Bispecific Antibodies: New Options

With more bispecific antibodies in development for hematologic malignancies, physicians must determine how best to incorporate them into practice once they reach market.

Monoclonal antibodies like rituximab helped to revolutionize the treatment of hematologic malignancies, but the recent advancements in the use of T-cell engager therapy and bispecific antibodies have revealed several clinical therapeutic advantages that experts hope will further improve outcomes and decrease adverse events.

“Most of us are excited and interested in bispecific antibodies because we are seeing groundbreaking updates from clinical trials [of these drugs],” said Bhagirathbhai Dholaria, MBBS, an Assistant Professor of Medicine in the Department of Medicine at Vanderbilt University Medical Center.

Bispecific antibodies differ from monoclonal antibodies by having two binding specificities against two different antigens in one antibody molecule. The most common bispecific antibodies in development act as a sort of bridge between cancer cells and T cells, Dr. Dholaria explained. For example, some bispecific antibodies being researched in multiple myeloma (MM) engage the tumor-specific B-cell maturation antigen (BCMA) and the CD3 antigen on T cells.

There are a multitude of bispecific antibodies under investigation right now in hematologic malignancies, with various tumor-specific targets, routes of administration, and treatment durations. Which drugs will make it to market first and how these drugs will be incorporated into treatment sequencing remains to be seen.

New Options

The first bispecific antibody to gain approval in a hematologic malignancy was the bispecific T-cell engager (BiTE™) blinatumomab, a molecule directed against CD19 and CD3. In 2014, the U.S. Food and Drug Administration (FDA) granted blinatumomab accelerated approval for Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children. The drug gained regular approval with an expanded label for all patients with relapsed or refractory B-cell precursor ALL in 2017.¹

The TOWER trial confirmed the clinical benefit of blinatumomab compared with standard of care in patients with relapsed or refractory B-cell precursor ALL. Overall survival (OS) was significantly prolonged in patients treated with blinatumomab (hazard ratio, 0.71; 95% CI, 0.55-0.93; P=.012). Median OS was 7.7 months with blinatumomab compared with 4.0 months with standard of care.²

“This provided the proof of principle that a bispecific antibody could lead to durable remission,” said Michael Dickinson, MD, Lead of the Aggressive Lymphoma Disease Group within Clinical Haematology at Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Australia. “This was an intravenous formulation given with continuous infusion. It is a small molecule with a short half-life.”

In leukemia, blinatumomab is an important tool for inducing remission, often as a bridge to transplant in ALL, Dr. Dickinson said. In lymphoma, blinatumomab has been less successful.

“We know blinatumomab works and can shrink tumors, but the rate of complete remission was not high enough to justify the complexity of infusion,” Dr. Dickinson said. “We haven’t seen blinatumomab move forward in common lymphomas, but it did show that a complete remission could be achieved with this mechanism.”

The newest bispecific antibody to gain regulatory approval in hematologic malignancies is teclistamab-cqyv, a bispecific BCMA-directed CD3 T-cell engager.³ Teclistamab was approved in October 2022 for adult patients with relapsed or refractory MM who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

The approval of teclistamab was based on the single-arm, open-label MajesTEC-1 trial that included an efficacy population of 110 patients. The overall response rate (ORR) with teclistamab was 61.8%, with an estimated duration of response of 90.6% at six months and 66.5% at nine months.⁴

“This drug is highly potent, with treatment responses in phase I showing an ORR of over 70% in these highly refractory patients,” said Dr. Dholaria. “The drug is also a subcutaneous formulation that is relatively easy to administer compared with blinatumomab. Patients go to the doctor’s office once a week and get a shot.”

Currently, teclistamab is given as long as the patient is responding.

“Right now, we don’t know if someone on teclistamab can stop therapy safely,” Dr. Dholaria said. “The answer might be that we can. Anecdotally, I have had a handful of patients who have stopped the drugs due to side effects [and] are still in remission.”

Teclistamab is not alone as a fifth-line therapy for MM. Even with the antibody-drug conjugate belantamab mafodotin now pulled from the market, patients still have two FDA-approved chimeric antigen receptor (CAR) T-cell therapies: idecabtagene vicleucel and ciltacabtagene autoleucel.

