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Perspectives on the Future Treatment of HCC

Panelists: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; A. Ruth He, MD, PhD, Georgetown University Medical Center; Mark W. Karwal, MD, University of Iowa Health Care; Mark H. OHara, MD, Hospital of the University of Pennsylvania; Manish R. Sharma, MD, University of Chicago; Amit Singal, MD, UT Southwestern Medical Center
Published: Tuesday, Oct 16, 2018



Transcript:

Ghassan K. Abou-Alfa, MD: I would like to give each of you the opportunity to share your final thoughts or perspectives. Let’s start with you, Mark.

Mark H. O’Hara, MD: Overall, as you introduced in this session, it’s been a very interesting time in HCC, in the last couple of years, with the approval of going from one therapy to multiple therapies. We’re stuck trying to figure out how to sequence each of these therapies, at this point. What’s the right approach? I don’t think there is going to be a right approach. I think there’s going to be a right approach for everyone—for each patient, it’s going to be something different. In some patients, you’re going to start with sorafenib, then go to regorafenib, and maybe use cabozantinib or nivolumab later on down the road. There may be someone for whom you do nivolumab as second-line therapy and keep some of the other TKIs for later on.

Ghassan K. Abou-Alfa, MD: You bring up a very impressive point. How do you choose? Ruth, how will you choose?

A. Ruth He, MD, PhD: Right now, we have the 2 TKIs as front-line therapy, and we have the I-O as a second-line option. In the future, we may also have an I-O in the first-line setting. I think it’s a very difficult question. There’s really no biomarker for selection at this point. Usually, I look at the toxicity profile. I also look at how much I want to have tumor shrinkage. If the patient is very symptomatic from the disease, I would choose a therapy with a high response rate. And then, of course, for I-O therapy, patients with any history of autoimmune disease are out. So, you look at all of the specifics. You personalize therapy for liver transplant.

Ghassan K. Abou-Alfa, MD: I totally agree that the biology is going to play quite a bit of a role. On the other hand, at the end of the day, as you calculate our thoughts, some of the adverse events and some of the response rates might come in to play. Ruth is applying things the same way that I would have said it. TKI therapy is one thing, and I-O therapy is another. Now, when you put it all together, are TKIs just competing among themselves? Where does I-O therapy stand?

Amit Singal, MD: One other thing that I would add is that there’s a little bit of patient preference factor to this too. It’s important to remember that the TKIs are typically oral and that the I-O therapy is an intravenous infusion. In HCC, it used to be every 2 weeks. They’ve now gotten approval to do it every month. I practice in Texas. We have people who sometimes drive a long distance to come to our center. The thought of even coming in once a month for an infusion, for some of these patients, can be difficult. And so, that is the other thing that we talk about—the logistical fashion in which these therapies are delivered.

Going back to your point, is it TKI versus TKI, or I-O versus I-O? Is there a cross battle? I think the Holy Grail here is to have response markers. MSI is something that can be used in other tumors. Unfortunately, as Ruth said, it’s pretty rare in HCC. It’s not the best response marker that we’re going to have for HCC.

People have talked about, going back to the whole biopsy thing, subclassifying tumors. People think that this may be something that correlates with response. We’ll see what the data bear out. I think that centers such as the ones that we practice in have to be at the forefront of research, looking for some kind of treatment response marker so that we can say to use I-O versus TKI, or I-O plus I-O, or I-O plus TKI—whatever it may be. We need to do better than we’re doing. Right now, we’re using too gross and too inaccurate response markers to guess at who’s going to respond or not respond.

Ghassan K. Abou-Alfa, MD: I totally agree with you. If anything, it’s quite fascinating. For example, take the data for lenvatinib—40.7% response. Again, the I-Os have a 20% response rate. There’s really one variable that might come into play; and another, for example, for cabozantinib. But remember, as Ruth said, we’ll talk about third-line HCC. In other words, this advantage carried on. Undoubtedly, there are many questions that need to be answered.  Manish, what are your thoughts?

