ONCAlert | Upfront Therapy for mRCC

The Future of BTK Inhibition in B-Cell Lymphomas

Targeted Oncology
Published Online:12:56 PM, Wed July 31, 2019

Harry P. Erba, MD, PhD: So we have all of these new toys to play with, right? Inhibiting different pathways—BCL2, PI3 kinase, BTK [Bruton tyrosine kinase], immunotherapies, chemotherapies—what’s the future hold?

Anthony R. Mato, MD, MSCE: That’s a good question. I think that the future will largely be novel combinations of drugs for which we’re treating patients for fixed durations. I don’t want to say fixed duration, I want to say treating patients toward depth of response with an opportunity to discontinue these combinations. I think everybody wants to stop using these drugs, whether they’re given as monotherapies or given in combination. We want to do it intelligently. We don’t want to just treat and stop in everybody, but maybe treat based on biology, based on depth of response, or the interactions between the 2. I think that as we are able to combine them, and this is really the infancy of this field, we are seeing responses that are MRD [minimal residual disease] undetectable more and more frequently. Whether that translates to potential, we don’t know.

I think it’s almost irresponsible to say that at this point. All we can say is that some of these drugs, in combination, induce deeper responses. Whether that translates into something else is hard to know. And I think it’s wrong to translate the experience with mutated IGHV patients treated with FCR [fludarabine/cyclophosphamide/rituximab] who become MRD undetectable and say the same expectation is with combination therapy. But I think that’s where we’re going, and with longer term follow-up we’ll learn whether that’s the case.

Harry P. Erba, MD, PhD: Are there any preclinical data that might help guide which combinations might be most helpful?

Anthony R. Mato, MD, MSCE: There really haven’t been. There are certainly preclinical data, but the actual combinations that are being tested are drugs in combination that may be additive in their effect but not necessarily clearly synergistic. They may be more based on who owns what drug and how those could be combined. So I think there’s a lot of room to go, in terms of picking the right partners based on biology. I think that’s a big weakness right now.

Harry P. Erba, MD, PhD: And we’ve heard recently about data coming out from our colleagues in myeloma research with BCL2 inhibition. How about BTK in myeloma? Is there any role there?

Anthony R. Mato, MD, MSCE: I think they have been studied, although I’m not really that familiar with the data. Certainly, it hasn’t changed the standard of care yet.

Harry P. Erba, MD, PhD: Let me ask you about a serious complication of CLL [chronic lymphocytic leukemia], and that’s progression to a Richter transformation. Any pearls of wisdom there? BTK inhibition alone or with chemotherapy? Does it have any role? Immunotherapies?

Anthony R. Mato, MD, MSCE: All being studied. I think a lot of it has to do with whether a patient had a BTK inhibitor as part of their CLL therapy. The data from several groups suggest that the median survival for Richter that evolves out of a BTK inhibitor is somewhere between 3 and 7 months.

So it’s a life-threatening situation. It’s probably the biggest unmet need in all of CLL right now. There have been combinations with targeted agents, with checkpoint inhibitors. Data presented at ASH [American Society of Hematology] looked at ibrutinib plus nivolumab. It looked exciting, but really the activity was in the BTK-naïve patients. Anthracycline-based chemoimmunotherapy backbones are being combined with acalabrutinib or ibrutinib or venetoclax, and this looks to be interesting but it is hard to know. The standard of care right now is still R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] chemotherapy for patients. Clonally unrelated patients do OK. Clonally related patients don’t do so well. I think the checkpoint inhibitors are exciting but not by themselves, probably in combination. We study them with a PI3K inhibitor. This also looks exciting, but is still a single-arm trial.

Harry P. Erba, MD, PhD: We do have a lot of new agents and a lot of pathways to target, but you must be seeing patients for whom none of these agents are working any more. Do you fall back on chemoimmunotherapy? Is that still a viable option?

Anthony R. Mato, MD, MSCE: We sometimes do, but it’s not studied. And so, there’s very little information for cases if you start off on a chemotherapy-free pathway, or a targeted pathway, and you’ve gone through ibrutinib, idelalisib, venetoclax. No one knows what to do. We’re studying that actively now. We’ve developed a consortium, depending on the study, of between 20 and 40 centers who combine their data to try to answer these questions. But questions remain: How to treat a venetoclax progressor who failed other therapies, and is there a role for a BTK inhibitor in a venetoclax failure for which the patient is BTK naïve? All unknown, and unstudied at this time.

Harry P. Erba, MD, PhD: Not long ago, for patients with CLL who had high-risk disease, 17p deletion, or had progressed after 1 or 2 cycles and were young and otherwise healthy, you would start thinking about allogeneic transplant. Is there still a role for allotransplant? And in which patients are you considering that?