“Hopefully, we will not see these agents working against each other, but working together for patients,” Dr. Dholaria said. “If I have a patient who qualifies for both, which would I prefer? It is too early to know. A comparative study has not been done.”

The currently available CAR T-cell therapies for MM have a four- to six-week manufacturing window, and patients cannot always wait that long. In that case, the “off-the-shelf” bispecific antibody may be a more appropriate drug, Dr. Dholaria said.

“However, the beauty of CAR T-cell therapy is that it is a one-time treatment,” he said. “If a patient responds, they can have a durable remission from that single infusion. That is a huge benefit compared with teclistamab, which is an ongoing therapy.”

Overflowing Pipeline

In addition to these therapies on the market, there are multiple bispecific antibodies that are close to or pending regulatory approval.

The FDA has granted elranatamab, another BCMA-, CD3-targeted bispecific antibody, breakthrough therapy designation for relapsed or refractory MM.⁵ This designation was based on six-month follow-up data from a cohort of the single-arm, open-label MagnetisMM-3 trial. Data from an interim analysis were presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting. With a median follow-up of 3.71 months, initial efficacy results showed an objective response rate of 60.6%, with a manageable safety profile.⁶

“In terms of response, this seems very close to what we see with teclistamab, with a comparable risk of cytokine release syndrome (CRS) and infections,” Dr. Dholaria said.

Abstracts from the 64th American Society of Hematology (ASH) Annual Meeting and Exposition include studies of elranatamab in combination with daratumumab and in patients naïve to BCMA-directed therapies.

In the lymphoma realm, there are several bispecific antibodies that appear to be promising, not the least of which is mosunetuzumab, a CD20×CD3-directed bispecific antibody that has already gained regulatory approval from the European Medicines Agency for adult patients with follicular lymphoma (FL).⁷ The FDA has granted mosunetuzumab priority review.

Mosunetuzumab is given intravenously with a step-up dosing strategy for a fixed course.

“It has been effective in inducing durable remissions in FL,” Dr. Dickinson said. “The striking thing is that it seems to be very well tolerated, with low CRS and low neurotoxicity, which means it can be delivered in an outpatient setting.”

Data from a phase II study of 90 patients with grade I-IIIa FL showed that intravenous mosunetuzumab was associated with a complete response (CR) rate of 60.0%, which was significantly higher than that of a historical control CR rate of 14% (P<.0001).⁸ CRS was predominantly grade 1 and primarily confined to the first cycle.

Another frontrunner in lymphoma is glofitamab, according to Amitkumar Mehta, MD, Associate Professor and Director of the Lymphoma Program at the University of Alabama, Birmingham. Glofitamab is a bivalent, CD20×CD3-targeting bispecific antibody under investigation for the treatment of aggressive lymphomas.

“Glofitamab is a little different than the other bispecifics because it has a 2:1 ratio of engaging CD20 to CD3,” Dr. Mehta explained. “All of the others have a 1:1 ratio. Glofitamab also has an intravenous administration.”

Dr. Dickinson and colleagues presented data from a phase II trial of glofitamab at the 2022 ASCO Annual Meeting that demonstrated that fixed-duration glofitamab induced a response in 51.6% of patients, with 39.4% achieving a CR.⁹

“In diffuse large B-cell lymphoma (DLBCL), even more than FL, CR is probably the most important endpoint,” Dr. Dickinson said. “We are trying to achieve deep and rapid remission that will translate into durable remission.”

Trailing a bit behind the others is epcoritamab, according to Dr. Mehta. Epcoritamab is an immunoglobulin G (IgG) 1 CD20×CD3 bispecific antibody that was recently accepted for priority review by the FDA for relapsed/refractory LBCL in patients with two or more prior lines of therapy.¹⁰

Regulatory approval would be based on results from the LBCL cohort (157 patients) of a multicenter, phase I/II trial. Patients received step-up dosing to a 4-mg intravenous dose of epcoritamab administered in 28-day cycles. The ORR was 63%, with a CR rate of 39%.¹¹ Patients naïve to CAR T-cell therapy had an ORR of 69%, with a 42% CR rate; those with prior CAR T-cell therapy had rates of 54% and 34%, respectively.

