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MCL: Differences in Trial Design Between BTK Inhibitors

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 13, 2019



Transcript: 

Bijal D. Shah, MD: Acalabrutinib was studied in a nonrandomized phase II trial of relapsed mantle cell lymphoma. It was studied as monotherapy. It appears to be quite effective. The long-term follow-up data are being presented at this meeting. What we’re seeing are very durable responses. The challenge in interpreting the data is understanding how these patients we enrolled compared with those who were treated on the original frontline ibrutinib trial. Where are they in terms of lines of therapy, again coming back to that question. We know from the original mantle cell lymphoma trial, the median number of lines was 3, on the acalabrutinib it was 2. Is that really what’s driving the higher complete remission rate?

Is that what’s really driving the durability of response that we’re seeing relative to what was seen on the ibrutinib trial? I’m not really sure. I don’t think we’re going to get a randomized trial comparing ibrutinib and acalabrutinib, but I’m not sure that’s the best thing to do either. I couldn’t count how many BTK presentations in terms of novel BTK inhibitors were being presented at this meeting. And if, really, a threshold is going to be a randomized trial against a preexisting BTK, I think we’re going to lose sight of what we’re doing here. I think the real question then becomes, “How do we differentiate the 2 agents?” And I’m not sure yet. It’s something that we’re trying to get a feel for.

The design of the acalabrutinib trial was very similar to the design of the ibrutinib trial. And that was purposeful. We wanted to get a sense of what this agent was going to do in relapsed/refractory mantle cell lymphoma. What differed was that we knew the benefit and the toxicity of ibrutinib prior to starting the acalabrutinib trial. It was an FDA-approved agent, and so we were familiar with the bruisability, we were familiar with some of the severe bleeding events that were seen with ibrutinib, and we were familiar with its efficacy.

So if you’re a treating oncologist and you’re excited about BTK inhibitors in mantle cell lymphoma, guess what, you’re going to get your patient on that acalabrutinib trial. You’re going to get them on earlier in terms of their lines of therapy. And if someone is really requiring a lot in the way of anticoagulation, you’re going to be a little bit more nervous about putting them on the acalabrutinib trial, recognizing what you saw in the ibrutinib trial. If you have that patient who already has a preexisting atrial dysrhythmia, let’s think about this. Maybe this isn’t the best option. Maybe I take you down a bendamustine- or a Revlimid- or a lenalidomide-based approach to better control your disease. And so I think these are nuances that are hard to appreciate as investigators are putting their patients on trial.

Lauren C. Pinter-Brown, MD: Patients had to have progressive disease to go on the initial ibrutinib trial or less than a partial response, the usual organ parameters. There was not, in the initial trial that I know of, an exclusion for different cardiac conditions initially, and that may be different from other trials.

The trial design for acalabrutinib excludes patients with cardiac conditions specifically, as I remember—MIs [myocardial infarctions], uncontrolled or symptomatic arrhythmias in the prior 6 months, coronary artery disease—and excluded patients who were on warfarin. Patients who had failed up to 5 prior treatments. And so the design of the trial was maybe slightly different, knowing more about the toxicities of BTK inhibitors than previous drug trials.

Transcript Edited for Clarity
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Transcript: 

Bijal D. Shah, MD: Acalabrutinib was studied in a nonrandomized phase II trial of relapsed mantle cell lymphoma. It was studied as monotherapy. It appears to be quite effective. The long-term follow-up data are being presented at this meeting. What we’re seeing are very durable responses. The challenge in interpreting the data is understanding how these patients we enrolled compared with those who were treated on the original frontline ibrutinib trial. Where are they in terms of lines of therapy, again coming back to that question. We know from the original mantle cell lymphoma trial, the median number of lines was 3, on the acalabrutinib it was 2. Is that really what’s driving the higher complete remission rate?

Is that what’s really driving the durability of response that we’re seeing relative to what was seen on the ibrutinib trial? I’m not really sure. I don’t think we’re going to get a randomized trial comparing ibrutinib and acalabrutinib, but I’m not sure that’s the best thing to do either. I couldn’t count how many BTK presentations in terms of novel BTK inhibitors were being presented at this meeting. And if, really, a threshold is going to be a randomized trial against a preexisting BTK, I think we’re going to lose sight of what we’re doing here. I think the real question then becomes, “How do we differentiate the 2 agents?” And I’m not sure yet. It’s something that we’re trying to get a feel for.

The design of the acalabrutinib trial was very similar to the design of the ibrutinib trial. And that was purposeful. We wanted to get a sense of what this agent was going to do in relapsed/refractory mantle cell lymphoma. What differed was that we knew the benefit and the toxicity of ibrutinib prior to starting the acalabrutinib trial. It was an FDA-approved agent, and so we were familiar with the bruisability, we were familiar with some of the severe bleeding events that were seen with ibrutinib, and we were familiar with its efficacy.

So if you’re a treating oncologist and you’re excited about BTK inhibitors in mantle cell lymphoma, guess what, you’re going to get your patient on that acalabrutinib trial. You’re going to get them on earlier in terms of their lines of therapy. And if someone is really requiring a lot in the way of anticoagulation, you’re going to be a little bit more nervous about putting them on the acalabrutinib trial, recognizing what you saw in the ibrutinib trial. If you have that patient who already has a preexisting atrial dysrhythmia, let’s think about this. Maybe this isn’t the best option. Maybe I take you down a bendamustine- or a Revlimid- or a lenalidomide-based approach to better control your disease. And so I think these are nuances that are hard to appreciate as investigators are putting their patients on trial.

Lauren C. Pinter-Brown, MD: Patients had to have progressive disease to go on the initial ibrutinib trial or less than a partial response, the usual organ parameters. There was not, in the initial trial that I know of, an exclusion for different cardiac conditions initially, and that may be different from other trials.

The trial design for acalabrutinib excludes patients with cardiac conditions specifically, as I remember—MIs [myocardial infarctions], uncontrolled or symptomatic arrhythmias in the prior 6 months, coronary artery disease—and excluded patients who were on warfarin. Patients who had failed up to 5 prior treatments. And so the design of the trial was maybe slightly different, knowing more about the toxicities of BTK inhibitors than previous drug trials.

Transcript Edited for Clarity
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