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Selection of a BTK Inhibitor in Relapsed/Refractory MCL

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Matthew S. Davids, MD, MMSc, Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute; Brad Kahl, MD, Washington University School of Medicine; John Pagel, MD, PhD, Swedish Cancer Institute
Published: Tuesday, Aug 13, 2019



Transcript: 

Ian W. Flinn, MD, PhD: John, let’s turn to the relapsed setting that Brad has nicely set up for us. Let’s use a typical patient like Brad has just described. Perhaps the patient has had BR [bendamustine/rituximab] front line, is an older patient, or had the more intensive induction and auto [autologous stem-cell transplantation]. Now, the patient has relapsed. What are you doing for that patient?

John Pagel, MD, PhD: I think it’s important to remember that when patients with mantle cell lymphomas relapse, that biology has changed in a significant number of patients. Going to another chemotherapy-based regimen, even if you nominally change the regimen from what they got before, is often not very helpful for those patients. We’re often approaching these patients who are a little bit older, as well.

These probably aren’t chemoimmunotherapy patients in the relapsed setting, at least in my practice, and that’s where I’m thinking about BTK [Bruton tyrosine kinase] inhibition and acalabrutinib. I think the data that led to its approval in the ACE-LY-004 trial were quite impressive. It had a response rate of about 80%, and the follow-up at 2 years showed that about half of those patients had achieved a complete remission. That’s the best single-agent data we’ve ever seen in relapsed mantle cell lymphoma.

There are some caveats around that that are important. You were probably going to ask about that, and I’ll just jump in. Comparing acalabrutinib with ibrutinib in this setting is a little bit tricky. These are different patient populations. The median number of prior therapies with acalabrutinib was just 1, whereas with ibrutinib, it was 2. They’re different patient populations, and we don’t know the direct comparison in patients who have failed the same number of lines of prior therapy.

It’s also important to understand that the criteria for assessing response was different in the 2 trials. In one trial, we’re using PET [positron emission tomography] scans, which are probably a lot more sensitive in many ways. Patients who got CT [computed tomography] scans in the ibrutinib trial might have had a partial remission, but PETs were not done. We weren’t calling them complete remissions. It’s important to understand that both of these agents are important and valuable in a relapsed patient. I think we’ll see that with zanubrutinib, as well.

Ian W. Flinn, MD, PhD: You’ve brought up a lot to talk about, including how you judge response. I think it’s probably most evident in follicular lymphoma that by using PET scans, you’re doubling or tripling your complete remission rate. Those studies are both incredibly impressive, right? Compared to what we were doing before, the natural history of this disease has been dramatically changed over the last 15 to 20 years. With those limitations in mind, Brad, let’s start with ibrutinib. You were probably using a lot of it. Are you still using ibrutinib?

Brad Kahl, MD: Acalabrutinib now has an indication for relapsed mantle cell lymphoma, so that’s the decision now. There’s no question that BTK inhibition gives you the best response rates in relapsed mantle cell lymphoma. Usually, BTK inhibition, whether it be with ibrutinib or acalabrutinib, is my preferred strategy for a relapsed patient. In my own experience, acalabrutinib is slightly better-tolerated, so I’ll often choose acalabrutinib for my relapsed mantle cell patients. Efficacy-wise, I think the 2 drugs are very comparable. There may be no difference, quite honestly.

An important thing to remember about any BTK inhibitor in relapsed mantle cell is that the data aren’t like CLL [chronic lymphocytic leukemia] data. The response rates aren’t 90%. They’re more like 70%. The complete response [CR] rates are quite low, and the median progression-free survival is often around a year or 18 months, at best. There is a significant problem in relapsed mantle cell lymphoma of patients who break through their BTK inhibition, and it happens at a much higher and faster rate than in does in CLL.

Ian W. Flinn, MD, PhD: I know that when I was starting as a junior faculty, the overall survival for those with mantle cell leukemia was 3 years from the time of diagnosis. Now, it’s so much better. There’s still a long way to go. I’d like to get your thoughts, Matt, on the differences between acalabrutinib and ibrutinib. In CLL, there’s a head-to-head study, right? It’s going to be important, because it’s going to highlight whether there are tolerability issues. It’s going to be important. If that comes out and shows substantial differences, do you think we can apply that data to every disease we treat with a BTK inhibitor?