Manish R. Sharma, MD: HCC is the new colorectal cancer. This is kind of cruel, right? This is what I was talking to some colleagues about. We now have an embarrassment of riches, in terms of the number of drugs that are effective in this disease. The next challenge is going to be figuring out how to sequence them. How do we use them? The reason I use colorectal cancer as an analogy is because, of course, there’s no right answer, right? You can use FOLFOX or FOLFIRI, right? We see the same thing here. What you’re going to pick in the frontline setting or the second-line setting may be a little bit of a stylistic preference. That’s the art of oncology. That’s what makes it fun.

But also, it’s great for our patients to have all of these options. In colorectal cancer, we ended up finding out the RAS story. Mutations matter. The sidedness of tumors matters. There’s different biology. Maybe we’ll find that in HCC. Maybe we’ll really be able to identify some biomarkers. Doing the deep dive of research that Amit was talking about, I think it’s really important to try to say, “OK, this treatment may work better in this patient, and this treatment may work better in that patient.” Hopefully we’ll get to that point, where we have some science to guide us as to how to really select these patients.

Ghassan K. Abou-Alfa, MD: I hear you loud and clear. Mark, your last thoughts?

Mark W. Karwal, MD: If you look at the history of the classic epithelial malignancies—breast, colon, lung, prostate—in the 1960s, those were all surgical diseases. There were no drugs. Along came drugs and surgery fades. I’m confident that in a few years, for some breast cancer patients, we can treat with a drug and radiation, and no surgery.
What do we have in liver cancer? You can’t operate because the liver is too sick. We have all of these interventional radiology things that you mentioned, and they’re great. But now that we have drugs, what are we going to do? It’s the same thing. It’s going to go from, “We’re just going to whittle on your liver until you’re dead,” to, “We’re going to start giving you drugs in different sequences and different combinations, and we’re going to patch you up for some time; and downstage potentially then operate, just like we do with other cancers.”

Ghassan K. Abou-Alfa, MD: That’s good. I’m very glad that you have a very positive view, and I totally agree with you. This is good for our patients. At the end of the day, the bottom line is to help people. I’m very happy to see that you have an optimistic view. And actually, to carry on with that, I’m sensing a lot of optimism in regard to oncology at this point in time. People are talking about an improvement in survival, or cure, which is kind of going into gigantic numbers by educators. I’m glad that you have that view as well. Ruth, what are your final thoughts?

A. Ruth He, MD, PhD: HCC is a heterogeneous disease, and there is a role for multidisciplinary care. We need to consider all of the options. We also need to keep our mind open for new therapies with biomarkers and biopsies. I think the concept of caring for HCC is just evolving in front of our eyes. We need to keep up with the new data.

Ghassan K. Abou-Alfa, MD: Absolutely. It is quite exciting. Amit, your final thoughts?

Amit Singal, MD: I’m going to provide a bit of a different perspective on this, since I’m the sole hepatologist here. Obviously, there’s a lot of excitement. I share the optimism, in terms of where the systemic therapies are going. It’s really nice to see that our tools in the toolbox are rapidly expanding. The thing that I want to highlight here is, at the end of the day, we want the best survival. The best survival comes with curative therapies. At the end of the day, it’s amazing to see the advances on this side of the spectrum. The things that we need to emphasize when we want to make the biggest difference for our patients are early diagnosis, early referrals for treatment, early initiation into multidisciplinary care, which has been shown to improve survival, and to apply curative therapies when possible. If they’re not eligible for curative therapy, we can actually look our patients in the eye and say, “We have things that are effective. We can actually prolong your survival and do so with good, tolerable drugs.” I think the key thing is early detection. That is important.

Ghassan K. Abou-Alfa, MD: If anything, I’m really thrilled that we all share a positive, optimistic view. We’re all excited about new drugs. As we said, after sorafenib we talk about regorafenib, or nivolumab, even though it is still conditional, pending the phase III trial. We also spoke quite a bit about lenvatinib and cabozantinib. This is really incredible information. We are all kind of eager and keen to practice with all of these drugs to help patients; and, at the same time, to see how we can move them forward.

