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BTK Combination Strategies for B-Cell Malignancies

Insights From: Brad S. Kahl, MD, Washington University School of Medicine; Steven P. Treon, MD, PhD, Harvard Medical School
Published: Wednesday, Apr 03, 2019



Transcript: 

Steven P. Treon, MD, PhD: We’re very excited now that we know that BTK [Bruton tyrosine kinase] inhibitors have a very important place in the treatment of Waldenström macroglobulinemia and, more importantly, that this is supported by the underlying genomics—knowing that the mutated MYD88 gene can actually transactivate through its protein production. Ibrutinib’s tyrosine kinase makes this spot on when one thinks about the disease itself.

So being able to optimize BTK inhibitors is really the challenge. There are a number of areas that we’re very interested in pursuing. One is the combination with CXCR4 inhibitors. We’re currently looking at the ulocuplumab monoclonal antibody that binds to the CXCR4 receptor and prevents its ligand, SDF1, or CXCL12 from engaging it.

This is actually a very important trial because this is the way we hope to optimize the use of BTK inhibitors in CXCR4-mutated Waldenström macroglobulinemia patients. That’s about 40% of all patients, so it’s a very, very large number. It’s particularly those patients who carry the nonsense mutations, where the drug shows lower responses, deep responses, and shows a longer time to obtaining a major response. So the use of CXCR4 antagonists represents a very nice and innovative way to be able to optimize BTK therapy in patients who are CXCR4 mutated.

The other is targeting BCL2. We were among the first to publish data that actually looked at the synergy that can be conferred when you use a drug like venetoclax that targets BCL2 in combination with ibrutinib. This is actually a very important point, because venetoclax is very active in the treatment of Waldenström macroglobulinemia. We know from the data that we presented that patients, regardless of prior exposure to ibrutinib or their CXCR4 mutation status, can obtain responses to venetoclax. So being able to combine venetoclax with ibrutinib is also a very important step forward, and a trial looking at this combination is planned for the first quarter of 2019.

Brad S. Kahl, MD: I think a really interesting question for BTK inhibition in CLL [chronic lymphocytic leukemia] is whether the addition of an anti-CD20 monoclonal antibody adds efficacy—either rituximab or obinutuzumab. There was just an FDA approval for ibrutinib combined with obinutuzumab in frontline CLL just last week. Looking at the data closely, across trials it’s not obvious to me that the anti-CD20 therapy, in this case the obinutuzumab, is really adding to the efficacy of what you can get with ibrutinib alone. So I think we need additional studies to help us tease out whether you need to add anti-CD20 therapy to your BTK inhibitor in CLL. I think that’s an unknown right now.

As far as other rational combinations, I think 1 of the most interesting combinations right now is the idea of combining a BTK inhibitor with venetoclax. Venetoclax is an oral small-molecule BCL2 inhibitor. It now has an approval in CLL. It’s very active in CLL. It’s active in other lymphoid malignancies. It’s quite active in mantle cell lymphoma, and it just received approval in elderly AML [acute myeloid leukemia]. It has activity across a variety of hematologic malignancies. We know that if you can knock BCL2 down inside cancer cells, those cells just become easier to kill. So venetoclax is a really attractive drug for combination therapies. There are now published reports of the combination of venetoclax with ibrutinib in relapsed mantle cell lymphoma, for example. We see very high complete response rates—much higher than you would see with either agent alone.

I think you’re going to start to see a lot of combination data in CLL. Some of this has been presented at meetings. BTK inhibitors like ibrutinib in combination with venetoclax—we don’t have anything yet in publication, but over the next year to 18 months I think we’ll see a lot of data related to combining BTK inhibitors with BCL2 inhibitors. The real goal here is to come up with strategies that allow us to give patients time-limited therapies. It’s 1 of the less desirable traits of BTK inhibitors. Patients are required to be on therapy chronically, and that can be years and years and years.

We would love it if we had therapies that patients could take for a shorter duration—6 months, 12 months, or even 24 months—but then stop, so that patients could enjoy nice, long treatment-free intervals and be free from all adverse effects of treatment. That’s really the next frontier in CLL therapy. I think you’re going to see a lot of combination studies with a goal of establishing the efficacy of time-limited therapies so patients can get therapeutic breaks, which would be good for quality-of-life reasons.

