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Hepatocellular Carcinoma's Future Treatment Paradigm

Insights From: Anthony El-Khoueiry, MD, USC Keck School of Medicine; Richard Finn, MD, UCLA Geffen School of Medicine
Published: Friday, Mar 22, 2019



Transcript: 

Richard Finn, MD: When we’re talking about better outcomes as with I-O [immune-oncology therapies], their approvals were based on response of about 15% to 16%, right? But response in liver cancer is never really correlated with outcomes. So, what is different about the response with I-O as compared to ramucirumab or the TKIs [tyrosine kinase inhibitors]?

Anthony El-Khoueiry, MD: The easy way to answer that question is by saying that the depth and durability of the responses can be certainly distinguishing characteristics of I-O agents. The challenge, as you said, is that it’s ultimately a minority of patients who achieve these deep, long-lasting responses. And one of our challenges is, how do we increase that percentage? How do we get more patients to have deep, long-lasting responses?

Richard Finn, MD: That’s a great introduction to a final thought as we’re thinking about the future. How do we increase those responses? I know there’s been great interest in other diseases, in immunology obviously. There haven’t been mature data in liver cancer, but PD-1 [programmed cell death protein 1] inhibitors plus CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] inhibitors. And in liver cancer there are some theoretical concerns about toxicity. And there is an arm in the CheckMate-040 study evaluating that, and we look forward to hearing data in the future. But, as we sit here today, there are some data. There’s the combination of bevacizumab and atezolizumab and lenvatinib and pembrolizumab. What’s your take on these data sets and where they’re going?

Anthony El-Khoueiry, MD: So these are early data sets that are evolving, mostly in a phase Ib-type setting. But to be specific, with the atezolizumab/bevacizumab most recently shared data at ESMO [the European Society for Medical Oncology meeting] 2018, the independently reviewed response rate was around 27%. The investigator-assessed response rate was around 32%, so roughly we could say 30% response rate safely. In theory, that could mean doubling from 15% to 30%. So that’s intriguing and promising with a reasonable safety profile.

Richard Finn, MD: And I think they got a breakthrough therapy designation based on that, right?

Anthony El-Khoueiry, MD: Correct. Similarly, the pembrolizumab/lenvatinib combination had a confirmed response rate just below 30%, so again another promising signal. So these are ways of combining antiangiogenic therapy with anti–PD-1 therapy based on some scientific rationale that seems to be showing promise. I-O/I-O combinations, as you alluded to, are another way that I think we’re going to see attempts to hopefully improve the chance of response.

Richard Finn, MD: The HIMALAYA study is a phase III study already launched of durvalumab and tremelimumab in advanced liver cancer, based on a small subset but also extrapolating from other diseases with bevacizumab and atezolizumab. I think that regimen shows a lot of activity in lung cancer. So it’s partly building on what we know about in liver cancer and then probably extrapolating also from other diseases.

Anthony El-Khoueiry, MD: It brings up one important thought, right? That this is still an area that’s evolving, and I think commitment of all physicians to enroll these patients onto clinical trial is absolutely critical.

Richard Finn, MD: For sure.

Anthony El-Khoueiry, MD: There are a lot of studies, a lot of investigations going on, and these patients are across the world with many practitioners. And I think being conscientious about diverting the right patients to the right trials is going to be important.

Richard Finn, MD: Yes. So, with that thought as we come to the close, there are a lot of agents available for patients—that’s fantastic. I think over time we’re going to see that sequencing these, we are improving survival for advanced liver cancer. This disease now has more options and I would argue a better outcome than pancreatic cancer. And we’ve moved very fast in a short period of time. And, even though there are these options, there’s always room for improvement. And I think referring patients to clinical studies—as self-serving as that is, us being in academics—is best for the field and best for patients. With that in mind, this has been an excellent discussion, Anthony. Next time we’ll talk about USC football and basketball and UCLA and their rivalry, but not in liver cancer. We hope that you found the information presented in this webinar to be valuable to your clinical practice. Thank you for watching OncLive® News Network.