Anthony R. Mato, MD, MSCE: That’s a great question. It’s unknown, and if you look at the data from the transplant registries, the number of transplants done in CLL has dropped so dramatically over the last several years that they can’t even answer that question. We’ve actually proposed that question as a formal study, and the answers we got were that there were just not enough patients available to answer that question. Whether having a BTK inhibitor or one of these other drugs on board alters the outcome of the transplant is unknown. The EBMT [European Society for Blood and Marrow Transplantation] have criteria that suggest that if you’re responding to your first targeted agent, even if you have a risk feature, you probably should not transplant.

If you’re on your second targeted agent, you can think about it more for those patients. So those are the kinds of patients that we think about, even identifying potential donors for us. But then competing with the allotransplant is the advent of cellular therapies and whether or not CAR-T [chimeric antigen receptor T-cell therapy] should come before an allotransplant, or whether they should be approved for CLL. There are some registrational trials that are ongoing right now. So, it’s unknown. We’re trying to gather that data ourselves to look at allotransplant in the novel agent era, but it’s not easy to do.

Harry P. Erba, MD, PhD: OK, last question, I promise.

Anthony R. Mato, MD, MSCE: OK.

Harry P. Erba, MD, PhD: You’re up for it? Mantle cell lymphoma. We are getting aggressive chemotherapy in autologous transplant, but as you said, most of these patients relapse. Is there any data on using BTK inhibition as a maintenance strategy after autotransplant in that disease or others?

Anthony R. Mato, MD, MSCE: To my knowledge, no.

Harry P. Erba, MD, PhD: Do you think it makes sense?

Anthony R. Mato, MD, MSCE: I think it may. Certainly, maintenance therapies in other hematologic malignancies, like myeloma, for example, have been well received in our standard of care on some level. I think that it does make sense biologically. Whether it’s been studied specifically as a post-transplant maintenance, I’m not aware. It’s possible that it already has and I just don’t know that data.

Harry P. Erba, MD, PhD: OK. I did promise that would be my last question. Thank you.

Anthony R. Mato, MD, MSCE: Thanks for having me.

Harry P. Erba, MD, PhD: Well, thank you Dr Mato. This has been an insightful discussion. And thank you to our audience for joining us for this Targeted Oncology presentation on precision medicine.

Transcript edited for clarity.

Harry P. Erba, MD, PhD: So we have all of these new toys to play with, right? Inhibiting different pathways—BCL2, PI3 kinase, BTK [Bruton tyrosine kinase], immunotherapies, chemotherapies—what’s the future hold?

Anthony R. Mato, MD, MSCE: That’s a good question. I think that the future will largely be novel combinations of drugs for which we’re treating patients for fixed durations. I don’t want to say fixed duration, I want to say treating patients toward depth of response with an opportunity to discontinue these combinations. I think everybody wants to stop using these drugs, whether they’re given as monotherapies or given in combination. We want to do it intelligently. We don’t want to just treat and stop in everybody, but maybe treat based on biology, based on depth of response, or the interactions between the 2. I think that as we are able to combine them, and this is really the infancy of this field, we are seeing responses that are MRD [minimal residual disease] undetectable more and more frequently. Whether that translates to potential, we don’t know.

I think it’s almost irresponsible to say that at this point. All we can say is that some of these drugs, in combination, induce deeper responses. Whether that translates into something else is hard to know. And I think it’s wrong to translate the experience with mutated IGHV patients treated with FCR [fludarabine/cyclophosphamide/rituximab] who become MRD undetectable and say the same expectation is with combination therapy. But I think that’s where we’re going, and with longer term follow-up we’ll learn whether that’s the case.

Harry P. Erba, MD, PhD: Are there any preclinical data that might help guide which combinations might be most helpful?

Anthony R. Mato, MD, MSCE: There really haven’t been. There are certainly preclinical data, but the actual combinations that are being tested are drugs in combination that may be additive in their effect but not necessarily clearly synergistic. They may be more based on who owns what drug and how those could be combined. So I think there’s a lot of room to go, in terms of picking the right partners based on biology. I think that’s a big weakness right now.

Harry P. Erba, MD, PhD: And we’ve heard recently about data coming out from our colleagues in myeloma research with BCL2 inhibition. How about BTK in myeloma? Is there any role there?

Anthony R. Mato, MD, MSCE: I think they have been studied, although I’m not really that familiar with the data. Certainly, it hasn’t changed the standard of care yet.

Harry P. Erba, MD, PhD: Let me ask you about a serious complication of CLL [chronic lymphocytic leukemia], and that’s progression to a Richter transformation. Any pearls of wisdom there? BTK inhibition alone or with chemotherapy? Does it have any role? Immunotherapies?

