Second-Line Therapy for MCL: Differentiating Available BTK Inhibitors


Moving to second-line therapy for mantle cell lymphoma, experts discuss available BTK inhibitors, including the novel agent pirtobrutinib.


Bijal D. Shah, MD, MS: One of the challenges you mentioned, Michael, was that mantle cell lymphoma is still an insidious disease. It comes back.

Michael Wang, MD: Yes.

Bijal D. Shah, MD, MS: As we think about how our therapies shape that outcome, I wonder is there a standard of care for relapsed mantle cell lymphoma? Ian, I’ll turn to you. We can talk about frontline and what we’re doing in the frontline setting as it relates to transplant, but do we know what to do for relapsed mantle cell?

Ian W. Flinn, MD, PhD: I think the most commonly used therapies are the BTK [Bruton tyrosine kinase] inhibitors, and we now have 3 different BTK inhibitors that are approved in the second line: ibrutinib, acalabrutinib, and zanubrutinib. There are several clinical trials that show, each of these has a pivotal phase 2 trial that showed high response rates, durable remissions with a very manageable safety profile. Thus, I think that has become a very common go-to therapy for second-line therapy. There are other choices. You could use the R2 regimen as well, lenalidomide and rituximab. That also has efficacy there. But I think most people are using BTK inhibitors because it’s easier, the efficacy is very good. Finally, I shouldn’t leave out CAR [chimeric antigen receptor] T-cell therapy. Brexucabtagene has been approved for patients with 1 prior therapy, and for very high-risk patients, I think that might also be a reasonable option.

Bijal D. Shah, MD, MS: That’s a good point. Brian, I have a quick question for you. How are we distinguishing all of these BTKs, and how will we continue to distinguish them?

Brian T. Hill, MD, PhD: A very good question. As Dr Flinn pointed, we do have 3; ibrutinib being first to market, it’s been approved now for 7 or 8 years. And subsequently acalabrutinib and zanubrutinib as well are approved in mantle cell. I think what we’ve learned through other diseases, and there have been randomized head-to-head trials in CLL [chronic lymphocytic leukemia] and in Waldenstrom macroglobulinemia, which have demonstrated noninferiority of both acalabrutinib and zanubrutinib and improved safety profile. Although we still have patients on ibrutinib, I think we see lower atrial fibrillation rates with the newer agents, possibly lower bleeding risk, which is a known toxicity of the covalent BTK inhibitors, and in some cases different toxicities that may be unique to individual agents. But I think most of the lymphoma specialists have moved to acalabrutinib and zanubrutinib.

Bijal D. Shah, MD, MS: Michael, there’s a new BTK on the block.

Michael Wang, MD: Yes. BTK, what’s called the Bruton tyrosine kinase, was discovered in the 1950s by [Ogden] Bruton, who was an army pediatric doctor. He was a serious scholar. He found that this Bruton kinase is very important in the B-cell immune system. That protein was found and later studied by many different scholars, showing that it has a very vital link in the B-cell receptor pathway. Antigen hits the B cell, and the signals are transferred all the way to the nucleus through this B-cell receptor pathway. The BTK, Bruton tyrosine kinase, is a critical link here. If we use inhibitors to hit this link and inhibit the pathway, then growth signals are blocked and the cells will die, the lymphoma cells will die. That’s the way. This is a very interesting target.

Thus, we now have 3 BTK inhibitors. The BTK inhibitor will bind covalently with a protein BTK and will not let it go. The new kid on the block is pirtobrutinib. Instead of binding it covalently and not letting it go, this one is noncovalent binding. It binds and then lets it go, it’s like a dynamic process. This is a brand-new way to inhibit the protein, very interesting. It’s also a pill. Yesterday I presented some clinical trial data that the drug is really very good, and the response rate after many lines of therapy is over 50%. People think this is a very promising drug. I have to tell everybody, if you’re on a BTK inhibitor and you think in the future it might stop working, the next time we can use this new kid. I hope that the drug will become available to patients very soon.

Bijal D. Shah, MD, MS: Wonderful. Brian, when you and I were talking earlier, we were talking about pirtobrutinib, and you said it’s a BTK inhibitor without BTK adverse effects.

Brian T. Hill, MD, PhD: Right, yes.

Bijal D. Shah, MD, MS: Tell me a little about the adverse effect profile. What are we seeing?

Brian T. Hill, MD, PhD: What’s remarkable in all of the covalent BTK inhibitors we mentioned is that we seem to see a class effect, which is they all have some atrial fibrillation, probably ibrutinib with the most. They all have some bleeding and bruising risk. There are some other toxicities, but those sort of become accepted as hallmarks of the covalent BTK inhibitors. And what’s remarkable with the noncovalent BTK inhibitor pirtobrutinib is we don’t see these things. Thus, very low incidence, probably just background incidence of atrial fibrillation, no bleeding risk, and minor cytopenias. It seems to be remarkably well tolerated, and I think that’s really going to be important going forward because many patients do have toxicities that require them to discontinue the covalent agents.

Transcript edited for clarity.

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