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BTK Inhibitors in Waldenstrom Macroglobulinemia

Insights From: Brad S. Kahl, MD, Washington University School of Medicine; Steven P. Treon, MD, PhD, Harvard Medical School
Published: Wednesday, Mar 20, 2019



Transcript: 

Steven P. Treon, MD, PhD: At this last ASH [American Society of Hematology] meeting we got a very nice update on the iNNOVATE trial. This is a trial that has been looking at ibrutinib plus Rituxan [rituximab] and comparing it with Rituxan as monotherapy. The study was predicated on the fact that when you look at SEER data here in the United States, as well as community practice data that come out of Europe, that Rituxan monotherapy has been used as the “community standard,” or the most used drug in the community setting. This is why iNNOVATE was actually targeted around seeing if we could move from the standard. Dr Christian Buske, from Germany, was able to provide an update, and the paper itself was actually published in the New England Journal of Medicine this past year. But it was really nice to see longer follow-up.

And what we saw with this data is that the patients, in general, continued to have a nice response. We are, however, starting to see separation among those patients who have the CXCR4 mutation versus those who are wild type. And this, I think, was very, very interesting to learn at this meeting because this again tells us that CXCR4 may be a predictor for early progression despite the fact that we still see, for most patients, ongoing response. But this also tells us that it’s time now to be thinking about how we can actually shut down CXCR4 in hopes of being able to improve or optimize BTK [Bruton tyrosine kinase] inhibitors. And 1 of the trials that we’re currently looking at right now is using an antagonist against CXCR4, ulocuplumab. So it helps put into perspective CXCR4 antagonists in this disease.

We also learned from Dr Buske’s data that the time to major response was actually positively impacted by the addition of Rituxan in the CXCR4-mutated patients. Often with ibrutinib monotherapy data that we’ve seen, there is this delay or lag to response. But it was very gratifying to see that if you added Rituxan, you could accelerate response in these patients. And I think that’s really important because when you do have a patient for whom you need a more immediate response, then the addition of rituximab may help those patients with CXCR4 mutations.

At the 10th International Workshop for Waldenström, we heard data on new BTK inhibitors, including acalabrutinib as well as zanubrutinib. There were very nice presentations that were made. Dr Richard Furman actually presented data on acalabrutinib, and Dr Constantine Tam presented very nice data on zanubrutinib. These are early stage studies, but what we see in these studies is that the overall responses were about 90% and between 75% and 80% of patients actually achieved a major response.

Now we didn’t have any data presented around the importance of genomics with response to acalabrutinib, but we did see some data with zanubrutinib that alluded to the fact that we were getting very high responses, even in patients who were CXCR4 mutated. Although there are still differences between CXCR4 wild type and CXCR4-mutated patients, akin to what we had shown with ibrutinib in previous trials.

When you look at the safety profile of the newer BTK inhibitors, they’re relatively comparable. This was 1 of the important observations that was discussed at the 10th International Workshop on Waldenström in New York this past year. We found that with all these BTK inhibitors you see that atrial fibrillation, as well as bleeding risk, seems to be fairly comparable. And some of it has to do with experience. The longer the follow-up, the more you tend to see some of these, particularly atrial fibrillation, being manifested and reported. It’s important for clinicians to keep in mind that with acalabrutinib there can also be headaches, at least in the first few months of their use, and that caffeine can be utilized as a way of treating those headaches during that interval period.

But I think at the end of the day, what we learned at the workshop is that these are comparable inhibitors. Whether you’re looking at ibrutinib, acalabrutinib, or zanubrutinib, the level of activity seems to be almost the same. We tend to see an adverse-effect profile that is very, very comparable and really wouldn’t motivate anybody to pick 1 over the other. It may come down ultimately to convenience—once a day administration with ibrutinib versus twice a day administration. And also, because of off-target effects, there might be adverse effects that may be present with ibrutinib that you may not see for a particular patient with these newer-generation inhibitors. So if somebody is unable to tolerate ibrutinib because of these ongoing grade 1 or grade 2 toxicities, at least knowing that new BTK inhibitors are present will allow one to be able to consider maybe using 1 of these in lieu of. And so this is why it’s exciting to see the development of all these new inhibitors targeting BTK in Waldenström.