Anthony R. Mato, MD, MSCE: All being studied. I think a lot of it has to do with whether a patient had a BTK inhibitor as part of their CLL therapy. The data from several groups suggest that the median survival for Richter that evolves out of a BTK inhibitor is somewhere between 3 and 7 months.

So it’s a life-threatening situation. It’s probably the biggest unmet need in all of CLL right now. There have been combinations with targeted agents, with checkpoint inhibitors. Data presented at ASH [American Society of Hematology] looked at ibrutinib plus nivolumab. It looked exciting, but really the activity was in the BTK-naïve patients. Anthracycline-based chemoimmunotherapy backbones are being combined with acalabrutinib or ibrutinib or venetoclax, and this looks to be interesting but it is hard to know. The standard of care right now is still R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] chemotherapy for patients. Clonally unrelated patients do OK. Clonally related patients don’t do so well. I think the checkpoint inhibitors are exciting but not by themselves, probably in combination. We study them with a PI3K inhibitor. This also looks exciting, but is still a single-arm trial.

Harry P. Erba, MD, PhD: We do have a lot of new agents and a lot of pathways to target, but you must be seeing patients for whom none of these agents are working any more. Do you fall back on chemoimmunotherapy? Is that still a viable option?

Anthony R. Mato, MD, MSCE: We sometimes do, but it’s not studied. And so, there’s very little information for cases if you start off on a chemotherapy-free pathway, or a targeted pathway, and you’ve gone through ibrutinib, idelalisib, venetoclax. No one knows what to do. We’re studying that actively now. We’ve developed a consortium, depending on the study, of between 20 and 40 centers who combine their data to try to answer these questions. But questions remain: How to treat a venetoclax progressor who failed other therapies, and is there a role for a BTK inhibitor in a venetoclax failure for which the patient is BTK naïve? All unknown, and unstudied at this time.

Harry P. Erba, MD, PhD: Not long ago, for patients with CLL who had high-risk disease, 17p deletion, or had progressed after 1 or 2 cycles and were young and otherwise healthy, you would start thinking about allogeneic transplant. Is there still a role for allotransplant? And in which patients are you considering that?

Anthony R. Mato, MD, MSCE: That’s a great question. It’s unknown, and if you look at the data from the transplant registries, the number of transplants done in CLL has dropped so dramatically over the last several years that they can’t even answer that question. We’ve actually proposed that question as a formal study, and the answers we got were that there were just not enough patients available to answer that question. Whether having a BTK inhibitor or one of these other drugs on board alters the outcome of the transplant is unknown. The EBMT [European Society for Blood and Marrow Transplantation] have criteria that suggest that if you’re responding to your first targeted agent, even if you have a risk feature, you probably should not transplant.

If you’re on your second targeted agent, you can think about it more for those patients. So those are the kinds of patients that we think about, even identifying potential donors for us. But then competing with the allotransplant is the advent of cellular therapies and whether or not CAR-T [chimeric antigen receptor T-cell therapy] should come before an allotransplant, or whether they should be approved for CLL. There are some registrational trials that are ongoing right now. So, it’s unknown. We’re trying to gather that data ourselves to look at allotransplant in the novel agent era, but it’s not easy to do.

Harry P. Erba, MD, PhD: OK, last question, I promise.

Anthony R. Mato, MD, MSCE: OK.

Harry P. Erba, MD, PhD: You’re up for it? Mantle cell lymphoma. We are getting aggressive chemotherapy in autologous transplant, but as you said, most of these patients relapse. Is there any data on using BTK inhibition as a maintenance strategy after autotransplant in that disease or others?

Anthony R. Mato, MD, MSCE: To my knowledge, no.

Harry P. Erba, MD, PhD: Do you think it makes sense?

Anthony R. Mato, MD, MSCE: I think it may. Certainly, maintenance therapies in other hematologic malignancies, like myeloma, for example, have been well received in our standard of care on some level. I think that it does make sense biologically. Whether it’s been studied specifically as a post-transplant maintenance, I’m not aware. It’s possible that it already has and I just don’t know that data.

Harry P. Erba, MD, PhD: OK. I did promise that would be my last question. Thank you.

Anthony R. Mato, MD, MSCE: Thanks for having me.

Harry P. Erba, MD, PhD: Well, thank you Dr Mato. This has been an insightful discussion. And thank you to our audience for joining us for this Targeted Oncology presentation on precision medicine.

Transcript edited for clarity.
Copyright © TargetedOnc 2019 Intellisphere, LLC. All Rights Reserved.