ONCAlert | Upfront Therapy for mRCC

BTK Inhibitors in Other B-cell Lymphomas

Targeted Oncology
Published Online:12:24 PM, Fri July 12, 2019

Harry P. Erba, MD, PhD: How about some of the other, more indolent B-cell lymphomas—marginal zone lymphoma, Waldenström? Any data there with the BTKis [Bruton tyrosine kinase inhibitors]?

Anthony R. Mato, MD, MSCE: There’s approval for ibrutinib, both in marginal zone lymphoma and Waldenström macroglobulinemia. This has been, for these rare diseases, or these sort of orphan diseases that are very infrequently studied relative to the other B-cell malignancies, a paradigm shift. Patients with Waldenström, for example, who are MYD88-mutated and don’t have a WHIM [warts, hypogammaglobulinemia, infections and myelokathexis]-like mutation are very sensitive to ibrutinib and can do incredibly well. They can do much better than one would have expected from standard chemotherapy plus or minus anti-CD20 antibodies. The same is true for marginal zone lymphoma, which there are very few drugs that are actually indicated or approved for treating.

Harry P. Erba, MD, PhD: Were those approvals in those rarer subtypes based on randomized data, or just activity in subsets?

Anthony R. Mato, MD, MSCE: Activity.

Harry P. Erba, MD, PhD: That’s important. It’s very hard to do those randomized trials in small subsets of patients.

Anthony R. Mato, MD, MSCE: Correct.

Harry P. Erba, MD, PhD: How about the other BTK inhibitors, like acalabrutinib or zanubrutinib? Anything in Waldenström?

Anthony R. Mato, MD, MSCE: There are head-to-head comparisons underway in indolent lymphomas as well. For example, zanubrutinib is being compared head-to-head to ibrutinib. This is sort of an ambitious trial that we’ll be really eager to see the results of.

Harry P. Erba, MD, PhD: How about in somewhat more aggressive lymphomas, like diffuse large B-cell lymphoma [DLBCL]? Any data there?

Anthony R. Mato, MD, MSCE: These drugs, particularly ibrutinib, have been studied as single agents. They are not very impressive, but there may be a signal that there’s activity in the ABC [activated B-cell] subtype versus the GCB [germinal center B-cell] subtype of DLBCL. That’s led to trials examining a standard of care chemoimmunotherapy backbone, R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] plus ibrutinib, specifically with a focus on the ABC subtype. The primary endpoints of the trial were reported and not met. It may be that DLBCL is a lot more complicated than we thought. It’s probably not just the simple Hans criteria by immunohistochemistry breaking down subgroups. Maybe it’s 5 subgroups or more, based on more modern molecular methods. And so we may need to refocus. But at this point, in the primary registrational trial, the endpoint was not met.

And so, even in the ABCs, across the board, ibrutinib didn’t add in terms of progression-free survival [PFS]. That may be due to the fact that, for example, in younger patients, the AE [adverse event] profile of ibrutinib plus R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] is OK. Patients could tolerate it to get to the point where PFS and EFS [event-free survival] were improved. That was the case in subgroup analyses. Whereas, in older patients, that was not the case. But unfortunately, when you design your trial, the primary endpoint is what it is and retrospectively you can’t then decide, “Hey, this subgroup did better.” Somebody said at a meeting recently, and I think this is true, if 1 subgroup did better and the end point is a wash, then somebody had to do worse in order for those curves to be balanced. And so I think we need to keep that in our minds.

Harry P. Erba, MD, PhD: We have to be very careful about making large conclusions from subset analyses. Even though there may be some scientific basis for thinking so, I get why that has to make you a bit timid about doing it.

Ibrutinib and R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone], that study didn’t meet its primary endpoint. How about acalabrutinib? Is that being added to rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone?

Anthony R. Mato, MD, MSCE: I actually don’t know the answer to that question if there’s an acalabrutinib/rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone study. Certainly, the BTK inhibitors are being added, for example, in mantle cell lymphoma to bendamustine/rituximab, but we don’t have those results back either. So I think you have to ask yourself the question: Is the treatment paradigm always going to be that chemoimmunotherapy has to be the backbone to move forward? I think we’re learning, at least from the CLL [chronic lymphocytic leukemia] experience, probably not in the relapsed/refractory setting, that chemotherapy backbones did nothing to enhance the activity of these targeted agents. Maybe that will be the case in lymphomas as well, where we really need to think outside the box in terms of pathway inhibition and not necessarily just throw something on top of a backbone in order to do better.

Harry P. Erba, MD, PhD: And moving past that, how about lymphoblastic lymphomas, Burkitt lymphoma? Is there any reason to suspect that BTK inhibition may be helpful?

Anthony R. Mato, MD, MSCE: I personally haven’t seen a lot of data, positive or negative, reported in the highly aggressive B-cell lymphomas. Certainly, not in the near future, there is no change in the standard of care with the addition of those drugs.

