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Progress in the Management of Hepatocellular Carcinoma

Insights From: R. Kate Kelley, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Josep Llovet, MD, PhD, Icahn School of Medicine at Mount Sinai; Masatoshi Kudo, MD, PhD, Kindai University; Arndt Vogel, MD, PhD, Hannover Medical School
Published: Monday, Jun 17, 2019



Transcript: 

R. Kate Kelley, MD: It’s certainly a privilege for me to be here today talking with you in this very exciting time in HCC [hepatocellular carcinoma]. We’ve seen a gigantic landscape change over the past 2 years, and I’d like to start by asking you, how do you perceive the changes in the landscape since you began your career in HCC?

Josep Llovet, MD, PhD: Certainly, thank you. It has been a revolution this past 2 years. I’ve been in the field of HCC for 24 years now. And I remember at the beginning that the patients with advanced HCC, unfortunately we did not have anything for them. Suddenly the first breakthrough happened in 2007, as you may remember.

R. Kate Kelley, MD: I was at that ASCO [American Society of Clinical Oncology annual meeting].

Josep Llovet, MD, PhD: You were at ASCO. This was a breakthrough, milestone I would say, in the management of the disease with the first systemic drug, sorafenib. And then after that, after sorafenib, we thought, “OK, it will be easy, other drugs will be coming very fast,” but it was not the case. So, for almost 10 years, nothing, and in the past 2 years we have had this revolution, such that we have 6 additional drugs. For me, I think it’s a very exciting time. Do you want to talk a bit about the differences in improvement in survival that we have experienced with these drugs?

R. Kate Kelley, MD: That’s absolutely the goal: not to just have more treatment options but also to see people living longer to try to treat them. And I think it’s quite remarkable to see in the last several trials from regorafenib, with the RESORCE trial, second-line patients living throughout the course of their systemic therapy now up to 20-plus months, in the 26-, 28-month range in patients who are able to get multiple lines of systemic therapy. And now we’re exceeding the 1-year benchmark for first-line survival in the REFLECT trial with sorafenib and lenvatinib. Both drugs are surpassing that. What we thought was an insurmountable barrier really is a testament to the efficacy of these new therapies. Though I think also in part, a better ability to provide supportive care and also refine the patients that enter trials. What’s your perspective? Do you think the survival times are improving purely as a metric of better trial design or also the ability of the sequential therapies to help?

Josep Llovet, MD, PhD: Yes. Well, there are 3 trials. In the first one, as you mentioned, the REFLECT trial, there is a matter of selection of patients, where patients that have main portal vein invasion were excluded. And also the management of the disease, in general, the management has improved throughout the last 10 years. You can recall that after lenvatinib in the trial, a percentage of patients, close to one-third of the patients, were receiving sorafenib. So now we have second-line therapies that are effective. I’m not saying that sorafenib is a second-line agent, I’m saying that after lenvatinib, some patients switch to sorafenib. And certainly I would say that for the next trials to come, we will see more and more survivals, around 15, 18, 20 months median survival in frontline because we have second and eventually third-line therapies in place.

Do you want to talk a bit about the predictive biomarkers or of response? It’s a very complicated issue in HCC. Certainly, for instance, only 1 drug, ramucirumab, is actually effective in patients with AFP [alpha-fetoprotein] more than 400. That is a good biomarker for selecting the population with aggressive disease. But the classical biomarkers, biological markers you see in oncology or amplification or mutations in KRAS, so on, so forth, are not effective in HCC at this point. How do you see the field evolving here?

R. Kate Kelley, MD: I think that’s definitely been the challenge of having HCC reach the genomic age in oncology, and there haven’t been classical driver mutations consistently within tumors or across patients. And often tumors are much more heterogeneous and have multiple drivers accumulate over the long evolution of development of cancer. But a couple years back we were starting to study MET-targeted therapies in a MET-selected population. And the tivantinib story with the METIV-HCC study did not show a survival benefit for MET-overexpressed HCC by immunohistochemistry, at least, for that particular genomic target or expression-based target.

Though, as you alluded to, I think the ramucirumab data that we’ll talk about more in a minute are certainly exciting as the first biomarker-selected agent in HCC. But as we now have these multiple drugs available for sequential therapy, in the oncology office it is really hard to choose between drugs and know how to sequence them. And I think what will be incumbent upon the studies ahead and the work we do with the samples is to try to refine what are the markers of response and predict those patients most likely to benefit from one strategy to the next, as we have choices at progression for the first time.

Josep Llovet, MD, PhD: Also, the effective drugs in the field of HCC, most of them are multikinase inhibitors. So with these kinases—sorafenib, regorafenib, lenvatinib, cabozantinib—that block several kinases at the same time, it’s very difficult to find a biomarker here. You need probably a gene signature or something. But, certainly, with ramucirumab, we have the AFP. And now with checkpoint inhibitors, as you are familiar with, there have been some studies trying to identify what is called the immune class or, on the other end of the spectrum, the immune-excluded class. And there are some already preliminary data also coming from Memorial Sloan Kettering, and we have an editorial talking about that in Clinical Cancer Research. Patients with beta-catenin mutations look as though they may be primary resistant to checkpoint inhibitors. These are only preliminary data, but they’re giving us some idea on how we can navigate in the treatment strategy based on biomarkers. Of course, this needs to be validated.

