Many clinicians who treat hematologic malignancies have begun the work of figuring out how to incorporate bispecific antibodies into the existing treatment armamentarium for these diseases. A handful of new bispecific antibodies have been granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of hematologic malignancies in 2023 alone — such as epcoritamab and glofitamab for diffuse large B-cell lymphoma (DLBCL); mosunetuzumab for follicular lymphoma (FL); talquetamab, teclistamab, and elranatmab for multiple myeloma (MM); and blinatumomab for acute lymphoblastic leukemia (ALL) — but none of the approved indications are in mantle cell lymphoma (MCL). That could change soon.
“Historically, MCL has been an incompletely understood and challenging-to-treat lymphoma,” explained Peter Martin, MD, MS, professor of medicine and chief of the lymphoma program of Weill Cornell Medicine in New York.
The introduction of Bruton tyrosine kinase (BTK) inhibitors and chimeric antigen receptor (CAR) T-cell therapy significantly changed the treatment of MCL, but progress in clinical trials of bispecific antibodies could introduce another new option for patients.
“A lot of people look at bispecific antibodies and wonder if they could be competitors or a replacement for CAR T-cell therapies, with the potential to be more practical, in that they could be administered in more broad settings,” Dr. Martin said.
ASH Clinical News recently spoke with several specialists in MCL about the status of current treatments, including the promise and reality of CAR T-cell therapy, and the future potential of bispecific antibodies.
MCL Advances
Historically, patients with MCL did not respond to chemotherapy regimens as well as might be expected, likely for a variety of reasons, explained Dr. Martin. Within the oncology space, the natural response to that challenge was to increase the intensity of therapies when possible.
“That led to use of more intensive treatment regimens, particularly in younger patients who could tolerate them,” Dr. Martin said. “In the trials that employed those more intensive regimens, outcomes were consistently better.”
That trend continued until things really started to change about a decade ago with the approval of BTK inhibitors.
“Consistent with what we saw with other B-cell lymphomas, there was a realization that there might be other kinds of treatment approaches for people with MCL and a path away from traditional chemotherapy – at least in the relapsed or refractory (R/R) setting,” Dr. Martin said.
Ibrutinib was initially granted accelerated approval for MCL in 2013 based on results from phase II clinical studies but was voluntarily withdrawn from the market in April 2023 after disappointing results from phase III confirmatory studies.1
In 2017, acalabrutinib was granted accelerated approval for patients with MCL with one or more prior therapies. The approval was based on a phase II trial that yielded an overall response rate (ORR) of 81%.2 Two years later, zanubrutinib also received accelerated approval for patients with MCL with one or more prior therapies. This approval was also based on phase II results showing an ORR of 84% and a median duration of response (DOR) of 19.5 months.3
“In the relapsed setting, we have heavily relied on BTK inhibitors in recent years,” said Matthew Matasar, MD, chief of the Division of Blood Disorders at Rutgers Cancer Institute in New Brunswick, New Jersey, and an associate editor of ASH Clinical News. “There is a lot of evidence that BTK inhibitors are active in relapsed MCL, but eventually patients will progress, and the third-line setting has remained challenging.”
One new option for the third line is the covalent BTK inhibitor pirtobrutinib, which was granted accelerated approval in January 2023.4 Pirtobrutinib was approved for MCL after at least two lines of therapy, including prior exposure to a noncovalent BTK inhibitor. Results of the BRUIN trial showed an ORR of 50% with an estimated DOR of 8.3 months.
“It seems likely that pirtobrutinib will be a bridge to something else,” said Tycel Phillips, MD, associate professor at City of Hope Comprehensive Cancer Center in Duarte, California. “If we have a patient who progresses on a covalent BTK, pirtobrutinib can bridge that patient to another treatment – like CAR T-cell therapy.”
Addressing Third-Line
The CAR T-cell therapy brexucabtagene autoleucel (brexu-cel) was one of the first treatments that led to any type of durable responses in the third-line setting, according to Dr. Phillips.
