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RAI-Refractory Differentiated Thyroid Cancer: Lenvatinib

Insights From: Marcia S. Brose, MD, PhD Abramson Cancer Center; Johannes Smit, MD, PhD Radboud University Nijmegen Medical Center
Published: Friday, Dec 14, 2018



Transcript: 

Marcia S. Brose, MD, PhD:
Lenvatinib was developed, or approved based on data from the SELECT trial. From that trial we know that it is safe and extremely effective to give. We know that patients have a progression-free survival of anywhere from 15 months if they’ve had sorafenib first to 18 months if they’re getting it in the first-line setting. So we know that it’s safe and it’s also effective in both the first- and the second-line settings. We also know that patients have very rapid responses, with most of the responses coming in the first 2 months. We also know that there are toxicities that we have to manage. We see more issues with hypertension. We have to be ready to treat that aggressively with antihypertensive medicine. It’s also a different safety profile or side effect profile. You need to know about that because it requires different management than if you were treating with other kinase inhibitors. So with every drug you need to know specifically what you’re going to have to manage. It is safe, but there are side effects that you need to be prepared for, so once you start you can intervene right away.

The [progression-free survival Kaplan–Meier curve from the SELECT data shows that there’s a significant separation between the placebo and the treatment arm, showing that progression-free survival is really prolonged. We know that the time to the first progression event, as I would tell a lot of people, is 15 months if they’ve had sorafenib before or 18 months if they’re using it in the first-line setting. And overall, it was approximately 18 months. The good thing to know about that is that the period of time has a significance clinically for the patient. That’s actually a period when they are not only [not] responding but also not progressing. If you’re not progressing, you’re not developing new symptoms. So clinically, the importance of that separation is meaningful to the patient because that’s a period of time, 18 months, when their disease isn’t progressing and they’re not having problems because of it.

Recently, about a year ago, we published some data from the SELECT trial that showed that the patients who are over age 65 actually had overall survival benefit. I believe that we’re having an overall survival benefit in all patients, but this is the first time we were able to prove it definitively within a single study. That does affect our treatment selection. For people who are over age 65, we might actually choose to use lenvatinib first because of the results from this study. This probably is giving us a hint that we may be getting a benefit by using the kinase inhibitors in all patients, but we have yet to actually prove it in the other setting.

Eric J. Sherman, MD: So lenvatinib’s dosage, based on the SELECT study, is 24 mg daily. For most patients, that’s what we start off with. But from the SELECT study we also see that about 70% of people will have to go to a lower dosage. In my practice, it seems to be at least 70%. There are a lot of potential side effects—high blood pressure, diarrhea, hand-foot syndrome—and patients often need to get a lower [dosage]. My preference, for most people, is still to start at 24 mg.

There are exceptions to that rule. There are people who are obviously not going to be able to tolerate those side effects at all. If you get someone who’s elderly and who doesn’t have a lot of support at home, you probably will want them started at a lower dosage.
There are other patients for whom it’s very obvious that if you get a lot of side effects, they’re never going to go back on that drug. I have had patients in the past who have been on a drug and had a lot of side effects. We tell them that we are going to go down to a lower dosage, and they say, “No, I will never go back on this drug again.” Not only that, but they may not go back on any treatment at all. So you have to look at the individual patient and decide what is the best thing for them. If it’s someone for whom you really worry about side effects, they will never receive any treatment again. They will refuse everything. Starting at a lower dosage makes a difference. The good thing about lenvatinib is that we’ve seen good responses in patients receiving a dosage as low as 10 mg daily. So you could go to a much lower dosage and still have some activity. The best activity in the clinical study says 24 mg, but you could do 10 mg or 14 mg in some patients. And then, if they’re doing well, you can try to go up. My preference, for most patients, is to start with 24 mg and go down.

Johannes (Jan) Smit, MD, PhD: An important point in the management of thyroid cancer patients with lenvatinib is that we really believe those patients should be treated in a multidisciplinary setting. Drugs like lenvatinib are complicated to use if you do not have much experience with them. The prevention and management of adverse effects is important. Lenvatinib has a spectrum of side effects that can be managed rather easily, but this management needs to be done through a multidisciplinary approach.

