Dr Michael Morse Discusses Current HCC Treatment Strategies and Future Directions

Michael Morse, MD, FACP, MHS, professor of medicine at Duke University School of Medicine and medical oncologist at Duke Cancer Center, explained the evolution of hepatocellular carcinoma (HCC) treatment in recent years, as well as ongoing research with potential to impact clinical practice.

Transcript

How has the treatment of HCC evolved over time, and how have novel treatment strategies impacted outcomes?

Well, HCC treatment has really changed dramatically. When I first started taking care of these patients in the late 1999 time point, it was chemotherapy, it was locoregional therapies, and that was pretty much it. And then we entered the tyrosine kinase era with sorafenib around 2007 or so. And for many years, there were other drugs that came along that were tested against sorafenib. But it took quite a while before even lenvatinib was shown to be noninferior for overall survival, but superior for some secondary end points. So now we had 2 tyrosine kinase inhibitors.

But the real advance has been the combinations with immune therapies—the anti–PD-1 and PD-L1 strategies or the combinations of anti–PD-1 and anti–CTLA-4. These have obviously increased survival and we now have higher response rates than we saw before. There are actually patients—they're uncommon—who even have complete responses or are downstaged enough that they can have other procedures done. So, we're really taking it from a uniformly fatal disease to one where there are some people who can have longer survivals than they had before.

How has the emergence of combination and immunotherapies impacted
HCC treatment?

Back in the beginning, we had the tyrosine kinase, or we can call them multikinase inhibitors, and they're used as single agents. And even when we had second-line multikinase inhibitors, they were still used as monotherapies. And then when immunotherapy came on the scene, again, it was monotherapy—we had nivolumab and pembrolizumab. But with combination therapies, we're now seeing longer overall survivals and higher response rates than we had previously seen before. So it offers the possibility that there are some patients who will survive a lot longer and will have enough disease control where they will be able to have additional procedures, maybe even get downstaged so that they can have a surgery or even a transplant. And that's really the direction the field has continued to go, is by putting these combinations together—whether it's checkpoint plus an anti-VEGF antibody or dual checkpoint inhibitors, or shortly we'll have approved a checkpoint plus a multikinase inhibitor.

Are there any ongoing trials or potential new HCC treatment strategies you're excited about?

Most of the research that's been ongoing, recently reported, and looking to the future has been looking at these different combinations. Is there a better or is there just another anti–PD-1 or PD-L1 that you can give with another immune checkpoint molecule, or a multikinase inhibitor plus immune checkpoint?

What we have today is the atezolizumab plus bevacizumab combination— anti–PD-L1 plus an anti-VEGF antibody—and we have the durvalumab plus tremelimumab—the anti–PD-L1 plus anti–CTLA-4 antibody. We have, hopefully shortly to be FDA approved, the combination of an anti–PD-1 antibody, camrelizumab, plus a kinase inhibitor, rivoceranib. So that'll now give us more flexibility as we have another combination. Also recently—we haven't seen the data for this—but there is the report on a company website that the combination of an anti–PD-1, nivolumab, plus a different anti–CTLA-4, ipilimumab, has also shown activity, "a positive study," in the front line. So it looks like we’re going to have at least 4 different possibilities for patients in the front line.

What's really exciting are the attempts to expand this further. The combinations that I've mentioned could be used as platforms to then add additional therapies—additional checkpoint blockade, for example—against different targets. For example, there's a platform using atezolizumab plus bevacizumab that is now allowing other drugs to be added on, one of those being tiragolumab, that's shown some interesting activity in a small preliminary study.

How is the treatment of HCC beyond the first line evolving?

I keep going back to when we started. When we started, very few people got systemic therapy. Finally, we had sorafenib, and then we had lenvatinib, and we had some other drugs that were being developed. And it just didn't even seem imaginable that people would get later lines of therapy, let alone the first line of systemic therapy.

But as new drugs were developed, they started to be tested in the second line. So, we had other multikinase inhibitors that showed a survival benefit. Keep in mind all of these studies, though, were done in people who had had sorafenib first. But in that setting, we had cabozantinib [show] survival benefit compared to placebo; regorafenib [show] survival benefit compared to placebo. Then we had ramucirumab that, at least in the AFP [alpha fetoprotein]-high population greater than 400 ng/mL, [showed] survival benefit compared to placebo.

We also did have activity for immune checkpoint inhibitors. Now, these these were originally tested as in single-arm studies, like nivolumab and pembrolizumab, and they also appeared to have activity in terms of response rate and some interesting longer-term outcomes. Pembrolizumab did end up, in a randomized trial, did not meet its end point—but subsequently, there was a pembrolizumab trial that did meet its end point in an Asian population.

So, we have a number of options. And then we also had combinations that were developed there, particularly nivolumab plus ipilimumab—again, not compared with placebo, just as a combination by itself. So, the problem being when all of this data, coming from patients who had previously had sorafenib, when we then reached the point that we were starting to use immune checkpoint inhibitors in the first line in these combination therapies—atezolizumab, bevacizumab, durvalumab, tremelimumab, for example—how do we interpret the data for second-line therapies? And this is still an open question right now.

The clinical reality is you have to do what you have to do. So, if somebody progresses on one of these frontline options, you can really use one of any of these therapies in my opinion. None of them have been directly compared with each other. Some individuals will choose to shift the paradigm over, so your second line could essentially be use of one of the first-line multikinase inhibitors, lenvatinib and sorafenib. Or you could choose the "established" second-line options and just say, "Well, we don't have as much data after these new frontline combinations, but these are viable second-line options."

Honestly, any of those is fine, however people prefer to practice. A lot of it has to do with comfort level with the different therapies. They do have some slight differences in their targets, and you might choose one based on the particular targeting that you think might be relevant to that patient. We are now starting to get these second-line studies. There's an innovative study coming from a community plus academic cooperative group that's taking people who have had atezolizumab plus bevacizumab and randomizing them to continuing the atezolizumab with either one of the tyrosine kinase inhibitors or just using one of the tyrosine kinase inhibitors in the second line. So we're going to start to get this type of data, but for right now, the clinician facing this really has a lot of options—but not a lot of data—in our current scenario.