Matthew S. Davids, MD, MMSc: That’s certainly something we should consider. I wouldn’t think that it’s definitive data, because we sometimes see different toxicities in different diseases. For example, in mantle cell lymphoma, we often see GI [gastrointestinal] tract involvement, so gastrointestinal bleeding could be a bit higher, for example, in that specific disease. I think it’s a useful data set. We can, to some degree, apply some of those lessons learned from CLL to other diseases. In mantle cell, it’s nice to have options. With ibrutinib in mantle cell, there is longer-term follow-up right now, so that’s something beneficial. With acalabrutinib, seeing these deeper responses and higher CR rates is promising, but we don’t have that long-term follow-up yet.

Over time, we’ll see if these differences become clearer. Going back to Brad’s point, one thing that is clear right now is that whichever BTK inhibitor we’re using, the durability of these responses is not going to be long. That prompts the need to develop combination approaches using BTK inhibitors and build on that with other active agents.

Ian W. Flinn, MD, PhD: What are your thoughts on that? What are you seeing? If you were designing a trial, what would you use?

Matthew S. Davids, MD, MMSc: One of the agents that I’ve worked a lot with is venetoclax, and in the phase I study, we saw about 75% of patients responding to venetoclax as a monotherapy in mantle cell lymphoma with about a 20% CR rate. The Australian group has now combined ibrutinib with venetoclax in mantle cell lymphoma and is seeing some very nice results with high CR rates.

Durability is still a question. The follow-up on that study is short. It’s a small study as well, but to me, that’s one of the more exciting combinations from a biological standpoint, and it’s worth exploring further.

Ian W. Flinn, MD, PhD: That original study that you were talking about had a high response rate using venetoclax as a single agent. As you mentioned, it had a very short duration. In the data that you just mentioned, is that still a problem when you combine it with ibrutinib?

Matthew S. Davids, MD, MMSc: I think it’s a little early to know, and they’re small numbers. We just need more data there.

Ian W. Flinn, MD, PhD: They certainly have the larger trials. We’re waiting for the data to emerge, and we’ll have an answer soon.

Transcript Edited for Clarity

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Transcript: 

Ian W. Flinn, MD, PhD: John, let’s turn to the relapsed setting that Brad has nicely set up for us. Let’s use a typical patient like Brad has just described. Perhaps the patient has had BR [bendamustine/rituximab] front line, is an older patient, or had the more intensive induction and auto [autologous stem-cell transplantation]. Now, the patient has relapsed. What are you doing for that patient?

John Pagel, MD, PhD: I think it’s important to remember that when patients with mantle cell lymphomas relapse, that biology has changed in a significant number of patients. Going to another chemotherapy-based regimen, even if you nominally change the regimen from what they got before, is often not very helpful for those patients. We’re often approaching these patients who are a little bit older, as well.

These probably aren’t chemoimmunotherapy patients in the relapsed setting, at least in my practice, and that’s where I’m thinking about BTK [Bruton tyrosine kinase] inhibition and acalabrutinib. I think the data that led to its approval in the ACE-LY-004 trial were quite impressive. It had a response rate of about 80%, and the follow-up at 2 years showed that about half of those patients had achieved a complete remission. That’s the best single-agent data we’ve ever seen in relapsed mantle cell lymphoma.

There are some caveats around that that are important. You were probably going to ask about that, and I’ll just jump in. Comparing acalabrutinib with ibrutinib in this setting is a little bit tricky. These are different patient populations. The median number of prior therapies with acalabrutinib was just 1, whereas with ibrutinib, it was 2. They’re different patient populations, and we don’t know the direct comparison in patients who have failed the same number of lines of prior therapy.

It’s also important to understand that the criteria for assessing response was different in the 2 trials. In one trial, we’re using PET [positron emission tomography] scans, which are probably a lot more sensitive in many ways. Patients who got CT [computed tomography] scans in the ibrutinib trial might have had a partial remission, but PETs were not done. We weren’t calling them complete remissions. It’s important to understand that both of these agents are important and valuable in a relapsed patient. I think we’ll see that with zanubrutinib, as well.