There is an ongoing phase III study that is looking at the impact of zanubrutinib as monotherapy compared with ibrutinib as monotherapy. We were told at the workshop this year that this study has now fully enrolled. It’s a study that is looking at the activity of these 2 BTK inhibitors head-on in both treatment-naïve as well as previously treated patients. And the data are eagerly awaited at this time.

In a head-to-head trial, what you’re really trying to see, particularly in this setting, is what the activity, including the depth of response and progression-free survival, is going to be for these BTK inhibitors. I think it’s important to keep in mind that both zanubrutinib as well as ibrutinib, at least in the trials that we’re privy to so far, seem to have a very comparable response rate, overall response rate, as well as major response rate. We know that these 2 drugs are active based on the data that we’ve seen so far. Whether or not a head-to-head trial is going to show superiority for 1 over the other remains to be seen. But at least what we know of so far shows that zanubrutinib is likely to be a very promising new agent for Waldenström, akin to what we’ve seen with ibrutinib.

At ASCO 2018 [the American Society of Clinical Oncology Annual Meeting], Dr Roger Owen presented data on the use of acalabrutinib. This was a trial in both treatment-naïve as well as previously treated patients with Waldenström. We saw an overall response rate of about 90% and just shy of 80% of patients achieved a major response. And this is a very exciting study because it also showed us that many of the patients attained very good partial responses reflecting the fact, particularly with ongoing therapy, that deeper responses could be attained.
Now the study included both treatment-naïve and previously treated patients. The follow-up is much longer in the previously treated patients, wherein these deeper VGPRs [very good partial responses] were observed. So it’s exciting to know that akin to our experiences with the other BTK inhibitors, with more time the responses deepen. And that’s actually a good thing for patients.

Transcript Edited for Clarity
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Transcript: 

Steven P. Treon, MD, PhD: At this last ASH [American Society of Hematology] meeting we got a very nice update on the iNNOVATE trial. This is a trial that has been looking at ibrutinib plus Rituxan [rituximab] and comparing it with Rituxan as monotherapy. The study was predicated on the fact that when you look at SEER data here in the United States, as well as community practice data that come out of Europe, that Rituxan monotherapy has been used as the “community standard,” or the most used drug in the community setting. This is why iNNOVATE was actually targeted around seeing if we could move from the standard. Dr Christian Buske, from Germany, was able to provide an update, and the paper itself was actually published in the New England Journal of Medicine this past year. But it was really nice to see longer follow-up.

And what we saw with this data is that the patients, in general, continued to have a nice response. We are, however, starting to see separation among those patients who have the CXCR4 mutation versus those who are wild type. And this, I think, was very, very interesting to learn at this meeting because this again tells us that CXCR4 may be a predictor for early progression despite the fact that we still see, for most patients, ongoing response. But this also tells us that it’s time now to be thinking about how we can actually shut down CXCR4 in hopes of being able to improve or optimize BTK [Bruton tyrosine kinase] inhibitors. And 1 of the trials that we’re currently looking at right now is using an antagonist against CXCR4, ulocuplumab. So it helps put into perspective CXCR4 antagonists in this disease.

We also learned from Dr Buske’s data that the time to major response was actually positively impacted by the addition of Rituxan in the CXCR4-mutated patients. Often with ibrutinib monotherapy data that we’ve seen, there is this delay or lag to response. But it was very gratifying to see that if you added Rituxan, you could accelerate response in these patients. And I think that’s really important because when you do have a patient for whom you need a more immediate response, then the addition of rituximab may help those patients with CXCR4 mutations.

