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Lenvatinib As Up-front Therapy for Unresectable HCC

Panelists: Ghassan K. Abou-Alfa, MD, Weill Cornell Medical College; Peter Galle, MD, PhD Johannes Gutenberg University, Mainz; Riad Salem, MD, Northwestern University; Amit Singal, MD UT Southwestern Medical Center
Published: Thursday, Dec 20, 2018



Transcript: 

Ghassan K. Abou-Alfa, MD: It’s fascinating how much more systemic therapy comes into play in the management of HCC [hepatocellular carcinoma]. I had a patient who I recommended for embolization. The patient refused. The patient said, “I heard that you have amazing new systemic therapies. I’m more interested in this.” It’s amazing how the mindset is changing. Peter, for 10 years, sorafenib was our only standard of care. Admittedly, we were doing a lot in between, and all experts in the field have been doing things globally in that regard. I’ve never seen a disease like this. Everything evolved so quickly. We have seen so many options within a year. Let’s start with the first one, lenvatinib. This was a noninferiority study compared to sorafenib [Nexavar]. Tell us a bit more.

Peter Galle, MD, PhD: When we started with sorafenib, the hope was that it would help to rapidly produce more drugs and more systemic options. Nothing happened. There were many negative trials, although this was a learning experience. We learned a lot. We had clear definitions. Placebo-treated patients in the second-line setting lived for 8 months or so. That was very helpful, but it was disappointing with respect to new options. And then we saw regorafenib in the second-line setting, and later on, lenvatinib entered the stage.

Lenvatinib was tested in an open-label design against sorafenib in the first-line setting. This was a noninferiority trial. It was clearly a positive trial. The outcome was comparable. Actually, numerically, it was better for lenvatinib and definitely opens the horizon in the first-line setting for having another option. The difference is that lenvatinib has a different safety profile. Tumor efficacy is not all we have to ask for. Toxicity is extremely relevant. Now we have the option to at least make a smart decision, although we have no head-to-head comparisons. But it’s now opening the seam and more than just sorafenib is being offered in the first-line setting.

What we also have learned is that some surrogate endpoints have been in favor of lenvatinib. Progression-free survival and time to progression were better for lenvatinib, although the overall survival data, again, were the same. What does that mean? It’s one of these situations where we need to discuss how we correlate the surrogate markers, surrogate endpoints, and overall survival. But it’s a definite step forward.

Ghassan K. Abou-Alfa, MD: I totally agree. If anything, the data for sorafenib and lenvatinib at 12 or 13 months have almost equal survival. Maybe, as Peter said, there is a small edge for lenvatinib. The data are comparable. But interestingly, the progression-free survival almost tripled for the lenvatinib arm. Remember that with sorafenib, responses exist. With lenvatinib, responses were a really important part of the story. Amit, tell us about that. What were the numbers there?

Amit Singal, MD: As you were saying, the progression-free survival was nearly double or triple what you saw with sorafenib. Similarly, you saw significant improvements in terms of time to progression and objective response rates. And so, it makes you excited. You start to see significant improvements in time to progression and the response rates are good. However, it didn’t actually translate into improved survival. Are these appropriate endpoints? Clinically, do these actually matter if they don’t translate into an improved survival?

Ghassan K. Abou-Alfa, MD: I hear you. Nonetheless, the response rate by RECIST [Response Evaluation Criteria in Solid Tumors] version 1.1 was close to 22%, 23%, or 24%. The modified RECIST showed a rate that was close to 41%. Wow.

Amit Singal, MD: It’s incredible, when you take a look at these response rates. Once again, if you’re a patient, you’re like, “I’m going to have some tumor response.” But it’s not going to actually improve survival. What does that actually mean?

Ghassan K. Abou-Alfa, MD: Riad, as an interventional radiology specialist, how do you look at this data?