Epcoritamab is also given on an indefinite basis.

Odronextamab, an IgG4-based CD20×CD3 bispecific antibody has also produced promising results for CD20-positive B-cell malignancies. Data from a single-arm, phase I study of 145 patients with a median of three prior therapies showed an objective response rate of 51%.¹² Odronextamab has had some delays, as it was placed on a partial clinical hold in late 2020 in order to reduce rates of severe CRS during step-up dosing; the hold has since been lifted.

There are also several bispecific antibodies being investigated for the treatment of other forms of lymphoma, including glofitamab for mantle cell lymphoma (MCL), as well as mosunetuzumab for chronic lymphocytic leukemia (CLL). Results of a first-in-human phase I study of NVG-111, a ROR1×CD3 bispecific antibody, in patients with relapsed or refractory CLL or MCL were presented at the 2022 ASCO Annual Meeting. Although results were only available for a small number of patients, the early data showed promising efficacy with a manageable safety profile.¹³

Drawbacks

Bispecific antibodies or T-cell-engaging therapies have advantages compared with existing therapies, like being more readily available, but they are still associated with certain adverse events.

“Because they are a T-cell-based therapy, they do share some similar toxicities seen with CAR T-cell therapy,” said Jing-Zhou Hou, MD, PhD, a medical oncologist, hematologist, and clinical investigator at the University of Pittsburgh Medical Center Hillman Cancer Center in Pennsylvania. “The two major side effects of concern are CRS and immune effector cell-associated neurotoxicity (ICANS).”

For example, teclistamab was given regulatory approval with a Boxed Warning for life-threatening or fatal CRS and neurologic toxicity, including ICANS. In the MajesTEC-1 trial, CRS occurred in 72% of patients, neurologic toxicity in 57%, and ICANS in 6%. However, grade 3 CRS only occurred in 0.6% of patients and grade 3/4 neurotoxicity in 2.4%.⁴

“The new thing about this drug compared with other myeloma therapies is the significantly high proportion of patients experiencing CRS, especially during the first one or two doses,” Dr. Dholaria said. “Patients are admitted to the hospital for 48 hours at a time during step-up dosing for monitoring for fever. Fortunately, CRS does not appear to be high in severity like with CAR T-cell therapy.”

Teclistamab is generally well tolerated after these initial doses, and the risk for CRS is minimal, indicating that the rest of treatment can be given in an outpatient setting, Dr. Dholaria said.

Similar adverse events were seen with the other bispecific antibodies as well.

“Across all of these studies, there has been the use of step-up dosing, which has been shown to be effective,” Dr. Dickinson said. “You give the first dose at a lower dose to get a lower overall rate of CRS. Across all of these agents, the second dose then had a lower rate of CRS compared with the first dose.”

The idea, Dr. Dickinson said, is to get the patient through that initial CRS with a low dose, and then step the patient up to the most effective dose. Different agents have had slightly different step-up strategies, with some still establishing the best step-up dose to balance CRS risk with treatment efficacy.

In addition to the possibility of adverse events, another potential drawback to these drugs is cost.

“These drugs are ridiculously expensive,” Dr. Dholaria said. “Teclistamab is currently quoted at $40,000 a month. This is an ongoing expense to the health care system infrastructure that all of us will have to pay for eventually, and as these drugs get incorporated into earlier lines of therapy, we will be treating a lot more patients with them.”

Dr. Dholaria noted that CAR T-cell therapy is also expensive but is a one-time treatment. In addition, if a patient achieves remission after CAR T-cell therapy, there is no subsequent treatment needed.

“The cumulative financial toxicity over time for bispecific antibodies is going to come close to a one-time CAR-T infusion, and that is something to consider not only on the patient level but as the treating physician as well,” Dr. Dholaria said. “Cost needs to be looked at, especially when they may be used in combination with other drugs that are equally as expensive.”

Future Use

It is important to consider the possible cost of bispecific antibodies in combination with other therapies because these off-the-shelf drugs lend themselves to combination, according to Dr. Dickinson.

