is okay, it’s not better than sorafenib. I mean, you take a study that’s noninferiority, and we make a lot of conclusions out of it. It’s still a noninferiority study. And you have two level-one evidence, albeit it’s in sorafenib failure, but two level-one evidence agents in the second- and third-line. I mean, you have to choose one of those four—

Richard S. Finn, MD: [Interposing] Yeah, I mean, those were versus placebo, the cabo and rego studies. Len study was an active control. I mean, personally, I still look at it front-line TKI, then second-line TKI. So maybe after progression, I would consider sorafenib or lenvatinb and then go to one of the other third-line or second-line, which are now third-line agents. One thing that very much I appreciate your comment about, it simplified things, because I think moving IO front-line takes it out as an option in second and third-line. But I’m very intrigued by CTLA4 and PD-1 inhibition. And I’ve looked into other malignancies, because certainly in melanoma and lung cancer where IO has been front-line for some time, they’ve been struggling to find that magic regimen when IO stops working. I don’t think that anyone has come up with it. I mean, is there data to think about using nivolumab/ipilimumab, for example, in second line after progression on atezolizumab/bevacizumab? Anthony, what’s your thought?

Anthony El-Khoueiry, MD: There’s currently no current data on doing this nivolumab/ipilimumab data that’s out there and the led to the accelerated approval was post-sorafenib. As you mentioned, in other malignancies now, we have evidence of nivolumab/ipilimumab working as a second-line regimen post-PD-1. So, there may be room to evaluate this in this setting. The question, though, again--and maybe always a theoretical question--will CTLA4 alone do the same in the second-line setting. I mean, the tremelimumab alone data from Katie’s study presented at ASCO 2020, to me, is intriguing still. But I think what it’s coming down to is there’s going to be ample opportunity for additional studies--not just opportunity. There’s an absolute need for additional studies in second and third-line with either novel agents or looking at different immune targets beyond PD-1 in that space.

Transcript Edited for Clarity