Riad Salem, MD: Well, it’s music to my ears as an interventional radiologist. Finally, oncologists and hepatologists recognize the importance of response. It does matter. You know as well as I do, if not better, that this is a discussion that you have with your patient. For any patient who is on a medication, a drug, or a therapy, if they’re not having toxicities that need to be managed, the main discussion point is response. “Show me that tumor. Is it smaller?”

It opens up the idea that you now have a systemic agent that can provide that high response rate. Now the reality is, are there discussions that you can start to think to have, in terms of using this therapy? The downstaging concept, right? Can you use that in bridging? I’m sure there’s going to be some research on that. Can you use that in downstaging, where a local therapy fails, for example, to bring the patient within transplant criteria? So I think that reinvigorates the discussion of response, which is an important one. This allows you to study responses as a surrogate of survival, which has been shown to be very important in clinical trials.

Ghassan K. Abou-Alfa, MD: I hear you. I totally agree. In regard to response, we are used to the terms “bigger,” “smaller,” or “the same.” These are easy to reference. One day, a patient really stunned me. I didn’t even know the answer. I looked at him and he asked, “So, what’s survival?” The best response I could come up with was, “The more you see me, the better you are.” I couldn’t come up with anything better than that. This really tells you how complex this is, in regard to understanding survival. Amit, do you have any experience, or what are your thoughts in regard to the side effects or adverse events that you may see with lenvatinib? How well tolerated is the drug?

Amit Singal, MD: As Peter was saying, I think the nice thing is that it appears to be better tolerated than sorafenib. When you take a look at the trial, you see that there were lower rates of hand-foot skin reaction with lenvatinib. However, there were higher rates of some of the other adverse events, like hypertension.

Ghassan K. Abou-Alfa, MD: I think the most common is hypertension, correct?

Amit Singal, MD: Yes, exactly. So, you saw higher rates of hypertension and higher rates of anorexia or weight loss. But I think the biggest thing, when we’ve taken a look at TKI [tyrosine kinase inhibitor] therapies, is the hand-foot skin reaction. That’s really been one of the toughest things, in terms of patients tolerating this treatment. And so, I think all of us are going to welcome an alternative therapy that offers significantly lower rates of hand-foot skin reaction.

Ghassan K. Abou-Alfa, MD: Sure.

Transcript Edited for Clarity

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Transcript: 

Ghassan K. Abou-Alfa, MD: It’s fascinating how much more systemic therapy comes into play in the management of HCC [hepatocellular carcinoma]. I had a patient who I recommended for embolization. The patient refused. The patient said, “I heard that you have amazing new systemic therapies. I’m more interested in this.” It’s amazing how the mindset is changing. Peter, for 10 years, sorafenib was our only standard of care. Admittedly, we were doing a lot in between, and all experts in the field have been doing things globally in that regard. I’ve never seen a disease like this. Everything evolved so quickly. We have seen so many options within a year. Let’s start with the first one, lenvatinib. This was a noninferiority study compared to sorafenib [Nexavar]. Tell us a bit more.

Peter Galle, MD, PhD: When we started with sorafenib, the hope was that it would help to rapidly produce more drugs and more systemic options. Nothing happened. There were many negative trials, although this was a learning experience. We learned a lot. We had clear definitions. Placebo-treated patients in the second-line setting lived for 8 months or so. That was very helpful, but it was disappointing with respect to new options. And then we saw regorafenib in the second-line setting, and later on, lenvatinib entered the stage.

Lenvatinib was tested in an open-label design against sorafenib in the first-line setting. This was a noninferiority trial. It was clearly a positive trial. The outcome was comparable. Actually, numerically, it was better for lenvatinib and definitely opens the horizon in the first-line setting for having another option. The difference is that lenvatinib has a different safety profile. Tumor efficacy is not all we have to ask for. Toxicity is extremely relevant. Now we have the option to at least make a smart decision, although we have no head-to-head comparisons. But it’s now opening the seam and more than just sorafenib is being offered in the first-line setting.