Transcript Edited for Clarity
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Transcript: 

Steven P. Treon, MD, PhD: We’re very excited now that we know that BTK [Bruton tyrosine kinase] inhibitors have a very important place in the treatment of Waldenström macroglobulinemia and, more importantly, that this is supported by the underlying genomics—knowing that the mutated MYD88 gene can actually transactivate through its protein production. Ibrutinib’s tyrosine kinase makes this spot on when one thinks about the disease itself.

So being able to optimize BTK inhibitors is really the challenge. There are a number of areas that we’re very interested in pursuing. One is the combination with CXCR4 inhibitors. We’re currently looking at the ulocuplumab monoclonal antibody that binds to the CXCR4 receptor and prevents its ligand, SDF1, or CXCL12 from engaging it.

This is actually a very important trial because this is the way we hope to optimize the use of BTK inhibitors in CXCR4-mutated Waldenström macroglobulinemia patients. That’s about 40% of all patients, so it’s a very, very large number. It’s particularly those patients who carry the nonsense mutations, where the drug shows lower responses, deep responses, and shows a longer time to obtaining a major response. So the use of CXCR4 antagonists represents a very nice and innovative way to be able to optimize BTK therapy in patients who are CXCR4 mutated.

The other is targeting BCL2. We were among the first to publish data that actually looked at the synergy that can be conferred when you use a drug like venetoclax that targets BCL2 in combination with ibrutinib. This is actually a very important point, because venetoclax is very active in the treatment of Waldenström macroglobulinemia. We know from the data that we presented that patients, regardless of prior exposure to ibrutinib or their CXCR4 mutation status, can obtain responses to venetoclax. So being able to combine venetoclax with ibrutinib is also a very important step forward, and a trial looking at this combination is planned for the first quarter of 2019.

Brad S. Kahl, MD: I think a really interesting question for BTK inhibition in CLL [chronic lymphocytic leukemia] is whether the addition of an anti-CD20 monoclonal antibody adds efficacy—either rituximab or obinutuzumab. There was just an FDA approval for ibrutinib combined with obinutuzumab in frontline CLL just last week. Looking at the data closely, across trials it’s not obvious to me that the anti-CD20 therapy, in this case the obinutuzumab, is really adding to the efficacy of what you can get with ibrutinib alone. So I think we need additional studies to help us tease out whether you need to add anti-CD20 therapy to your BTK inhibitor in CLL. I think that’s an unknown right now.

As far as other rational combinations, I think 1 of the most interesting combinations right now is the idea of combining a BTK inhibitor with venetoclax. Venetoclax is an oral small-molecule BCL2 inhibitor. It now has an approval in CLL. It’s very active in CLL. It’s active in other lymphoid malignancies. It’s quite active in mantle cell lymphoma, and it just received approval in elderly AML [acute myeloid leukemia]. It has activity across a variety of hematologic malignancies. We know that if you can knock BCL2 down inside cancer cells, those cells just become easier to kill. So venetoclax is a really attractive drug for combination therapies. There are now published reports of the combination of venetoclax with ibrutinib in relapsed mantle cell lymphoma, for example. We see very high complete response rates—much higher than you would see with either agent alone.

I think you’re going to start to see a lot of combination data in CLL. Some of this has been presented at meetings. BTK inhibitors like ibrutinib in combination with venetoclax—we don’t have anything yet in publication, but over the next year to 18 months I think we’ll see a lot of data related to combining BTK inhibitors with BCL2 inhibitors. The real goal here is to come up with strategies that allow us to give patients time-limited therapies. It’s 1 of the less desirable traits of BTK inhibitors. Patients are required to be on therapy chronically, and that can be years and years and years.

We would love it if we had therapies that patients could take for a shorter duration—6 months, 12 months, or even 24 months—but then stop, so that patients could enjoy nice, long treatment-free intervals and be free from all adverse effects of treatment. That’s really the next frontier in CLL therapy. I think you’re going to see a lot of combination studies with a goal of establishing the efficacy of time-limited therapies so patients can get therapeutic breaks, which would be good for quality-of-life reasons.

Transcript Edited for Clarity
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