Ongoing Trials Could Shift BTK Inhibitors to Earlier Settings in MCL


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Brad S. Kahl, MD, discusses the evolving role of BTK inhibitors in the treatment of patients with mantle cell lymphoma, expands on key ongoing trials investigating these agents in earlier settings and in different combinations, and expands on what the addition of pirtobrutinib to the treatment arsenal has meant for this population.

Brad S. Kahl, MD

Brad S. Kahl, MD

Although covalent BTK inhibitors have an established role in the second-line treatment of patients with mantle cell lymphoma (MCL), ongoing studies and the recent FDA approval of the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) for the treatment of patients with relapsed/refractory MCL following at least 2 lines of systemic therapy, including a BTK inhibitor, could shift how and when these agents are used in clinical practice, according to Brad S. Kahl, MD.1,2

“BTK inhibitors are on the cusp of moving into the frontline [setting] in MCL,” Kahl said. “You could envision a world in which pirtobrutinib is moved very quickly into the second line. We're not there right now, but I could see us there in a year or 2, depending on how the data from some of these ongoing trials look.”

In an interview with OncLive®, Kahl, a professor in the Department of Medicine Oncology and the Division of Medical Oncology at Washington University in St. Louis, Missouri, discussed the evolving role of BTK inhibitors in the treatment of patients with MCL, expanded on key ongoing trials investigating these agents in earlier settings and in different combinations, and expanded on what the addition of pirtobrutinib to the treatment arsenal has meant for patients with MCL.

OncLive: What has the FDA approval of pirtobrutinib meant for the MCL treatment paradigm?

Kahl: The approval of pirtobrutinib is significant in MCL. For patients progressing on a covalent BTK inhibitor, [subsequent] options were a bit limited, with brexucabtagene autoleucel [brexu-cel; Tecartus] as your best option. However, not all patients are good candidates for [brexu-cel] or can even [access treatment]. Therefore, to have an off-the-shelf option with good tolerability and a good response rate like pirtobrutinib, we're happy to have that in the toolbox for patients with relapsed MCL.

There is the ongoing, randomized phase 3 [BRUIN MCL-321] trial [NCT04662255] comparing pirtobrutinib against the covalent BTK inhibitors [ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa)]. That will be an interesting and very important trial when the data read out. However, we are probably a couple years away from that, and [the trial] is still enrolling. For now, pirtobrutinib is 1 of our preferred options for patients who progress following a covalent BTK inhibitor.

Along with BRUIN MCL-321, what other ongoing trials could shift how BTK inhibitors are used in the treatment of patients with MCL?

MCL is in flux right now. We had the phase 3 SHINE trial [NCT01776840] presented in 2022 for older patients with MCL. We had the phase 3 TRIANGLE study [NCT02858258], and now we have pirtobrutinib trying to move up. Based upon TRAINGLE and other trials that are close to reading out, such as the phase 3 ECHO trial [NCT02972840], which is testing [frontline] acalabrutinib plus [bendamustine and rituximab (Rituxan)], or the phase 3 MANGROVE trial [NCT04002297], which is testing [frontline] zanubrutinib plus [rituximab], you could envision that within a year or 2, covalent BTK inhibitors may be used commonly in the frontline in combination.

Are there other novel BTK inhibitors under investigation that can continue to add to this treatment paradigm?

There are other noncovalent BTK inhibitors in development, such as nemtabrutinib [MK-1026, formerly ARQ-531] and others. [These agents] have less data behind them. Will they be materially different than pirtobrutinib? We don't know that yet. However, we're watching these emerging agents very closely.

We saw some interesting data at the 2022 ASH Annual Meeting on glofitamab-gxbm [Columvi] in relapsed MCL. I'm anxious to see more bispecific data in relapsed MCL because we don't have enough good options for relapsed MCL right now, and we need more. I hope that bispecifics pan out and become another good option to offer our patients with MCL.

What could the movement of BTK inhibitors into earlier lines of therapy mean for the MCL treatment space?

We're waiting for mature data and a [full] publication from the TRIANGLE study. However, there is already an National Comprehensive Cancer Network compendium listing, listing [the ibrutinib-based regimen from TRIANGLE] as a preferred [frontline] option. Therefore, you could add a BTK inhibitor to your intense induction for younger patients with MCL. You could then give 2 years of a maintenance BTK inhibitor after finishing induction. That's available right now, if you can get insurance approval, though we don't have regulatory approval for that despite the compendium listing. A lot of insurances will allow you to do that.

We don't have the same kind of compendium listing for a BTK inhibitor in the frontline treatment of older patients with MCL. [For those patients], I would say to save your BTK inhibitor and pull it out in second-line. However, I could see this changing in the next couple years, where BTK inhibitors move up-front due to the ongoing studies.


  1. Kahl BS. Mantle cell lymphoma: novel therapeutic strategies using the new generation of BTK inhibitors. Presented at: 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX.
  2. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. News release. FDA. January 27, 2023. Accessed September 13, 2023.
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