Multidisciplinary Treatment Strategies for Hepatocellular Carcinoma - Episode 12
Transcript: Ghassan K. Abou-Alfa, MD: We are not done yet because, of course—and this is not because we’re talking about any cancer—but we have to talk about checkpoint inhibitors and immunotherapy [I/O]. But it’s super valid with regard to HCC [hepatocellular carcinoma], but at the same time a little bit more confusing. I’ll start with Farshid. We hear that nivolumab is already conditionally approved by the FDA based on phase II data. Tell us, what’s that phase II data about? What did we see there?
Farshid Dayyani, MD: Nivolumab in the CheckMate trial, there was a phase I/II trial where they stratified patients by HBV [hepatitis B], HCV [hepatitis C], and no viral hepatitis based on sorafenib progressors or intolerance and then dose escalated in a 3+3 fashion quickly, established 3 mg/kg every 2 weeks as the expansion dose. And it included a large number, about 120, if I’m not mistaken, in the expansion group. The approval was based on somewhere between a 15% to 20% response rate. But more importantly, the durable response is in excess of median about 13 months or so.
Ghassan K. Abou-Alfa, MD: You are right on, actually. I totally agree with you, the response rate, the 15%, been there, seen that, but it’s more about the durability of the response per se. And Amit, back to you. So durability of response, quite intriguing. But interestingly, nivolumab, which is being evaluated in a first-line setting versus sorafenib. Now we’re talking about a checkpoint inhibitor and still no data on that study. What do we know about that?
Amit Singal, MD: There have been a couple of interim analyses that have looked to see if there’s a significant difference between the 2, and there hasn’t been a significant difference so far. I think that what we’ve seen is that there are less events than expected, and this can be related to several different reasons. One of the potential of many reasons, is maybe this whole expansion of second-line therapies that we’ve talked about. Those patients who are on sorafenib can be treated with several second-line therapies now, which we know prolong survival. So based on the secondary analysis that you talked about by Rich Finn, MD, and colleagues, we know that there’s prolonged survival. And so this may be decreasing the number of expected events and therefore dragging this trial out much longer than we expected.
Ghassan K. Abou-Alfa, MD: Fair enough. Katie, what do you think about adverse events in regard to checkpoint inhibitor—safe, not safe? What do you think?
Katie Kelley, MD: I think one of the most reassuring things about our experience with checkpoints so far is that the safety appears to be very similar in hepatocellular carcinoma [HCC] as we see in other solid tumor types. And originally the reason for the design of the CheckMate-040 trial with distinct viral cohorts was the concern that there could be some immunologic phenomenon resulting in a fulminant hepatitis or an immune response to the virus in the setting with checkpoint inhibitor. And thankfully, that has not been shown to be the case with the rates of immune hepatitis in the pembrolizumab trial, the nivolumab trial, or camrelizumab. All in the 5% or less range or at least the steroid requirement for hepatitis, all mirroring a low rate that we expect or perhaps even lower than we see in some other solid tumor types. So that’s very reassuring that the safety profile in hepatocellular carcinoma is similar to other solid tumors. I’d say overall the safety is very good.
Ghassan K. Abou-Alfa, MD: Fair enough. Farshid, the nivolumab as we know is not the only drug that already has been conditionally approved by the FDA. Tell us about pembrolizumab.
Farshid Dayyani, MD: Pembrolizumab achieved accelerated approval, conditional approval also in the second-line based on the single-arm phase II trial, very similar response rates, durable responses. And what we will hear about at ASCO [the American Society of Clinical Oncology] Annual Meeting 2019 is the randomized KEYNOTE trial where pembrolizumab is randomized to best supportive care. The press release showed the trial was negative, although overall survival [OS] and progression-free survival [PFS] actually had a lower hazard ratio.
Ghassan K. Abou-Alfa, MD: I understand, but we’ll wait to hear about all of that study, respectfully. We are in Chicago but we didn’t hear yet about that study. We look very much forward to hear the results and see the reflection of those results. But nonetheless, exactly as you said, durable response with the pembrolizumab, same as with the nivolumab, led to the FDA approval. And this adds 2 more drugs to the 5 TKIs [tyrosine kinase inhibitors] that are there. To go back to you, Amit, Katie touched on an important point, and it’s very important to pass on to our colleagues. You have a patient with hepatitis, can I use checkpoint inhibitors?