“Sponsors are aggressively developing bispecifics in combination with other drugs,” Dr. Dickinson said. “We know there are a number of trials looking at patients in first or subsequent relapse using conventional platinum-containing chemotherapy combinations or in combination with R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, with promising early safety data.”

For example, data presented at the 2022 ASH Annual Meeting and Exposition looked at teclistamab in combination with daratumumab and lenalidomide (MajesTEC-2).¹⁴ There were also multiple abstracts looking at bispecific antibodies with different targets. Dr. Hou presented data from a phase I study of TNB-486, a CD19×CD3 bispecific antibody for patients with relapsed or refractory B-cell non-Hodgkin lymphoma.¹⁵ Early data showed an ORR of 81.2%, with a CR rate of 68.7% at doses 2.4 mg and higher. For patients with relapsed/refractory FL, the ORR is 87.5%, and all responders achieved a complete metabolic response. Responses were also seen among patients with previous CAR T-cell therapy.

“This drug was engineered with a prolonged half-life,” Dr. Hou explained. “The half-life is about nine to 11 days, which would allow for biweekly or even monthly dosing.”

Bispecific antibodies are also expected to be incorporated into earlier lines of therapy. For example, another phase I study presented at the 2022 ASH Annual Meeting and Exposition compared lenalidomide with or without teclistamab as a maintenance therapy after transplantation in patients with newly diagnosed MM.¹⁶

As availability of bispecific antibodies grows, there is also the expectation that access to these drugs will expand into community cancer centers. Unlike CAR T-cell therapy, which is administered at specialized treatment centers, bispecific antibodies are expected to be used in an outpatient setting.

“I think these drugs can be safely used in a community oncology center, but there will need to be a degree of understanding about toxicities so that when severe toxicities occur, there is a reliable response,” Dr. Dickinson said.

Dr. Hou agreed, adding that it is possible that since CRS and neurotoxicity are most likely to occur in the first or second cycle that these drugs may be initially administered in the hospital until practitioners learn how to best minimize risk.

The Association of Community Cancer Centers (ACCC) conducted a survey in 2020 on bispecific antibodies with 129 community providers responding. Some of the common challenges to use of blinatumomab (the only available bispecific antibody at the time) included transitioning patients from the inpatient to outpatient setting (41%), managing patients in remote areas (28%), managing side effects (27%), assisting patients with treatment-related costs (24%), and lacking in-house expertise with the drug class (22%).¹⁷

Subsequently, the ACCC and the Society for Immunotherapy of Cancer developed an educational initiative on best practices in expanding access to bispecific antibodies and adverse event management.

“The toxicities with these drugs are no worse than those we see from CHOP chemotherapy, which is routinely given as a frontline regimen,” Dr. Dickinson said. “While CRS and fever after an infusion are different from toxicities from conventional agents, once people get their head around them, they will realize that they are less severe and as manageable.”

Experts eagerly await future trial results and decisions from the FDA on regulatory approval of some of these agents, all of which point to expanded use throughout the cancer care community.

“These are highly active agents in a number of treatment setting that do not require the complexity that CAR T-cell treatment might require and exposes the patient to a mechanism of cancer cell killing that is not the traditional cytotoxic method,” said Dr. Dickinson.

Moving forward, Dr. Hou said he envisions ongoing availability of both new and improved CAR T-cell therapy options and bispecific antibodies.

“If a patient fails CAR T-cell therapy, they can get a bispecific antibody and vice versa,” Dr. Hou said. “These two treatments should complement each other, give patients more options, and give physicians more weapons to fight these deadly diseases.”

Leah Lawrence is a freelance health writer and editor based in Delaware.

