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Underlying Cirrhosis in the Second-Line Setting of HCC

Panelists: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; Richard S. Finn, MD, UCLA; Laura M. Kulik, MD, Northwestern University Feinberg School of Medicine; R. Kate Kelley, MD, University of California-San Francisco; Riad Salem, MD, Northwestern University Feinberg School of Medicine
Published Online: Sunday, Mar 19, 2017



Transcript:

Ghassan K. Abou-Alfa, MD:
It’s fascinating. No question, this has come to a point where the high selectivity that we’ve tried with different drugs, like an antiangiogenic that we saw at the longer extent in the first-line setting in addition to the different clinical targets that happen in second-line setting, you come with the multikinase and not necessarily a fully understood mechanism of action. But obviously, it has this ability to target different kinases. With those positive results, no doubt it remains a fascinating component that I think we are, in the field of HCC, going to probably spend quite a bit of time trying to analyze. With this said, one more challenge we’re going to face, Katie, is that at the end of the day, regorafenib is already approved in colorectal, as we heard, and GIST. And especially in colorectal, it’s like third-line therapy. Admittedly, it’s not necessarily something that will come to mind because until you get there, it’s a really long projected time for a colorectal patient. And now we’re going to try to celebrate a drug that has not necessarily the most glorified position, if you want to call it that way. So, how can we do that? How can we explain that this is not really the same story?

R. Kate Kelley, MD: I think it really depends on context and how healthy the patients are in their liver function and in their visceral function, particularly in colorectal patients at the time of starting the drug. I mentioned earlier, GIST patients often have very good tolerability of regorafenib, very similar to their tolerability of sorafenib, in my experience. I think, as Rich mentioned, the window of opportunity is to give patients a chance to try the drug when they’re most fit to benefit and when they’re most fit to have the least toxicity when liver function permits. So, I think if we push sorafenib beyond progression until there’s clinical decompensation or worsening liver function, it’s logical to expect that the toxicity of a drug that’s partially hepatic, metabolizing will be greater and the tolerability will be lower. And that’s, I think, also our experience from colorectal; that in the fourth-line setting or after, patients have exhausted so many other therapeutic options—as regorafenib has experience in the colorectal cancer population in many of our cases—that there is more toxicity. And so, I think that the balance and the art of this will be learning when to transition from first-line therapy to regorafenib and identifying progression at a time when patients are able to capitalize on a second-line agent.

Ghassan K. Abou-Alfa, MD: Laura, back to you. As we can see, our armamentarium is growing. We’re at 2 drugs now, but interestingly in the community setting, oncologists are not necessarily comfortable all the time with HCC, especially because of the cirrhotic component, which is understandable. It can be quite complex. Can you just help us with some guidance that we can share with our colleagues in the community setting in regard to the management of the cirrhosis, who should be involved, and why they should not necessarily worry all the time?

Laura M. Kulik, MD: Well, it is important for a hepatologist to be involved to alleviate some of those fears and work as a group. The multidisciplinary approach doesn’t stop in our academic centers. I think it goes into the community as well. These patients need, as I said earlier, to be screened for varices. This should be done. Patients with liver cancer are much more likely to die of variceal bleeding. Also, trying to help with ascites and encephalopathy is key. So, I think pairing up with a hepatologist is going to be important for keeping patients on the drug. They may want to stop that because they develop encephalopathy for the first time, and it may be an inciting factor that can you say, “Okay, this is why this happened. We’ll lower the diuretics.” There’s a lot of things that can lead to encephalopathy, so trying to figure out how to control those side effects, as well as the symptoms of underlying cirrhosis, is also going to make the patient want to stay on the drug longer.

I think this drug being second-line now is very important for patients because, again, what I hear from patients is, “I don’t want to take sorafenib because this is all you have left for me and after that there’s nothing else.” So, patients are waiting and waiting until they say, “Okay, I’m ready to go on it.” Now, if you can tell them, “Okay, there’s something else,” I think there will be more from a psychological standpoint, a willingness to go on to systemic therapy as well.

Ghassan K. Abou-Alfa, MD: That’s very important as well. Definitely, we go back and you keep hearing us repeating the multidisciplinary approach that’s quite necessary in that regard. That brings us to an important summary over here, at least about the current status of the therapies that really have shown improvement in outcome. As we just heard, sorafenib improved in outcome, with 10.7 months versus 7.9 for placebo, and established the drug as a standard of care over a decade, as Dr. Finn mentioned, really with noble efforts trying to out-eat it with different approaches, especially strong antiangiogenics, and didn’t happen. And now we have the advent of regorafenib, another multikinase, very close, but with some different mechanistic actions and targets, which again bring up an improvement in survival for the extent of close or near to 11 months in the second-line setting.