Brexu-cel gained regulatory approval in 2020 for R/R MCL based on the ZUMA-2 trial.5 Initial results showed an ORR of 87% with a complete response (CR) rate of 62%. Three-year follow-up results showed ORR of 91% with a 68% CR and a median DOR of 28.2 months.6
Trials of another CAR T-cell therapy, lisocabtagene maraleucel, have also shown similar efficacy, with an ORR of 86.5% and a CR of 74.3%,7 but this option is not yet FDA-approved for MCL.
Although the ZUMA-2 trial included patients who had been treated with anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody, and a BTK inhibitor, the FDA’s approval does not specify prior lines of therapy, pointed out Bijal Shah, MD, MS, associate member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.
“There were a number of patients who we never brought to CAR-T because we had to expose them to a BTK to qualify them for the trial,” Dr. Shah said. “We were never able to rescue those patients, get their disease under control, and get them to CAR-T.”
Part of the rationale for this broader approval, Dr. Shah said, may have to do with what clinicians know is the natural progression of the development of BTK inhibitors and the likelihood that they may move to a frontline setting.
“Everyone agrees that across the board CAR T-cell therapy is very effective in MCL,” Dr. Martin said. “But I think everybody also agrees that it is unlikely that CAR T-cell therapies cure most patients.”
Dr. Phillips agreed. “We see higher response rates and better response than with any other treatment … but in every update of the original study, the data show that more and more patients are relapsing, and instead of seeing curves that look like stairs going to a landing like what occurred in DLBCL, we see continually descending stairs, which suggests this treatment isn’t curative in MCL.”
Dr. Shah said that at his high-volume CAR T-cell therapy center, it is clear they may have a different risk tolerance for this approach than other centers.
“I do not shy away from giving CAR-T to 80-year-old patients,” Dr. Shah said. “You will see more in the way of toxicity, but the risk of dying from those toxicities, at least at our center, is exceptionally low.”
Dr. Shah’s team worries more about the consequences of those toxicities than the toxicities themselves.
“Experiencing something like CRS [cytokine release syndrome] means more time in bed or possibly getting weak or losing weight,” Dr. Shah said. “What would be a 10-day sail through CAR-T infusion could turn into a longer hospitalization plus rehab on the back end to get them into shape. That’s the challenge.”
However, Dr. Shah added that he understands why the risks of CRS and neurotoxicity, which are very real and lethal toxicities, cause hesitation for others.
Even when successful, clinicians are faced with the knowledge that as time goes on, most, if not all, patients will relapse after CAR T-cell therapy. Ongoing analyses of data on brexu-cel indicated that Eastern Cooperative Oncology Group (ECOG) score, tumor burden, and bridging therapy could affect response, and the treatment may be more effective if administered earlier in the disease course.
When discussing these options, clinicians sometimes assume that patients will get to try every option, Dr. Martin said.
“Some patients will get firstline therapy only and will not make it to second-line; the same is true for second- to third-line,” Dr. Martin said. “One question we should be asking is if there are scenarios where one treatment should be used earlier and could potentially be more effective.”
Current Bispecific Progress
That is exactly the question being asked about bispecific antibodies, which seem to be as effective as CAR T-cell therapies but with a lower risk of certain associated toxicities. According to Dr. Matasar, the development of bispecific antibodies for MCL has been slower than for other B-cell lymphomas.
“The development has been limited not by concerns about activity but concerns about tolerability with higher rates of CRS than other histologic subtypes,” Dr. Matasar said. “Thankfully, there are newer data suggesting that they can be given safely with high overall CR rates.”
Dr. Matasar was referring to recent data on intravenous glofitamab, a CD20xCD3-targeting bispecific antibody. The glofitamab program is likely the most well developed at this point and the closest to FDA approval.