Ian W. Flinn, MD, PhD: You’ve brought up a lot to talk about, including how you judge response. I think it’s probably most evident in follicular lymphoma that by using PET scans, you’re doubling or tripling your complete remission rate. Those studies are both incredibly impressive, right? Compared to what we were doing before, the natural history of this disease has been dramatically changed over the last 15 to 20 years. With those limitations in mind, Brad, let’s start with ibrutinib. You were probably using a lot of it. Are you still using ibrutinib?

Brad Kahl, MD: Acalabrutinib now has an indication for relapsed mantle cell lymphoma, so that’s the decision now. There’s no question that BTK inhibition gives you the best response rates in relapsed mantle cell lymphoma. Usually, BTK inhibition, whether it be with ibrutinib or acalabrutinib, is my preferred strategy for a relapsed patient. In my own experience, acalabrutinib is slightly better-tolerated, so I’ll often choose acalabrutinib for my relapsed mantle cell patients. Efficacy-wise, I think the 2 drugs are very comparable. There may be no difference, quite honestly.

An important thing to remember about any BTK inhibitor in relapsed mantle cell is that the data aren’t like CLL [chronic lymphocytic leukemia] data. The response rates aren’t 90%. They’re more like 70%. The complete response [CR] rates are quite low, and the median progression-free survival is often around a year or 18 months, at best. There is a significant problem in relapsed mantle cell lymphoma of patients who break through their BTK inhibition, and it happens at a much higher and faster rate than in does in CLL.

Ian W. Flinn, MD, PhD: I know that when I was starting as a junior faculty, the overall survival for those with mantle cell leukemia was 3 years from the time of diagnosis. Now, it’s so much better. There’s still a long way to go. I’d like to get your thoughts, Matt, on the differences between acalabrutinib and ibrutinib. In CLL, there’s a head-to-head study, right? It’s going to be important, because it’s going to highlight whether there are tolerability issues. It’s going to be important. If that comes out and shows substantial differences, do you think we can apply that data to every disease we treat with a BTK inhibitor?

Matthew S. Davids, MD, MMSc: That’s certainly something we should consider. I wouldn’t think that it’s definitive data, because we sometimes see different toxicities in different diseases. For example, in mantle cell lymphoma, we often see GI [gastrointestinal] tract involvement, so gastrointestinal bleeding could be a bit higher, for example, in that specific disease. I think it’s a useful data set. We can, to some degree, apply some of those lessons learned from CLL to other diseases. In mantle cell, it’s nice to have options. With ibrutinib in mantle cell, there is longer-term follow-up right now, so that’s something beneficial. With acalabrutinib, seeing these deeper responses and higher CR rates is promising, but we don’t have that long-term follow-up yet.

Over time, we’ll see if these differences become clearer. Going back to Brad’s point, one thing that is clear right now is that whichever BTK inhibitor we’re using, the durability of these responses is not going to be long. That prompts the need to develop combination approaches using BTK inhibitors and build on that with other active agents.

Ian W. Flinn, MD, PhD: What are your thoughts on that? What are you seeing? If you were designing a trial, what would you use?

Matthew S. Davids, MD, MMSc: One of the agents that I’ve worked a lot with is venetoclax, and in the phase I study, we saw about 75% of patients responding to venetoclax as a monotherapy in mantle cell lymphoma with about a 20% CR rate. The Australian group has now combined ibrutinib with venetoclax in mantle cell lymphoma and is seeing some very nice results with high CR rates.

Durability is still a question. The follow-up on that study is short. It’s a small study as well, but to me, that’s one of the more exciting combinations from a biological standpoint, and it’s worth exploring further.

Ian W. Flinn, MD, PhD: That original study that you were talking about had a high response rate using venetoclax as a single agent. As you mentioned, it had a very short duration. In the data that you just mentioned, is that still a problem when you combine it with ibrutinib?

Matthew S. Davids, MD, MMSc: I think it’s a little early to know, and they’re small numbers. We just need more data there.

Ian W. Flinn, MD, PhD: They certainly have the larger trials. We’re waiting for the data to emerge, and we’ll have an answer soon.

Transcript Edited for Clarity
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