References

1. S. Food & Drug Administration. FDA grants regular approval to blinatumomab and expands indication to include Philadelphia chromosome-positive B cell. July 12, 2017. Accessed December 6, 2022. www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-blinatumomab-and-expands-indication-include-philadelphia-chromosome
2. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847.
3. S. Food & Drug Administration. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. October 25, 2022. Accessed December 6, 2022. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma
4. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387:495-505.
5. Pfizer press release. Pfizer’s elranatamab granted FDA breakthrough therapy designation for relapsed or refractory multiple myeloma. November 3, 2022. Accessed December 8, 2022. www.pfizer.com/news/press-release/press-release-detail/pfizers-elranatamab-granted-fda-breakthrough-therapy
6. Lesokhin AM, Arnulf B, Niesvizky R, et al. Initial safety results for MagnetisMM-3: A phase 2 trial of elranatamab, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM). J Clin Oncol. doi:10.1200/JCO.2022.40.16_suppl.8006
7. Roche press release. European Commission approves Roche’s first-in-class bispecific antibody Lunsumio for people with relapsed or refractory follicular lymphoma. June 8, 2022. Accessed December 7, 2022. www.globenewswire.com/news-release/2022/06/08/2458330/0/en/European-Commission-approves-Roche-s-first-in-class-bispecific-antibody-Lunsumio-for-people-with-relapsed-or-refractory-follicular-lymphoma.html
8. Budde LE, Sehn LH, Matasar M, et al. Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol. 2022;23(8):1055-1065.
9. Dickinson M, Carlo-Stella C, Morschhauser F, et al. Glofitamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and ≥ 2 prior therapies: pivotal phase II expansion results. J Clin Oncol. doi:10.1200/JCO.2022.40.16_suppl.7500
10. AbbVie press release. U.S. FDA accepts for priority review the Biologics License Application for epcoritamab (DuoBody®-CD3xCD20) for the treatment of relapsed/refractory large B-cell lymphoma. November 21, 2022. Accessed December 7, 2022. https://news.abbvie.com/news/press-releases/us-fda-accepts-for-priority-review-biologics-license-application-for-epcoritamab-duobody-cd3xcd20-for-treatment-relapsedrefractory-large-b-cell-
    htm
11. AbbVie press release. AbbVie announces late-breaking results from phase 2 trial of investigational epcoritamab (DuoBody®-CD3xCD20) in patients with relapsed/refractory large B-cell lymphoma (LBCL) at the European Hematology Association (EHA) Annual Congress. June 11, 2022. Accessed December 7, 2022. https://news.abbvie.com/news/press-releases/abbvie-announces-late-breaking-results-from-phase-2-trial-investigational-epcoritamab-duobody-cd3xcd20-in-patients-with-relapsedrefractory-large-b-cell-lymphoma-lbcl-at-european-hematology-association-eha-annual-congress.htm
12. Bannerji R, Arnason JE, Advani RH, et al. Odronextamab, a human CD20×CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial. Lancet Haematol. 2022;9(5):e327-e339.
13. Jasani P, Townsend W, Asher S, et al. First-in-human phase I study of a ROR1-targeting bispecific T-cell engager (NVG-111) shows evidence of efficacy in patients with relapsed/refractory CLL and MCL. J Clin Oncol. doi:10.1200/JCO.2022.40.16_suppl.7535
14. Searle E, Quach H, Wong SW, et al. Teclistamab in combination with subcutaneous daratumumab and lenalidomide in patients with multiple myeloma: results from one cohort of MajesTEC-2, a phase1b, multicohort study. Abstract #160. Presented at the 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana.
15. Hou J-Z, Jacobs R, Cho S-G, et al. Interim results of the phase 1 study of Tnb-486, a novel CD19xCD3 T-cell engager, in patients with relapsed/refractory (R/R) B-NHL. Abstract #612. Presented at the 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana.
16. Zamagni E, Boccadoro M, Spencer A, et al. MajesTEC-4 (EMN30): a phase 3 trial of teclistamab + lenalidomide versus lenalidomide alone as maintenance therapy following autologous stem cell transplantation in patients with newly diagnosed multiple myeloma. Abstract #3242. Presented at the 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana.
17. Association of Community Cancer Centers. Using bispecific antibodies in community practice: challenges and opportunities. Accessed on December 6, 2022. www.accc-cancer.org/docs/projects/bispecific-antibodies/using-bispecific-antibodies-in-community-practice.pdf?sfvrsn=f5b5ac13_0