Dr. Phillips and colleagues worked to establish a step-up dosing regimen for glofitamab given in combination with obinutuzumab pretreatment. Detailed at the 2021 American Society of Hematology (ASH) Annual Meeting and Exposition, this early work was done in patients with R/R MCL, most of whom had failed prior BTK inhibitor therapy.
Glofitamab is given in step-up doses of 2.5 mg the first week, 10 mg the second week, and then 30 mg every three weeks. The obinutuzumab pretreatment was given to help reduce the risk for CRS. At first assessment, the ORR was 81%, with 66.7% of patients achieving complete metabolic response (CMR).8
In 2022, Dr. Phillips and colleagues presented updated findings from the phase I/II trial of single-agent glofitamab at the ASH annual meeting. With a fixed treatment duration of 12 cycles, the ORR was 83.8%, with 73.0% of patients achieving CMR. The ORR was 75.0% among patients with prior BTK inhibitor exposure. Although three-quarters of patients experienced CRS, the majority was grade 1 or grade 2. Neurologic adverse events occurred in about half of patients, and all but one were grade 1 or 2.9
“If it does prove to be durable, the advantage of bispecific antibodies is that while CRS rates are about the same as CAR-T, there is really no ICANS [immune effector cell-associated neurotoxicity syndrome],” Dr. Phillips said. “Bispecifics are also off-the-shelf; they do not need bridging or manufacturing. If you see a patient, you can treat a patient.”
The bispecific antibody mosunetuzumab, which has FDA approval for FL,10 did not have any significant single-agent response or activity in MCL, according to Dr. Phillips. The subcutaneously administered CD20xCD3-targeting bispecific antibody epcoritamab is being explored for MCL in the EPCORE study, but the study is yet to report any data.
“I can imagine a scenario in which bispecific antibodies offer a significantly larger group of high-risk patients access to T-cell-engaging options than what is currently achieved with the limited deployment of CAR T-cell therapy to date,” Dr. Matasar said.
Choosing One or Both?
Even in diseases that already have both FDA-approved CAR T-cell therapy and bispecific antibodies, clinicians are still trying to answer the questions of which patients should be getting each treatment and when.
“For MCL, which is arguably more complicated and rare of a disease with fewer patients available to go on clinical trial, I don’t even know how we will ever be able to study that question,” Dr. Martin said.
Each approach does seem to have benefits and drawbacks. For example, even though CAR T-cell therapy may be the more challenging treatment to deliver, after it is delivered, it is a watch-and-wait scenario, Dr. Shah said. In contrast, the T-cell-engaging bispecific antibodies require multiple treatments.
“Think about the operational piece of that,” Dr. Shah said. “If you can’t deliver it for whatever reason, you are opening the door for disease to recur.”
On the flip side, a patient undergoing CAR T-cell therapy may experience a toxicity that cannot be reversed; however, with a bispecific antibody, the drug can stop being delivered, and rescue medications can be given.
Dr. Matasar agreed that it is unlikely that clinicians will ever have head-to-head data to help answer this question.
“Practically speaking, choices may not be made based on high-quality data informing the choice of sequence but rather using patient considerations,” Dr. Matasar said. “Which treatment do they have access to? Which are they comfortable with? Which will they tolerate better?”
Dr. Shah hoped that instead of choosing one or the other, the two approaches will eventually be found complementary, such as in the case of ALL where CAR T-cell therapy can be followed by blinatumomab maintenance.
“The other area where bispecific antibodies may have the opportunity to shine is if we can follow through on their use in the community setting,” Dr. Shah said.
Bispecifics in the Community
Dr. Phillips said that if community physicians gain comfort with the use of bispecific antibodies, he could imagine more patients with MCL receiving these drugs before CAR T-cell therapy, “especially if bispecific data support a DOR comparable to CAR-T.”