R. Kate Kelley, MD: It also is reminiscent of what we see in melanoma, too, with the beta-catenin pathway signature. I think that work is really provocative and in large part from your lab.

Transcript Edited for Clarity
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Transcript: 

R. Kate Kelley, MD: It’s certainly a privilege for me to be here today talking with you in this very exciting time in HCC [hepatocellular carcinoma]. We’ve seen a gigantic landscape change over the past 2 years, and I’d like to start by asking you, how do you perceive the changes in the landscape since you began your career in HCC?

Josep Llovet, MD, PhD: Certainly, thank you. It has been a revolution this past 2 years. I’ve been in the field of HCC for 24 years now. And I remember at the beginning that the patients with advanced HCC, unfortunately we did not have anything for them. Suddenly the first breakthrough happened in 2007, as you may remember.

R. Kate Kelley, MD: I was at that ASCO [American Society of Clinical Oncology annual meeting].

Josep Llovet, MD, PhD: You were at ASCO. This was a breakthrough, milestone I would say, in the management of the disease with the first systemic drug, sorafenib. And then after that, after sorafenib, we thought, “OK, it will be easy, other drugs will be coming very fast,” but it was not the case. So, for almost 10 years, nothing, and in the past 2 years we have had this revolution, such that we have 6 additional drugs. For me, I think it’s a very exciting time. Do you want to talk a bit about the differences in improvement in survival that we have experienced with these drugs?

R. Kate Kelley, MD: That’s absolutely the goal: not to just have more treatment options but also to see people living longer to try to treat them. And I think it’s quite remarkable to see in the last several trials from regorafenib, with the RESORCE trial, second-line patients living throughout the course of their systemic therapy now up to 20-plus months, in the 26-, 28-month range in patients who are able to get multiple lines of systemic therapy. And now we’re exceeding the 1-year benchmark for first-line survival in the REFLECT trial with sorafenib and lenvatinib. Both drugs are surpassing that. What we thought was an insurmountable barrier really is a testament to the efficacy of these new therapies. Though I think also in part, a better ability to provide supportive care and also refine the patients that enter trials. What’s your perspective? Do you think the survival times are improving purely as a metric of better trial design or also the ability of the sequential therapies to help?

Josep Llovet, MD, PhD: Yes. Well, there are 3 trials. In the first one, as you mentioned, the REFLECT trial, there is a matter of selection of patients, where patients that have main portal vein invasion were excluded. And also the management of the disease, in general, the management has improved throughout the last 10 years. You can recall that after lenvatinib in the trial, a percentage of patients, close to one-third of the patients, were receiving sorafenib. So now we have second-line therapies that are effective. I’m not saying that sorafenib is a second-line agent, I’m saying that after lenvatinib, some patients switch to sorafenib. And certainly I would say that for the next trials to come, we will see more and more survivals, around 15, 18, 20 months median survival in frontline because we have second and eventually third-line therapies in place.

Do you want to talk a bit about the predictive biomarkers or of response? It’s a very complicated issue in HCC. Certainly, for instance, only 1 drug, ramucirumab, is actually effective in patients with AFP [alpha-fetoprotein] more than 400. That is a good biomarker for selecting the population with aggressive disease. But the classical biomarkers, biological markers you see in oncology or amplification or mutations in KRAS, so on, so forth, are not effective in HCC at this point. How do you see the field evolving here?

R. Kate Kelley, MD: I think that’s definitely been the challenge of having HCC reach the genomic age in oncology, and there haven’t been classical driver mutations consistently within tumors or across patients. And often tumors are much more heterogeneous and have multiple drivers accumulate over the long evolution of development of cancer. But a couple years back we were starting to study MET-targeted therapies in a MET-selected population. And the tivantinib story with the METIV-HCC study did not show a survival benefit for MET-overexpressed HCC by immunohistochemistry, at least, for that particular genomic target or expression-based target.

Though, as you alluded to, I think the ramucirumab data that we’ll talk about more in a minute are certainly exciting as the first biomarker-selected agent in HCC. But as we now have these multiple drugs available for sequential therapy, in the oncology office it is really hard to choose between drugs and know how to sequence them. And I think what will be incumbent upon the studies ahead and the work we do with the samples is to try to refine what are the markers of response and predict those patients most likely to benefit from one strategy to the next, as we have choices at progression for the first time.

Josep Llovet, MD, PhD: Also, the effective drugs in the field of HCC, most of them are multikinase inhibitors. So with these kinases—sorafenib, regorafenib, lenvatinib, cabozantinib—that block several kinases at the same time, it’s very difficult to find a biomarker here. You need probably a gene signature or something. But, certainly, with ramucirumab, we have the AFP. And now with checkpoint inhibitors, as you are familiar with, there have been some studies trying to identify what is called the immune class or, on the other end of the spectrum, the immune-excluded class. And there are some already preliminary data also coming from Memorial Sloan Kettering, and we have an editorial talking about that in Clinical Cancer Research. Patients with beta-catenin mutations look as though they may be primary resistant to checkpoint inhibitors. These are only preliminary data, but they’re giving us some idea on how we can navigate in the treatment strategy based on biomarkers. Of course, this needs to be validated.

R. Kate Kelley, MD: It also is reminiscent of what we see in melanoma, too, with the beta-catenin pathway signature. I think that work is really provocative and in large part from your lab.

Transcript Edited for Clarity
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