What we also have learned is that some surrogate endpoints have been in favor of lenvatinib. Progression-free survival and time to progression were better for lenvatinib, although the overall survival data, again, were the same. What does that mean? It’s one of these situations where we need to discuss how we correlate the surrogate markers, surrogate endpoints, and overall survival. But it’s a definite step forward.

Ghassan K. Abou-Alfa, MD: I totally agree. If anything, the data for sorafenib and lenvatinib at 12 or 13 months have almost equal survival. Maybe, as Peter said, there is a small edge for lenvatinib. The data are comparable. But interestingly, the progression-free survival almost tripled for the lenvatinib arm. Remember that with sorafenib, responses exist. With lenvatinib, responses were a really important part of the story. Amit, tell us about that. What were the numbers there?

Amit Singal, MD: As you were saying, the progression-free survival was nearly double or triple what you saw with sorafenib. Similarly, you saw significant improvements in terms of time to progression and objective response rates. And so, it makes you excited. You start to see significant improvements in time to progression and the response rates are good. However, it didn’t actually translate into improved survival. Are these appropriate endpoints? Clinically, do these actually matter if they don’t translate into an improved survival?

Ghassan K. Abou-Alfa, MD: I hear you. Nonetheless, the response rate by RECIST [Response Evaluation Criteria in Solid Tumors] version 1.1 was close to 22%, 23%, or 24%. The modified RECIST showed a rate that was close to 41%. Wow.

Amit Singal, MD: It’s incredible, when you take a look at these response rates. Once again, if you’re a patient, you’re like, “I’m going to have some tumor response.” But it’s not going to actually improve survival. What does that actually mean?

Ghassan K. Abou-Alfa, MD: Riad, as an interventional radiology specialist, how do you look at this data?

Riad Salem, MD: Well, it’s music to my ears as an interventional radiologist. Finally, oncologists and hepatologists recognize the importance of response. It does matter. You know as well as I do, if not better, that this is a discussion that you have with your patient. For any patient who is on a medication, a drug, or a therapy, if they’re not having toxicities that need to be managed, the main discussion point is response. “Show me that tumor. Is it smaller?”

It opens up the idea that you now have a systemic agent that can provide that high response rate. Now the reality is, are there discussions that you can start to think to have, in terms of using this therapy? The downstaging concept, right? Can you use that in bridging? I’m sure there’s going to be some research on that. Can you use that in downstaging, where a local therapy fails, for example, to bring the patient within transplant criteria? So I think that reinvigorates the discussion of response, which is an important one. This allows you to study responses as a surrogate of survival, which has been shown to be very important in clinical trials.

Ghassan K. Abou-Alfa, MD: I hear you. I totally agree. In regard to response, we are used to the terms “bigger,” “smaller,” or “the same.” These are easy to reference. One day, a patient really stunned me. I didn’t even know the answer. I looked at him and he asked, “So, what’s survival?” The best response I could come up with was, “The more you see me, the better you are.” I couldn’t come up with anything better than that. This really tells you how complex this is, in regard to understanding survival. Amit, do you have any experience, or what are your thoughts in regard to the side effects or adverse events that you may see with lenvatinib? How well tolerated is the drug?

Amit Singal, MD: As Peter was saying, I think the nice thing is that it appears to be better tolerated than sorafenib. When you take a look at the trial, you see that there were lower rates of hand-foot skin reaction with lenvatinib. However, there were higher rates of some of the other adverse events, like hypertension.

Ghassan K. Abou-Alfa, MD: I think the most common is hypertension, correct?

Amit Singal, MD: Yes, exactly. So, you saw higher rates of hypertension and higher rates of anorexia or weight loss. But I think the biggest thing, when we’ve taken a look at TKI [tyrosine kinase inhibitor] therapies, is the hand-foot skin reaction. That’s really been one of the toughest things, in terms of patients tolerating this treatment. And so, I think all of us are going to welcome an alternative therapy that offers significantly lower rates of hand-foot skin reaction.

Ghassan K. Abou-Alfa, MD: Sure.

Transcript Edited for Clarity
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