In 2020, the Association of Community Cancer Centers conducted a survey of 129 oncologists, advanced practice providers, nurses, and pharmacists about their experiences with blinatumomab, the only FDA-approved bispecific at that time. Results showed that just under half of medical oncologists/hematologists were familiar with blinatumomab. Common barriers to its use included the need to transition patients from the inpatient to the outpatient setting (41%), managing patients in remote areas (33%), managing side effects (27%), and lack of in-house expertise with the drug (22%). The majority desired written guidelines, best practices, and care recommendations related to blinatumomab’s use.11
Dr. Shah said he is unsure if the promise of bispecific antibodies in the community will pan out.
“I am trying to imagine owning a private practice and purchasing these expensive drugs for the purpose of delivering them to a patient with a rare disease, and if that patient doesn’t tolerate it, what do I do with the remaining drug?” he said.
At a minimum, Dr. Shah said that getting patients through the initial doses of a bispecific antibody will likely fall to academic centers.
Dr. Matasar said although it is going to take a lot of work to get there, he absolutely believes that these drugs will be administered in the community.
“The value of bispecific antibodies in multiple histologies and subtypes is what is going to drive that change. This is not just one drug in one disease; these drugs are in FL, DLBCL, MM, and, likely, eventually in solid tumors,” Dr. Matasar said. “I don’t see a future in which oncologists who want a robust practice will be able to ignore how to safely and effectively administer these treatments in their practices.”
References
- Update on IMBRUVICA® (ibrutinib) U.S. accelerated approvals for mantle cell lymphoma and marginal zone lymphoma indications. April 6, 2023. Accessed September 22, 2023. https://www.jnj.com/update-on-imbruvica-ibrutinib-u-s-accelerated-approvals-for-mantle-cell-lymphoma-and-marginal-zone-lymphoma-indications#:~:text=HORSHAM%2C%20Pa.%2C%20April%206,of%20patients%20with%20mantle%20cell.
- U.S. Food and Drug Administration. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. October 31, 2017. Accessed September 22, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-acalabrutinib-mantle-cell-lymphoma.
- U.S. Food and Drug Administration. FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma. November 15, 2019. Accessed September 22, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanubrutinib-mantle-cell-lymphoma.
- U.S. Food and Drug Administration. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. January 27, 2023. Accessed September 22, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-relapsed-or-refractory-mantle-cell-lymphoma.
- U.S. Food and Drug Administration. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. July 27, 2020. Accessed September 22, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-mantle-cell-lymphoma.
- Wang M, Munoz J, Goy A, et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study. J Clin Oncol. 2023;41(3):555-567
- Wang M, Siddiqi T, Gordon LI, et al. Lisocabtagene maraleucel (liso-cel) in R/R MCL: primary analysis results from the MCL cohort of the single-arm, multicenter, seamless design TRANSCEND NHL 001 study. Hematological Oncology. 2023;41(S2):875-877.
- Phillips T, Dickinson M, Morschhauser F, et al. Glofitamab step-up dosing induces high response rates in patients (pts) with relapsed or refractory (R/R) mantle cell lymphoma (MCL), most of whom had failed prior Bruton’s tyrosine kinase inhibitor (BTKi) therapy. Blood. 2021;138(suppl 1):130.
- Phillips TJ, Dickinson M, Morschhauser F, et al. Glofitamab monotherapy induces high complete response rates in patients with heavily pretreated relapsed or refractory mantle cell lymphoma. Blood. 2022;140(suppl 1):178-180.
- U.S. Food and Drug Administration. FDA grants accelerated approval to mosunetuzumab-axgb for relapsed or refractory follicular lymphoma. December 23, 2022. Accessed September 25, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mosunetuzumab-axgb-relapsed-or-refractory-follicular-lymphoma.
- Association of Community Cancer Centers. Using bispecific antibodies in community practice: challenges and opportunities. https://www.accc-cancer.org/docs/projects/bispecific-antibodies/using-bispecific-antibodies-in-community-practice.pdf?sfvrsn=f5b5ac13_0.
