Advancements in Immunotherapy Expand and Improve the Treatment Landscape for MCL

Joshua Brody, MD

Novel therapeutic options for the treatment of patients with mantle cell lymphoma (MCL) have demonstrated promising efficacy in patients with significant unmet need, thereby increasing the focus on developing synergistic targeted therapy and immunotherapy approaches for this population. Resulting combination strategies could elicit deeper and more durable responses to treatment, without significant additive toxicities, according to Joshua Brody, MD.

“MCL is probably one of the greatest [areas of] unmet need amongst B-cell lymphomas, and we still think of it as incurable in the majority of patients,” said Brody. “It is not inherently incurable; we just have not been able to cure it with old standard chemotherapies and gentle immunotherapies like rituximab [Rituxan]. I am optimistic that [these novel] immunotherapies [will] shift how we [approach] MCL, and hope that it will be mostly curable in [the near future].”

In an interview with OncLive®, Brody discussed significant updates in MCL treatment presented at the 2022 ASH Annual Meeting, including results from the phase 1/2 BRUIN trial (NCT03740529) of pirtobrutinib (LOXO-305), follow-up data from the phase 2 ZUMA-7 trial (NCT03391466) on CAR T-cell therapies, and next steps to expand the development of immunotherapies in this disease.

Brody is a faculty member at Icahn Genomics Institute and director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at Mount Sinai in New York, NY.

OncLive^®: How has the evolution of immunotherapies for B-cell lymphomas affected the treatment paradigm in MCL?

Brody: The immunotherapy revolution has been even more exciting in MCL than in other lymphomas. First, the [degree of] unmet need was greater for MCL than for follicular lymphoma and diffuse large B-cell lymphoma [DLBCL].

[Second, early] immunotherapies, specifically [those] targeting CD20, have paved the way for newer, more effective immunotherapies [in MCL]. For example, rituximab maintenance therapy is [historically] not very helpful in follicular [lymphoma] or DLBCL but yields an overall survival [OS] benefit in MCL after initial chemoimmunotherapy with R-CHOP or autologous stem cell transplant. Yielding an OS benefit with a gentle therapy like rituximab maintenance is already quite striking, but we still need better [options] for our patients with MCL.

What distinguishes pirtobrutinib from previous BTK inhibitors developed for patients with relapsed/refractory MCL?

Pirtobrutinib is the first of a new class of BTK inhibitors called noncovalent, or reversible BTK inhibitors. It is mechanistically distinct from the covalent, or irreversible BTK inhibitors we were using every day, [like] ibrutinib [Imbruvica], acalabrutinib [Calquence] and zanubrutinib [Brukinsa]. All those irreversible inhibitors share mutations in C481 of the tumor cell, which is a common relapse mechanism. Pirtobrutinib and [other drugs in] this new class avoid that shortcoming, [although] they may have others.

I’ve been impressed with how safe and clean pirtobrutinib [is compared with] acalabrutinib and ibrutinib. I thought it might have more off-target toxicities and [adverse effects], but it seems to have been extremely well tolerated [by patients.] [In] that way, [it may be] like these BTK inhibitors we are already comfortable with.

What key data from the BRUIN trial were presented at the 2022 ASH Annual Meeting?

At ASH 2022, [we presented] follow-up [analysis of] a subset of patients with MCL from the BRUIN trial. [This subgroup shows] high response rates and an [approximate] 20% complete remission [CR] rate. [About] half of patients that progressed on another prior BTK inhibitor still had responses. This suggests that pirtobrutinib can be effective for patients with MCL [after] other covalent BTK inhibitors were ineffective. That’s been previously shown for CLL, but this is the first and best data [set] for [this drug in] MCL.

[We now have] more data showing long-term safety and good response rates [with pirtobrutinib] in MCL, even in patients [who are] refractory to ibrutinib, acalabrutinib and zanubrutinib. [It is] encouraging to have another tool in the arsenal for patients with MCL who still need more [treatment options].

What do updated findings from the ZUMA-2 trial indicate about the potential effects of CAR T-cell therapy on the treatment paradigm for MCL?

