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MCL: Novel BTK Inhibitor Combination Strategies

Insights From: Bijal D. Shah, MD, H. Lee Moffitt Cancer Center & Research Institute; Lauren C. Pinter-Brown, MD, UCI Health; Eduardo Sotomayor, MD, GW Cancer Center
Published: Wednesday, Feb 20, 2019



Transcript:

Bijal D. Shah, MD:
There have been several clinical trials designed over the past couple of years, looking at novel combinations with ibrutinib: ibrutinib/rituximab, ibrutinib/Revlimid/rituximab, ibrutinib/venetoclax, ibrutinib/rituximab followed by high-dose chemotherapy, and so on. I think at best what I can say is the data are largely preliminary. I think right now there’s a lot of interest in understanding how the ibrutinib/venetoclax approach will fare out in a randomized trial, and I suspect it will improve PFS [progression-free survival]. The big question is by how much and for what subgroups of patients. Are we going to be really addressing the noncanonical NF-kappa-B mutations in mantle cell lymphoma [MCL]? It seemed that as a risk factor was less important when we brought in the venetoclax. But are there other subgroups of patients that were going to benefit that otherwise would have seen worse outcomes? Only time will tell.

Eduardo Sotomayor, MD: Regarding the question of ibrutinib frontline therapy, I am optimistic about seeing, at some point, ibrutinib becoming the backbone of the treatment for all patients with mantle cell lymphoma. We are going to get there. So we are seeing the impact. Again, in chronic lymphocytic leukemia [CLL], we are all excited about presentations in this ASH [American Society of Hematology] meeting about ibrutinib being better than chemoimmunotherapy that we currently have for CLL frontline. Are we going to see the same in mantle cell lymphoma? I am very hopeful that is going to be the case, but the clinical trial needs to show that.

                There is a clinical trial that was completed to accrual of ibrutinib plus bendamustine/rituximab versus bendamustine/rituximab. That has been completed, so we are waiting for the data to be presented or published. There is interest also in combining ibrutinib with other chemoimmunotherapy as a frontline. But, to me, one of the most exciting combinations that we’re going to see in mantle cell lymphoma is the combination of ibrutinib with a BCL2 inhibitor, venetoclax. Significant activity in relapsed setting, ibrutinib/venetoclax. As we move into the frontline setting, first in patients with de novo mantle cell lymphoma, we might see a second major change in that landscape for how we treat mantle cell lymphoma.

                There is going to be a role in terms of combination in frontline therapy. So we are awaiting the data of a clinical trial in which ibrutinib was added to bendamustine/rituximab versus bendamustine/rituximab alone. So we are waiting for that. Also, I think there is interest to know what the value will be of adding ibrutinib to R-CHOP [Rituxan + cyclophosphamide, doxorubicin, vincristine, and prednisone] in mantle cell lymphoma. We are disappointed that the combination, although in a different disease, didn’t work well in large cell lymphoma. Ibrutinib plus R-CHOP didn’t add much. Is that going to be the case in mantle cell lymphoma, that remains to be seen.

Lauren C. Pinter-Brown, MD: What I’m looking at are more data regarding the combination of ibrutinib and venetoclax, or the sequencing of those drugs, with or without a CD20-directed antibody. There have been reports that MRD [minimal residual disease] can be achieved with that combination, and that may allow us to have limited amounts of therapy, which is really the downside of current therapies at the present time: They’re continuous.

Transcript edited for clarity.
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Transcript:

Bijal D. Shah, MD:
There have been several clinical trials designed over the past couple of years, looking at novel combinations with ibrutinib: ibrutinib/rituximab, ibrutinib/Revlimid/rituximab, ibrutinib/venetoclax, ibrutinib/rituximab followed by high-dose chemotherapy, and so on. I think at best what I can say is the data are largely preliminary. I think right now there’s a lot of interest in understanding how the ibrutinib/venetoclax approach will fare out in a randomized trial, and I suspect it will improve PFS [progression-free survival]. The big question is by how much and for what subgroups of patients. Are we going to be really addressing the noncanonical NF-kappa-B mutations in mantle cell lymphoma [MCL]? It seemed that as a risk factor was less important when we brought in the venetoclax. But are there other subgroups of patients that were going to benefit that otherwise would have seen worse outcomes? Only time will tell.

Eduardo Sotomayor, MD: Regarding the question of ibrutinib frontline therapy, I am optimistic about seeing, at some point, ibrutinib becoming the backbone of the treatment for all patients with mantle cell lymphoma. We are going to get there. So we are seeing the impact. Again, in chronic lymphocytic leukemia [CLL], we are all excited about presentations in this ASH [American Society of Hematology] meeting about ibrutinib being better than chemoimmunotherapy that we currently have for CLL frontline. Are we going to see the same in mantle cell lymphoma? I am very hopeful that is going to be the case, but the clinical trial needs to show that.

                There is a clinical trial that was completed to accrual of ibrutinib plus bendamustine/rituximab versus bendamustine/rituximab. That has been completed, so we are waiting for the data to be presented or published. There is interest also in combining ibrutinib with other chemoimmunotherapy as a frontline. But, to me, one of the most exciting combinations that we’re going to see in mantle cell lymphoma is the combination of ibrutinib with a BCL2 inhibitor, venetoclax. Significant activity in relapsed setting, ibrutinib/venetoclax. As we move into the frontline setting, first in patients with de novo mantle cell lymphoma, we might see a second major change in that landscape for how we treat mantle cell lymphoma.

                There is going to be a role in terms of combination in frontline therapy. So we are awaiting the data of a clinical trial in which ibrutinib was added to bendamustine/rituximab versus bendamustine/rituximab alone. So we are waiting for that. Also, I think there is interest to know what the value will be of adding ibrutinib to R-CHOP [Rituxan + cyclophosphamide, doxorubicin, vincristine, and prednisone] in mantle cell lymphoma. We are disappointed that the combination, although in a different disease, didn’t work well in large cell lymphoma. Ibrutinib plus R-CHOP didn’t add much. Is that going to be the case in mantle cell lymphoma, that remains to be seen.

Lauren C. Pinter-Brown, MD: What I’m looking at are more data regarding the combination of ibrutinib and venetoclax, or the sequencing of those drugs, with or without a CD20-directed antibody. There have been reports that MRD [minimal residual disease] can be achieved with that combination, and that may allow us to have limited amounts of therapy, which is really the downside of current therapies at the present time: They’re continuous.

Transcript edited for clarity.
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