I would like to thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us. We hope that you found this OncLive® Peer Exchange® to be useful and informative.

Transcript Edited for Clarity.

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Transcript:

Ghassan K. Abou-Alfa, MD: I would like to give each of you the opportunity to share your final thoughts or perspectives. Let’s start with you, Mark.

Mark H. O’Hara, MD: Overall, as you introduced in this session, it’s been a very interesting time in HCC, in the last couple of years, with the approval of going from one therapy to multiple therapies. We’re stuck trying to figure out how to sequence each of these therapies, at this point. What’s the right approach? I don’t think there is going to be a right approach. I think there’s going to be a right approach for everyone—for each patient, it’s going to be something different. In some patients, you’re going to start with sorafenib, then go to regorafenib, and maybe use cabozantinib or nivolumab later on down the road. There may be someone for whom you do nivolumab as second-line therapy and keep some of the other TKIs for later on.

Ghassan K. Abou-Alfa, MD: You bring up a very impressive point. How do you choose? Ruth, how will you choose?

A. Ruth He, MD, PhD: Right now, we have the 2 TKIs as front-line therapy, and we have the I-O as a second-line option. In the future, we may also have an I-O in the first-line setting. I think it’s a very difficult question. There’s really no biomarker for selection at this point. Usually, I look at the toxicity profile. I also look at how much I want to have tumor shrinkage. If the patient is very symptomatic from the disease, I would choose a therapy with a high response rate. And then, of course, for I-O therapy, patients with any history of autoimmune disease are out. So, you look at all of the specifics. You personalize therapy for liver transplant.

Ghassan K. Abou-Alfa, MD: I totally agree that the biology is going to play quite a bit of a role. On the other hand, at the end of the day, as you calculate our thoughts, some of the adverse events and some of the response rates might come in to play. Ruth is applying things the same way that I would have said it. TKI therapy is one thing, and I-O therapy is another. Now, when you put it all together, are TKIs just competing among themselves? Where does I-O therapy stand?

Amit Singal, MD: One other thing that I would add is that there’s a little bit of patient preference factor to this too. It’s important to remember that the TKIs are typically oral and that the I-O therapy is an intravenous infusion. In HCC, it used to be every 2 weeks. They’ve now gotten approval to do it every month. I practice in Texas. We have people who sometimes drive a long distance to come to our center. The thought of even coming in once a month for an infusion, for some of these patients, can be difficult. And so, that is the other thing that we talk about—the logistical fashion in which these therapies are delivered.

Going back to your point, is it TKI versus TKI, or I-O versus I-O? Is there a cross battle? I think the Holy Grail here is to have response markers. MSI is something that can be used in other tumors. Unfortunately, as Ruth said, it’s pretty rare in HCC. It’s not the best response marker that we’re going to have for HCC.

People have talked about, going back to the whole biopsy thing, subclassifying tumors. People think that this may be something that correlates with response. We’ll see what the data bear out. I think that centers such as the ones that we practice in have to be at the forefront of research, looking for some kind of treatment response marker so that we can say to use I-O versus TKI, or I-O plus I-O, or I-O plus TKI—whatever it may be. We need to do better than we’re doing. Right now, we’re using too gross and too inaccurate response markers to guess at who’s going to respond or not respond.

Ghassan K. Abou-Alfa, MD: I totally agree with you. If anything, it’s quite fascinating. For example, take the data for lenvatinib—40.7% response. Again, the I-Os have a 20% response rate. There’s really one variable that might come into play; and another, for example, for cabozantinib. But remember, as Ruth said, we’ll talk about third-line HCC. In other words, this advantage carried on. Undoubtedly, there are many questions that need to be answered.  Manish, what are your thoughts?