With lenvatinib, we have seen impressive results. We see a couple of patients with impressive tumor regression and relief of symptoms. On the other hand, we also see patients who do not respond to the drug and patients who, after an initial episode of response, progress. So the whole spectrum of response, from beneficial response to absence of response and progression after response, occurs.

Marcia S. Brose, MD, PhD: Lenvatinib actually has a very rapid reduction, especially when given at its recommended dosage of 24 mg. It’s a very good option for patients who are symptomatic, who need to benefit from a rapid reduction right away. There’s a little caution for that. If the patient has invasion into the neck structure or if they’ve had radiation to the neck, with that rapid reduction would be at a higher risk of getting a fistula. So in that case I’d have to be extremely careful about whether or not to give lenvatinib, and I might choose to use another agent instead.

I think the best patient for this drug is really somebody who’s symptomatic. That said, all patients with progressive disease would benefit from lenvatinib as well. It’s a tolerable agent. It has side effects that are manageable. If somebody has very high blood pressure issues prior to starting therapy, that might be a person who I wouldn’t select for lenvatinib for. Lenvatinib causes quite an extreme increase in blood pressure. So I think that you might not select this drug for people who have invasion and really bad blood pressure problems. However, all the other patients are benefiting very much from getting lenvatinib.

Eric J. Sherman, MD: My personal experience is that it works. I have not seen any complete responses with lenvatinib. There were a few patients on the clinical study who had these complete responses. I think those might be more in exaggeration to what we really ever truly see. But at the same time, lenvatinib definitely works. It can work for quite a while. It can make the tumors really shrink, but you have to watch for adverse effects.

I talk to patients about checking their blood pressure on a daily basis for the first 6 weeks while on sorafenib. With lenvatinib, you have to do it. You have to be ready to add blood pressure medications very, very quickly in these people. You have to warn them about everything they need to know. If they have any other adverse effects, you tell them to call you immediately, so you can make whatever adjustments that need to be done. But at the same time, they probably have the highest response rate with lenvatinib. It really does keep the disease in check for quite a while. I’ve had patients who have been on it for a very long period of time, who are doing extremely well.


Transcript Edited for Clarity
 
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Transcript: 

Marcia S. Brose, MD, PhD:
Lenvatinib was developed, or approved based on data from the SELECT trial. From that trial we know that it is safe and extremely effective to give. We know that patients have a progression-free survival of anywhere from 15 months if they’ve had sorafenib first to 18 months if they’re getting it in the first-line setting. So we know that it’s safe and it’s also effective in both the first- and the second-line settings. We also know that patients have very rapid responses, with most of the responses coming in the first 2 months. We also know that there are toxicities that we have to manage. We see more issues with hypertension. We have to be ready to treat that aggressively with antihypertensive medicine. It’s also a different safety profile or side effect profile. You need to know about that because it requires different management than if you were treating with other kinase inhibitors. So with every drug you need to know specifically what you’re going to have to manage. It is safe, but there are side effects that you need to be prepared for, so once you start you can intervene right away.

The [progression-free survival Kaplan–Meier curve from the SELECT data shows that there’s a significant separation between the placebo and the treatment arm, showing that progression-free survival is really prolonged. We know that the time to the first progression event, as I would tell a lot of people, is 15 months if they’ve had sorafenib before or 18 months if they’re using it in the first-line setting. And overall, it was approximately 18 months. The good thing to know about that is that the period of time has a significance clinically for the patient. That’s actually a period when they are not only [not] responding but also not progressing. If you’re not progressing, you’re not developing new symptoms. So clinically, the importance of that separation is meaningful to the patient because that’s a period of time, 18 months, when their disease isn’t progressing and they’re not having problems because of it.

Recently, about a year ago, we published some data from the SELECT trial that showed that the patients who are over age 65 actually had overall survival benefit. I believe that we’re having an overall survival benefit in all patients, but this is the first time we were able to prove it definitively within a single study. That does affect our treatment selection. For people who are over age 65, we might actually choose to use lenvatinib first because of the results from this study. This probably is giving us a hint that we may be getting a benefit by using the kinase inhibitors in all patients, but we have yet to actually prove it in the other setting.