Transcript edited for clarity.

Harry P. Erba, MD, PhD: How about some of the other, more indolent B-cell lymphomas—marginal zone lymphoma, Waldenström? Any data there with the BTKis [Bruton tyrosine kinase inhibitors]?

Anthony R. Mato, MD, MSCE: There’s approval for ibrutinib, both in marginal zone lymphoma and Waldenström macroglobulinemia. This has been, for these rare diseases, or these sort of orphan diseases that are very infrequently studied relative to the other B-cell malignancies, a paradigm shift. Patients with Waldenström, for example, who are MYD88-mutated and don’t have a WHIM [warts, hypogammaglobulinemia, infections and myelokathexis]-like mutation are very sensitive to ibrutinib and can do incredibly well. They can do much better than one would have expected from standard chemotherapy plus or minus anti-CD20 antibodies. The same is true for marginal zone lymphoma, which there are very few drugs that are actually indicated or approved for treating.

Harry P. Erba, MD, PhD: Were those approvals in those rarer subtypes based on randomized data, or just activity in subsets?

Anthony R. Mato, MD, MSCE: Activity.

Harry P. Erba, MD, PhD: That’s important. It’s very hard to do those randomized trials in small subsets of patients.

Anthony R. Mato, MD, MSCE: Correct.

Harry P. Erba, MD, PhD: How about the other BTK inhibitors, like acalabrutinib or zanubrutinib? Anything in Waldenström?

Anthony R. Mato, MD, MSCE: There are head-to-head comparisons underway in indolent lymphomas as well. For example, zanubrutinib is being compared head-to-head to ibrutinib. This is sort of an ambitious trial that we’ll be really eager to see the results of.

Harry P. Erba, MD, PhD: How about in somewhat more aggressive lymphomas, like diffuse large B-cell lymphoma [DLBCL]? Any data there?

Anthony R. Mato, MD, MSCE: These drugs, particularly ibrutinib, have been studied as single agents. They are not very impressive, but there may be a signal that there’s activity in the ABC [activated B-cell] subtype versus the GCB [germinal center B-cell] subtype of DLBCL. That’s led to trials examining a standard of care chemoimmunotherapy backbone, R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] plus ibrutinib, specifically with a focus on the ABC subtype. The primary endpoints of the trial were reported and not met. It may be that DLBCL is a lot more complicated than we thought. It’s probably not just the simple Hans criteria by immunohistochemistry breaking down subgroups. Maybe it’s 5 subgroups or more, based on more modern molecular methods. And so we may need to refocus. But at this point, in the primary registrational trial, the endpoint was not met.

And so, even in the ABCs, across the board, ibrutinib didn’t add in terms of progression-free survival [PFS]. That may be due to the fact that, for example, in younger patients, the AE [adverse event] profile of ibrutinib plus R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] is OK. Patients could tolerate it to get to the point where PFS and EFS [event-free survival] were improved. That was the case in subgroup analyses. Whereas, in older patients, that was not the case. But unfortunately, when you design your trial, the primary endpoint is what it is and retrospectively you can’t then decide, “Hey, this subgroup did better.” Somebody said at a meeting recently, and I think this is true, if 1 subgroup did better and the end point is a wash, then somebody had to do worse in order for those curves to be balanced. And so I think we need to keep that in our minds.

Harry P. Erba, MD, PhD: We have to be very careful about making large conclusions from subset analyses. Even though there may be some scientific basis for thinking so, I get why that has to make you a bit timid about doing it.

Ibrutinib and R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone], that study didn’t meet its primary endpoint. How about acalabrutinib? Is that being added to rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone?

Anthony R. Mato, MD, MSCE: I actually don’t know the answer to that question if there’s an acalabrutinib/rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone study. Certainly, the BTK inhibitors are being added, for example, in mantle cell lymphoma to bendamustine/rituximab, but we don’t have those results back either. So I think you have to ask yourself the question: Is the treatment paradigm always going to be that chemoimmunotherapy has to be the backbone to move forward? I think we’re learning, at least from the CLL [chronic lymphocytic leukemia] experience, probably not in the relapsed/refractory setting, that chemotherapy backbones did nothing to enhance the activity of these targeted agents. Maybe that will be the case in lymphomas as well, where we really need to think outside the box in terms of pathway inhibition and not necessarily just throw something on top of a backbone in order to do better.

Harry P. Erba, MD, PhD: And moving past that, how about lymphoblastic lymphomas, Burkitt lymphoma? Is there any reason to suspect that BTK inhibition may be helpful?

Anthony R. Mato, MD, MSCE: I personally haven’t seen a lot of data, positive or negative, reported in the highly aggressive B-cell lymphomas. Certainly, not in the near future, there is no change in the standard of care with the addition of those drugs.

Transcript edited for clarity.
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