ZUMA-2 [is the] first large trial using [brexucabtagene autoleucel (KTE-X19; brexu-cel)]. [Brexu-cel is] like [axicabtagene ciloleucel (Yescarta; axi-cel)] by Gilead and Kite [Oncology], but just has slightly different manufacturing. [In initial data] from ZUMA-2 [published] in the New England Journal of Medicine, brexu-cel [showed] very high response rates and CR rates in more than two-thirds of patients. That’s about the best [data] we’ve seen with any CAR T-cell [therapy] in any B-cell lymphoma.

Updated [findings] show that about half of those patients that [achieved] CR at the early data cutoff are still in remission more than 2 years later. [We can’t] call that a cure yet, but durable remission is [a key] metric on the way to [finding a] cure. Efficacy-wise, [these results are] better than just about any other therapy we’ve seen for [those] with relapsed/refractory MCL.

The update [also shows] that patients with better performance status and lower tumor burden tolerated therapy better and correlated with the best durable responses, which is not surprising. The author concludes that we should be open-minded to [using] CAR T-cell therapy earlier in treatment for our patients with MCL. We [still] don’t know whether this should be a third-line or second-line therapy.

Is there anything else you’d like to note about the updated results from ZUMA-2?

The ZUMA-2 follow-up [showed] promising results, but we don’t want to oversell CAR T-cell safety or simplicity. It’s still a complex therapy and is not always accessible to everybody. The time investment [associated with] personalized therapy is a luxury that not every patient has. Toxicities [with CAR T-cell therapy] were significant in terms of cytokine release syndrome [CRS] and neurotoxicities [like] ICANS [immune effector cell–associated neurotoxicity syndrome], so we still need to improve on that. [Still,] for some patients, these durable responses are very exciting.

What has been seen with the use of bispecific antibodies in MCL?

Bispecific antibodies targeting CD20 are probably the most exciting thing for all B-cell lymphomas in the past couple of years. [They show great] efficacy data, pretty good safety data, and good feasibility and ease of use. At ASH 2022, we are going to get updated [data on] glofitamab, the bispecific antibody furthest along in [development in] MCL. The efficacy [of glofitamab] has been incredible in MCL and other lymphomas. [In the updated data] we will see complete remission rates approaching 70%, depending on the [patient] subgroup. This is much higher than what we’ve seen in DLBCL.

Again, we don’t want to oversell the safety data. There was more CRS in the MCL group than we’ve seen [in other B-cell malignancies.] These patients still need monitoring and may eventually need a different dose-escalation paradigm. [Dose adjustment] could be a simple fix [to reduce toxicity] without making an inherent change in the therapy. [Another] caveat is that the trial is smaller. [Still,] the glofitamab data for MCL is the most we’ve seen with any bispecific antibody for this disease so far, and the efficacy data are near unprecedented. I think that this agent will quickly work its way into second-line and first-line [settings] in the next few years, which is very exciting.

What next steps do you envision for the development of immunotherapies in MCL?

The future development of therapies in MCL is full of [promising] opportunities. The basis of medical oncology is combining therapies with non-overlapping toxicities. This is how we cured acute leukemia in the 1970s, and Hodgkin lymphoma in the 1980s. We’re mentioning exciting results with BTK inhibitors like pirtobrutinib, bispecific [antibodies], and CAR T-cell therapies, but we still [see good efficacy] with acalabrutinib andzanubrutinib as well. It’s a no-brainer that we should be able to combine BTK inhibitors and immunotherapies in a rational way to get deeper remissions and hopefully cures without much additive toxicity.

What ongoing research in MCL are you particularly excited about?

At Mount Sinai, we are [investigating] the differential immunomodulatory effects of BTK inhibitors. We focus on the fact that they target BTK but can target other Tec family kinases like ITK and TXK that are expressed in T cells, natural killer cells, and other immune cells. BTK inhibitors can be immunomodulatory in both helpful and harmful ways.

It is easy to imagine that those therapies could be combined as a second-line therapy.

We’re already looking at BTK inhibitors as a frontline monotherapy for older non–transplant-eligible patients, so there’s no reason that these relatively safe combinations couldn’t be studied in this setting. We just have to be smart about [the development of] future trials evaluating BTK inhibitors plus bispecific antibodies.

Editor's Note: This interview was conducted prior to the 2022 ASH Annual Meeting.