Manish R. Sharma, MD: HCC is the new colorectal cancer. This is kind of cruel, right? This is what I was talking to some colleagues about. We now have an embarrassment of riches, in terms of the number of drugs that are effective in this disease. The next challenge is going to be figuring out how to sequence them. How do we use them? The reason I use colorectal cancer as an analogy is because, of course, there’s no right answer, right? You can use FOLFOX or FOLFIRI, right? We see the same thing here. What you’re going to pick in the frontline setting or the second-line setting may be a little bit of a stylistic preference. That’s the art of oncology. That’s what makes it fun.

But also, it’s great for our patients to have all of these options. In colorectal cancer, we ended up finding out the RAS story. Mutations matter. The sidedness of tumors matters. There’s different biology. Maybe we’ll find that in HCC. Maybe we’ll really be able to identify some biomarkers. Doing the deep dive of research that Amit was talking about, I think it’s really important to try to say, “OK, this treatment may work better in this patient, and this treatment may work better in that patient.” Hopefully we’ll get to that point, where we have some science to guide us as to how to really select these patients.

Ghassan K. Abou-Alfa, MD: I hear you loud and clear. Mark, your last thoughts?

Mark W. Karwal, MD: If you look at the history of the classic epithelial malignancies—breast, colon, lung, prostate—in the 1960s, those were all surgical diseases. There were no drugs. Along came drugs and surgery fades. I’m confident that in a few years, for some breast cancer patients, we can treat with a drug and radiation, and no surgery.
What do we have in liver cancer? You can’t operate because the liver is too sick. We have all of these interventional radiology things that you mentioned, and they’re great. But now that we have drugs, what are we going to do? It’s the same thing. It’s going to go from, “We’re just going to whittle on your liver until you’re dead,” to, “We’re going to start giving you drugs in different sequences and different combinations, and we’re going to patch you up for some time; and downstage potentially then operate, just like we do with other cancers.”

Ghassan K. Abou-Alfa, MD: That’s good. I’m very glad that you have a very positive view, and I totally agree with you. This is good for our patients. At the end of the day, the bottom line is to help people. I’m very happy to see that you have an optimistic view. And actually, to carry on with that, I’m sensing a lot of optimism in regard to oncology at this point in time. People are talking about an improvement in survival, or cure, which is kind of going into gigantic numbers by educators. I’m glad that you have that view as well. Ruth, what are your final thoughts?

A. Ruth He, MD, PhD: HCC is a heterogeneous disease, and there is a role for multidisciplinary care. We need to consider all of the options. We also need to keep our mind open for new therapies with biomarkers and biopsies. I think the concept of caring for HCC is just evolving in front of our eyes. We need to keep up with the new data.

Ghassan K. Abou-Alfa, MD: Absolutely. It is quite exciting. Amit, your final thoughts?

Amit Singal, MD: I’m going to provide a bit of a different perspective on this, since I’m the sole hepatologist here. Obviously, there’s a lot of excitement. I share the optimism, in terms of where the systemic therapies are going. It’s really nice to see that our tools in the toolbox are rapidly expanding. The thing that I want to highlight here is, at the end of the day, we want the best survival. The best survival comes with curative therapies. At the end of the day, it’s amazing to see the advances on this side of the spectrum. The things that we need to emphasize when we want to make the biggest difference for our patients are early diagnosis, early referrals for treatment, early initiation into multidisciplinary care, which has been shown to improve survival, and to apply curative therapies when possible. If they’re not eligible for curative therapy, we can actually look our patients in the eye and say, “We have things that are effective. We can actually prolong your survival and do so with good, tolerable drugs.” I think the key thing is early detection. That is important.

Ghassan K. Abou-Alfa, MD: If anything, I’m really thrilled that we all share a positive, optimistic view. We’re all excited about new drugs. As we said, after sorafenib we talk about regorafenib, or nivolumab, even though it is still conditional, pending the phase III trial. We also spoke quite a bit about lenvatinib and cabozantinib. This is really incredible information. We are all kind of eager and keen to practice with all of these drugs to help patients; and, at the same time, to see how we can move them forward.

I would like to thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us. We hope that you found this OncLive® Peer Exchange® to be useful and informative.

Transcript Edited for Clarity.
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