At the 10th International Workshop for Waldenström, we heard data on new BTK inhibitors, including acalabrutinib as well as zanubrutinib. There were very nice presentations that were made. Dr Richard Furman actually presented data on acalabrutinib, and Dr Constantine Tam presented very nice data on zanubrutinib. These are early stage studies, but what we see in these studies is that the overall responses were about 90% and between 75% and 80% of patients actually achieved a major response.

Now we didn’t have any data presented around the importance of genomics with response to acalabrutinib, but we did see some data with zanubrutinib that alluded to the fact that we were getting very high responses, even in patients who were CXCR4 mutated. Although there are still differences between CXCR4 wild type and CXCR4-mutated patients, akin to what we had shown with ibrutinib in previous trials.

When you look at the safety profile of the newer BTK inhibitors, they’re relatively comparable. This was 1 of the important observations that was discussed at the 10th International Workshop on Waldenström in New York this past year. We found that with all these BTK inhibitors you see that atrial fibrillation, as well as bleeding risk, seems to be fairly comparable. And some of it has to do with experience. The longer the follow-up, the more you tend to see some of these, particularly atrial fibrillation, being manifested and reported. It’s important for clinicians to keep in mind that with acalabrutinib there can also be headaches, at least in the first few months of their use, and that caffeine can be utilized as a way of treating those headaches during that interval period.

But I think at the end of the day, what we learned at the workshop is that these are comparable inhibitors. Whether you’re looking at ibrutinib, acalabrutinib, or zanubrutinib, the level of activity seems to be almost the same. We tend to see an adverse-effect profile that is very, very comparable and really wouldn’t motivate anybody to pick 1 over the other. It may come down ultimately to convenience—once a day administration with ibrutinib versus twice a day administration. And also, because of off-target effects, there might be adverse effects that may be present with ibrutinib that you may not see for a particular patient with these newer-generation inhibitors. So if somebody is unable to tolerate ibrutinib because of these ongoing grade 1 or grade 2 toxicities, at least knowing that new BTK inhibitors are present will allow one to be able to consider maybe using 1 of these in lieu of. And so this is why it’s exciting to see the development of all these new inhibitors targeting BTK in Waldenström.

There is an ongoing phase III study that is looking at the impact of zanubrutinib as monotherapy compared with ibrutinib as monotherapy. We were told at the workshop this year that this study has now fully enrolled. It’s a study that is looking at the activity of these 2 BTK inhibitors head-on in both treatment-naïve as well as previously treated patients. And the data are eagerly awaited at this time.

In a head-to-head trial, what you’re really trying to see, particularly in this setting, is what the activity, including the depth of response and progression-free survival, is going to be for these BTK inhibitors. I think it’s important to keep in mind that both zanubrutinib as well as ibrutinib, at least in the trials that we’re privy to so far, seem to have a very comparable response rate, overall response rate, as well as major response rate. We know that these 2 drugs are active based on the data that we’ve seen so far. Whether or not a head-to-head trial is going to show superiority for 1 over the other remains to be seen. But at least what we know of so far shows that zanubrutinib is likely to be a very promising new agent for Waldenström, akin to what we’ve seen with ibrutinib.

At ASCO 2018 [the American Society of Clinical Oncology Annual Meeting], Dr Roger Owen presented data on the use of acalabrutinib. This was a trial in both treatment-naïve as well as previously treated patients with Waldenström. We saw an overall response rate of about 90% and just shy of 80% of patients achieved a major response. And this is a very exciting study because it also showed us that many of the patients attained very good partial responses reflecting the fact, particularly with ongoing therapy, that deeper responses could be attained.
Now the study included both treatment-naïve and previously treated patients. The follow-up is much longer in the previously treated patients, wherein these deeper VGPRs [very good partial responses] were observed. So it’s exciting to know that akin to our experiences with the other BTK inhibitors, with more time the responses deepen. And that’s actually a good thing for patients.

Transcript Edited for Clarity
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