Amit Singal, MD: I think that both phase II trials basically showed us that this can be well tolerated in patients with viral hepatitis or any other underlying liver disease. I do think that once again, as we talked about before, if you have somebody who has chronic hepatitis B, it’s important to put them on antiviral therapy, get that under control before starting the immunotherapy. In contrast, hepatitis C, you do not need to treat prior to starting I/O therapy.
Ghassan K. Abou-Alfa, MD: This is very important. Let’s review that one more time because this is very critical what you mentioned. Correct me if I’m wrong. Any patient who has an active cancer who was on active therapy, if they have hepatitis B, you’ve got to treat the hepatitis B. Fair?
Amit Singal, MD: Yes.
Ghassan K. Abou-Alfa, MD: And this is very important. Make sure to either refer them to a hepatologist or at least make sure that they are seen already by a hepatologist and getting treatment for that purpose. But also you bring in another point. Hepatitis C, if there is an established cancer, you don’t need to treat. Tell us more about that.
Amit Singal, MD: So hepatitis B, what you’re really treating for is because you can get a flare of the hepatitis B. And as Katie brought up, you can develop fulminant hepatitis. We don’t see that same phenomenon with hepatitis C. That’s why we don’t typically treat patients going in to therapy. Now, without getting into the details, there’s been this whole controversy, if you treat hepatitis C, do you reduce immune surveillance? Can you cause tumor growth and actually make prognosis worse? The data since the initial studies haven’t borne that out, but it is still something that we’re debating back and forth. The one thing we do know is that the hepatitis C therapies are actually less effective in the setting of active cancer. So your sustained viral response rates to hepatitis C therapy are significantly lower in the setting of active HCC than in the absence of HCC.
Ghassan K. Abou-Alfa, MD: That’s impressive. To review all what we spoke about here because these are very important, number 1, is nivolumab in HCC is approved in the second-line setting. We’re waiting for the nivolumab versus sorafenib data. Exactly as Amit said, we’re aware that the interim analyses have been not yet declared in regard to any positive study, and the study is still continuing, waiting for events. So we’re waiting to see when this might occur.
Number 2, pembrolizumab is approved in second-line setting based on the phase II data. And exactly as Farshid said, for nivolumab and pembrolizumab, the most critical point is the prolonged response that we have seen with them. However, as Farshid also said, there was talk that the pembrolizumab versus placebo was negative. That data will be presented here in Chicago where we are today, and we’re going to learn more about what’s negative there.
No doubt those 2 studies are going to bring in a lot of perspective in regard to where do checkpoint inhibitors play. I think we probably all agree that checkpoint inhibitors do work in HCC. The matter is what’s before them, what’s after them, exactly as Amit said, that with the advent of said many therapies, probably the alignment or the lining up of those treatments we are not yet experts on to understand better. Independent of the discussion about the checkpoint inhibitors, but nonetheless Amit brought up a very important point that is very pertinent to what we do. If you have a patient with hepatitis B, by all means, it’s got to be treatment. Remember, hepatitis B is a DNA virus. It’s part of our same DNA and as such, it can integrate in our genetic material, can cause certain activations that would cause those flares of the virus that cause the viral events, as well as probably worsening of the cancer per se.
On the other hand, hepatitis C is an RNA virus. Actually, B and C have nothing to do with each other. I jokingly always say that they just happened to be standing up for coffee and one was given number B and the other one number C, but they have nothing to do with each other. And hepatitis C is an RNA virus and as such, the damage already is done, and treating the virus would not matter. Amit brought up some controversial data that we are not really sure yet what it means, that if you treat a patient who has hepatitis C and HCC, the treatment of hepatitis C can actually worsen the HCC itself. We don’t know, but nonetheless, the data were reported and we ought to discover more of that specific scenario.
Transcript Edited for Clarity