Emerging Treatment Patterns for Hepatocellular Carcinoma - Episode 12
Ghassan K. Abou-Alfa, MD: Let’s switch gears, because this is really not the end of the story. To summarize, we’ve talked about sorafenib, regorafenib, lenvatinib, cabozantinib, ramucirumab, and we’re still talking about TKIs [tyrosine kinase inhibitors]. And, of course, we have checkpoint inhibitor immunotherapy. This is a story that really started in many other diseases. As you know, in melanoma we saw the discovery phase of the checkpoint inhibitors. Look where we are now. We are very heavily involved with checkpoint inhibitors in HCC [hepatocellular carcinoma]. There’s one in conditional approval.
Peter, let’s talk about nivolumab. What is it? What does it do? Why did it get conditional approval by the FDA in the United States?
Peter Galle, MD, PhD: The concept is striking and is the continuation of what was started in 2011 in melanoma. The checkpoint inhibitors are basically a break which, in the end, stops the immune system from overreaction. If you loosen that break, antitumor action is reinstalled. That’s the simple mechanism.
Ghassan K. Abou-Alfa, MD: I like what you said. This is very important. There’s a lot of complexity to this. But really, it’s a brake and a pedal of gas. And if anything, this is removing your foot from holding the brake pedal. I like that. Go ahead.
Peter Galle, MD, PhD: So if we have that sort of antitumor efficacy, it is probably more likely happening in an inflammatory tumor. Hepatocellular carcinoma is typically taking place in a setting of inflamed liver hepatitis. So that all fits.
And then we have seen impressive results in given patients. The problem is that this conditional approval is based on the CheckMate-040 trial, which was an uncontrolled phase II trial. So this is unusual. We have the potential for inclusion bias and we have seen many phase II trials that did not mature in similar results in phase III studies.
But what we saw were impressive waterfall plots. There was a lot happening in individual patients. And, we saw duration of response. That is probably what impressed the FDA, neglecting the fact that this was nonrandomized in the phase II trial. We are waiting on the CheckMate-459 trial, where sorafenib and nivolumab are compared head-to-head.
Ghassan K. Abou-Alfa, MD: Fair enough. The best understanding we have is that the response rate is about 15% to 20%. That’s probably not what the FDA was most excited about. It’s, rather, the prolonged response—patients staying on therapy for long periods of time. That’s really probably why there was such a push.
Riad, Peter is mentioning CheckMate 459. I understand that nothing is reported yet. If you recall, it’s sorafenib versus nivolumab. Tell us a little more about your perspective on this? Where does it stand?
Riad Salem, MD: My perspective, from an interventional radiology standpoint, is that we’ve heard about these immune-oncologies for a long time. There is tremendous promise, as Peter mentioned. There is a modest response rate, but there’s a subgroup that has a very long duration of response. That’s what I think the agency was mesmerized by. I’ve been there several times. They’ve quoted that and that’s what they want to see in other clinical trials.
We’re obviously all waiting for the results of the head-to-head analysis. Are these results real? Is this therapy really as good as it is purported to be? So this is going to be the first one that compares the drugs in the first-line setting, head-to-head. We’re waiting. I was hoping to hear news by the time I got here. I haven’t heard anything, but it may redefine the landscape. One of the things that we’ve seen is that with these 5 drugs that you just mentioned, Ghassan, we’re trying to sort of compartmentalize how we do things. If this becomes a first-line option, what bumps to the second-line setting? Who is competing with what?
It’s a very active field. We’ll see what happens. I can assure you that post progression treatment is going to be a parameter here. I suspect that some of the patients who are progressing are going to cross over. I’ll be interested to see how the statistics are managed for that. It’s exciting to see these things.
One thing I want to mention, as a radiologist, is that response is important for these therapies. Response is a little different now. We see pseudoprogression. This is a new concept now. Peter described this very elegantly. In some cases, you see the response. It looks like it may be a bit larger. There is some inflammation from swelling. It looks like progression by all classical criteria, but it turns out that you maintain the patient on treatment and at the next scan of response you have some long-term survivors. Again, it’s what Peter was mentioning.
This is another very important field of research. We have to figure out what a real progression is versus pseudoprogression. I fear that we have a lot of patients who are actually progressing and are being delayed from an alternate treatment versus those who really have pseudoprogression. From a radiological standpoint, I think it is going to be important to study.
Transcript Edited for Clarity