Eric J. Sherman, MD: So lenvatinib’s dosage, based on the SELECT study, is 24 mg daily. For most patients, that’s what we start off with. But from the SELECT study we also see that about 70% of people will have to go to a lower dosage. In my practice, it seems to be at least 70%. There are a lot of potential side effects—high blood pressure, diarrhea, hand-foot syndrome—and patients often need to get a lower [dosage]. My preference, for most people, is still to start at 24 mg.

There are exceptions to that rule. There are people who are obviously not going to be able to tolerate those side effects at all. If you get someone who’s elderly and who doesn’t have a lot of support at home, you probably will want them started at a lower dosage.
There are other patients for whom it’s very obvious that if you get a lot of side effects, they’re never going to go back on that drug. I have had patients in the past who have been on a drug and had a lot of side effects. We tell them that we are going to go down to a lower dosage, and they say, “No, I will never go back on this drug again.” Not only that, but they may not go back on any treatment at all. So you have to look at the individual patient and decide what is the best thing for them. If it’s someone for whom you really worry about side effects, they will never receive any treatment again. They will refuse everything. Starting at a lower dosage makes a difference. The good thing about lenvatinib is that we’ve seen good responses in patients receiving a dosage as low as 10 mg daily. So you could go to a much lower dosage and still have some activity. The best activity in the clinical study says 24 mg, but you could do 10 mg or 14 mg in some patients. And then, if they’re doing well, you can try to go up. My preference, for most patients, is to start with 24 mg and go down.

Johannes (Jan) Smit, MD, PhD: An important point in the management of thyroid cancer patients with lenvatinib is that we really believe those patients should be treated in a multidisciplinary setting. Drugs like lenvatinib are complicated to use if you do not have much experience with them. The prevention and management of adverse effects is important. Lenvatinib has a spectrum of side effects that can be managed rather easily, but this management needs to be done through a multidisciplinary approach.

With lenvatinib, we have seen impressive results. We see a couple of patients with impressive tumor regression and relief of symptoms. On the other hand, we also see patients who do not respond to the drug and patients who, after an initial episode of response, progress. So the whole spectrum of response, from beneficial response to absence of response and progression after response, occurs.

Marcia S. Brose, MD, PhD: Lenvatinib actually has a very rapid reduction, especially when given at its recommended dosage of 24 mg. It’s a very good option for patients who are symptomatic, who need to benefit from a rapid reduction right away. There’s a little caution for that. If the patient has invasion into the neck structure or if they’ve had radiation to the neck, with that rapid reduction would be at a higher risk of getting a fistula. So in that case I’d have to be extremely careful about whether or not to give lenvatinib, and I might choose to use another agent instead.

I think the best patient for this drug is really somebody who’s symptomatic. That said, all patients with progressive disease would benefit from lenvatinib as well. It’s a tolerable agent. It has side effects that are manageable. If somebody has very high blood pressure issues prior to starting therapy, that might be a person who I wouldn’t select for lenvatinib for. Lenvatinib causes quite an extreme increase in blood pressure. So I think that you might not select this drug for people who have invasion and really bad blood pressure problems. However, all the other patients are benefiting very much from getting lenvatinib.

Eric J. Sherman, MD: My personal experience is that it works. I have not seen any complete responses with lenvatinib. There were a few patients on the clinical study who had these complete responses. I think those might be more in exaggeration to what we really ever truly see. But at the same time, lenvatinib definitely works. It can work for quite a while. It can make the tumors really shrink, but you have to watch for adverse effects.

I talk to patients about checking their blood pressure on a daily basis for the first 6 weeks while on sorafenib. With lenvatinib, you have to do it. You have to be ready to add blood pressure medications very, very quickly in these people. You have to warn them about everything they need to know. If they have any other adverse effects, you tell them to call you immediately, so you can make whatever adjustments that need to be done. But at the same time, they probably have the highest response rate with lenvatinib. It really does keep the disease in check for quite a while. I’ve had patients who have been on it for a very long period of time, who are doing extremely well.


Transcript Edited for Clarity
 
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