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Ask the Expert: How Have BTK Inhibitors Impacted MCL Treatment?

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Published on May 6, 2021

The Impact of BTK Inhibitors on Mantle Cell Lymphoma Treatment

Follow along as Dr. Peter Martin, MD, Associate Professor of Medicine and Chief of the Lymphoma Program at Weill Cornell Medicine, explains the importance of BTK inhibitors in the treatment of mantle cell lymphoma, what the current FDA approved options are, and the findings of ongoing studies focusing on BTK inhibitors in combination with other treatment drugs.

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Transcript | Ask the Expert: How Have BTK Inhibitors Impacted MCL Treatment?

Peter Martin: Hi. I'm Peter Martin from Weill Cornell Medicine in New York City. I was asked to talk a little bit about BTK inhibitors and their role in mantle cell lymphoma. Beginning in, actually I think it was November of 2013, the first BTK inhibitor ibrutinib (Imbruvica) was approved. That was really a record setting pace for drug approval, considering that it had only entered clinical trials in 2009 and since then, we really haven't looked back. In the subsequent years, two additional BTK inhibitors were approved in the same space as ibrutinib had been approved. Namely, these were for people who had previously treated mantle cell lymphoma. And I can tell you, I've told the story many times, that in some of the early clinical trials we saw people who were clearly headed in one direction and the treatment with the BTK inhibitor turned their life around completely.

What Do We Know About BTK Inhibitors for Mantle Cell Lymphoma?

I think there is still, however, room for improvement. One thing that's become clear is that there are some people with mantle cell lymphoma who do remarkably well with BTK inhibitors. I can think of several of our patients who have been on BTK inhibitors for, now actually, close to a decade, which is great, but the majority of people with mantle cell lymphoma are going to respond for a shorter period of time, typically in the one-to-two-year range. So, we think about why it is that those responses might be shorter than optimal. And what are the things that we could do to improve those treatment outcomes. And options really are, one: come up with a better BTK inhibitor. Now, some people have argued that acalabrutinib (Calquence) and zanubrutinib (Brukinsa) may be better. We don't have head-to-head data to say that that's necessarily true, although there are clearly different safety profiles or side effect profiles between the medications.

There are other BTK inhibitors in development, and we look forward to seeing where those land. Another scenario is we optimize the BTK inhibitor population of patients. So, rather than using it later on, potentially using it earlier makes them seem to work better and that's not really surprising. But we've seen data that when we use BTK inhibitors in the second-line setting, instead of the third or fourth-line setting may work better. And so, we're seeing a number of clinical trials now use them even earlier on, including a clinical trial that we have at Cornell led by Dr. Ruan with the acalabrutinib, lenalidomide (Revlimid) and rituximab (Rituxan).

Are BTK Inhibitors Combined With Other Drugs for the Treatment of MCL?

And these data are also demonstrating activity that I think is promising. And then lastly, we look at combinations. So, combinations of BTK inhibitors with other drugs also have the potential to improve on the efficacy of BTK inhibitors.

Specifically, I think of combinations with venetoclax (Venclexta), which are really all over the country and all over the world. As well, we've seen combinations with rituximab, with lenalidomide as I mentioned, with proteasome inhibitors. At Cornell and Ohio State, and other institutions we have a trial with a combination of ibrutinib plus palbociclib (Ibrance), a CDK4 inhibitor. So, lots of room to grow, and I think what we're going to see is that this huge change that we saw from no BTK inhibitors to BTK inhibitors is going to continue as we learn how to use BTK inhibitors, better on it, who is most likely to benefit and who maybe should be selecting different kinds of therapies that are also in development, and maybe using BTK inhibitors for shorter periods of time or potentially even not at all. It's an interesting time. It's almost hard to keep up with how fast it's changing, but I think that's good for all of us.

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