Transcript Edited for Clarity

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Transcript:

Ghassan K. Abou-Alfa, MD:
It’s fascinating. No question, this has come to a point where the high selectivity that we’ve tried with different drugs, like an antiangiogenic that we saw at the longer extent in the first-line setting in addition to the different clinical targets that happen in second-line setting, you come with the multikinase and not necessarily a fully understood mechanism of action. But obviously, it has this ability to target different kinases. With those positive results, no doubt it remains a fascinating component that I think we are, in the field of HCC, going to probably spend quite a bit of time trying to analyze. With this said, one more challenge we’re going to face, Katie, is that at the end of the day, regorafenib is already approved in colorectal, as we heard, and GIST. And especially in colorectal, it’s like third-line therapy. Admittedly, it’s not necessarily something that will come to mind because until you get there, it’s a really long projected time for a colorectal patient. And now we’re going to try to celebrate a drug that has not necessarily the most glorified position, if you want to call it that way. So, how can we do that? How can we explain that this is not really the same story?

R. Kate Kelley, MD: I think it really depends on context and how healthy the patients are in their liver function and in their visceral function, particularly in colorectal patients at the time of starting the drug. I mentioned earlier, GIST patients often have very good tolerability of regorafenib, very similar to their tolerability of sorafenib, in my experience. I think, as Rich mentioned, the window of opportunity is to give patients a chance to try the drug when they’re most fit to benefit and when they’re most fit to have the least toxicity when liver function permits. So, I think if we push sorafenib beyond progression until there’s clinical decompensation or worsening liver function, it’s logical to expect that the toxicity of a drug that’s partially hepatic, metabolizing will be greater and the tolerability will be lower. And that’s, I think, also our experience from colorectal; that in the fourth-line setting or after, patients have exhausted so many other therapeutic options—as regorafenib has experience in the colorectal cancer population in many of our cases—that there is more toxicity. And so, I think that the balance and the art of this will be learning when to transition from first-line therapy to regorafenib and identifying progression at a time when patients are able to capitalize on a second-line agent.

Ghassan K. Abou-Alfa, MD: Laura, back to you. As we can see, our armamentarium is growing. We’re at 2 drugs now, but interestingly in the community setting, oncologists are not necessarily comfortable all the time with HCC, especially because of the cirrhotic component, which is understandable. It can be quite complex. Can you just help us with some guidance that we can share with our colleagues in the community setting in regard to the management of the cirrhosis, who should be involved, and why they should not necessarily worry all the time?

Laura M. Kulik, MD: Well, it is important for a hepatologist to be involved to alleviate some of those fears and work as a group. The multidisciplinary approach doesn’t stop in our academic centers. I think it goes into the community as well. These patients need, as I said earlier, to be screened for varices. This should be done. Patients with liver cancer are much more likely to die of variceal bleeding. Also, trying to help with ascites and encephalopathy is key. So, I think pairing up with a hepatologist is going to be important for keeping patients on the drug. They may want to stop that because they develop encephalopathy for the first time, and it may be an inciting factor that can you say, “Okay, this is why this happened. We’ll lower the diuretics.” There’s a lot of things that can lead to encephalopathy, so trying to figure out how to control those side effects, as well as the symptoms of underlying cirrhosis, is also going to make the patient want to stay on the drug longer.

I think this drug being second-line now is very important for patients because, again, what I hear from patients is, “I don’t want to take sorafenib because this is all you have left for me and after that there’s nothing else.” So, patients are waiting and waiting until they say, “Okay, I’m ready to go on it.” Now, if you can tell them, “Okay, there’s something else,” I think there will be more from a psychological standpoint, a willingness to go on to systemic therapy as well.

Ghassan K. Abou-Alfa, MD: That’s very important as well. Definitely, we go back and you keep hearing us repeating the multidisciplinary approach that’s quite necessary in that regard. That brings us to an important summary over here, at least about the current status of the therapies that really have shown improvement in outcome. As we just heard, sorafenib improved in outcome, with 10.7 months versus 7.9 for placebo, and established the drug as a standard of care over a decade, as Dr. Finn mentioned, really with noble efforts trying to out-eat it with different approaches, especially strong antiangiogenics, and didn’t happen. And now we have the advent of regorafenib, another multikinase, very close, but with some different mechanistic actions and targets, which again bring up an improvement in survival for the extent of close or near to 11 months in the second-line setting.

Transcript Edited for Clarity
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