Transcript Edited for Clarity
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Transcript: 

Richard Finn, MD: When we’re talking about better outcomes as with I-O [immune-oncology therapies], their approvals were based on response of about 15% to 16%, right? But response in liver cancer is never really correlated with outcomes. So, what is different about the response with I-O as compared to ramucirumab or the TKIs [tyrosine kinase inhibitors]?

Anthony El-Khoueiry, MD: The easy way to answer that question is by saying that the depth and durability of the responses can be certainly distinguishing characteristics of I-O agents. The challenge, as you said, is that it’s ultimately a minority of patients who achieve these deep, long-lasting responses. And one of our challenges is, how do we increase that percentage? How do we get more patients to have deep, long-lasting responses?

Richard Finn, MD: That’s a great introduction to a final thought as we’re thinking about the future. How do we increase those responses? I know there’s been great interest in other diseases, in immunology obviously. There haven’t been mature data in liver cancer, but PD-1 [programmed cell death protein 1] inhibitors plus CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] inhibitors. And in liver cancer there are some theoretical concerns about toxicity. And there is an arm in the CheckMate-040 study evaluating that, and we look forward to hearing data in the future. But, as we sit here today, there are some data. There’s the combination of bevacizumab and atezolizumab and lenvatinib and pembrolizumab. What’s your take on these data sets and where they’re going?

Anthony El-Khoueiry, MD: So these are early data sets that are evolving, mostly in a phase Ib-type setting. But to be specific, with the atezolizumab/bevacizumab most recently shared data at ESMO [the European Society for Medical Oncology meeting] 2018, the independently reviewed response rate was around 27%. The investigator-assessed response rate was around 32%, so roughly we could say 30% response rate safely. In theory, that could mean doubling from 15% to 30%. So that’s intriguing and promising with a reasonable safety profile.

Richard Finn, MD: And I think they got a breakthrough therapy designation based on that, right?

Anthony El-Khoueiry, MD: Correct. Similarly, the pembrolizumab/lenvatinib combination had a confirmed response rate just below 30%, so again another promising signal. So these are ways of combining antiangiogenic therapy with anti–PD-1 therapy based on some scientific rationale that seems to be showing promise. I-O/I-O combinations, as you alluded to, are another way that I think we’re going to see attempts to hopefully improve the chance of response.

Richard Finn, MD: The HIMALAYA study is a phase III study already launched of durvalumab and tremelimumab in advanced liver cancer, based on a small subset but also extrapolating from other diseases with bevacizumab and atezolizumab. I think that regimen shows a lot of activity in lung cancer. So it’s partly building on what we know about in liver cancer and then probably extrapolating also from other diseases.

Anthony El-Khoueiry, MD: It brings up one important thought, right? That this is still an area that’s evolving, and I think commitment of all physicians to enroll these patients onto clinical trial is absolutely critical.

Richard Finn, MD: For sure.

Anthony El-Khoueiry, MD: There are a lot of studies, a lot of investigations going on, and these patients are across the world with many practitioners. And I think being conscientious about diverting the right patients to the right trials is going to be important.

Richard Finn, MD: Yes. So, with that thought as we come to the close, there are a lot of agents available for patients—that’s fantastic. I think over time we’re going to see that sequencing these, we are improving survival for advanced liver cancer. This disease now has more options and I would argue a better outcome than pancreatic cancer. And we’ve moved very fast in a short period of time. And, even though there are these options, there’s always room for improvement. And I think referring patients to clinical studies—as self-serving as that is, us being in academics—is best for the field and best for patients. With that in mind, this has been an excellent discussion, Anthony. Next time we’ll talk about USC football and basketball and UCLA and their rivalry, but not in liver cancer. We hope that you found the information presented in this webinar to be valuable to your clinical practice. Thank you for watching OncLive® News Network.

Transcript Edited for Clarity
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