Bispecific Antibodies Provide a New Tool in B-Cell Lymphoma Treatment

Matthew Matasar, MD

While traditional therapies used for the treatment of B-cell lymphomas often come with limitations, including delayed treatment initiation, harsh adverse effects (AEs), and limited effectiveness, bispecific antibodies are ushering in a new wave of hope, offering an off-the-shelf and promising alternative for care.

Unlike chimeric antigen receptor (CAR) T-cell therapy, which require time for manufacturing, bispecific antibodies are readily available. This translates to quicker treatment initiation, which is key in improving patient outcomes.

Bispecific therapies are already approved for the treatment of patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), including glofitamab-gxbm (Columvi) based on results from the phase 1/2 NP30179 study (NCT03075696) and epcoritamab-bysp (Epkinly) for DLBCL and mosunetuzumab-axgb (Lunsumio) for FL. Now, this class of drugs are showing promise in the treatment of mantle cell lymphoma.

Studies have shown improved response rates with bispecifics, ranging from 60% to 80% in different types of lymphoma. Unlike other T-cell-engaging therapies, the AEs observed with these agents generally are more mild and less frequent, including low rates of cytokine release syndrome and immune-related events.

Experts like Matthew Matasar, MD, are optimistic about the future of bispecific antibodies as they are easy to use, show a promising safety profile, and have demonstrated effectiveness against B-cell lymphomas. Ongoing research continues to explore wider applications and identify the optimal settings for each agent to improve patient outcomes.

In an interview with Targeted Oncology^TM, Matasar, chief of the division of blood disorders at the Rutgers Cancer Institute and professor at the Rutgers Robert Wood Johnson Medical School, discussed the advantages and current applications of bispecific antibodies for the treatment of B-cell lymphomas.

Illustration of lymphoma cell: © Dr_Microbe - stock.adobe.com

Targeted Oncology: What is the most significant advantage of using a bispecific antibody vs traditional therapies in earlier lines of treatment?

Matasar: Bispecifics are a powerful and emerging option for us in the management of B-cell lymphomas. They [have many] advantages. First, they are an off-the-shelf therapy, which allows for more immediate time from clinical decision making to treating a patient. They are potent in both indolent and aggressive lymphomas. We have data leading to the approval of mosunetuzumab with an overall response rate of 80% and a [complete response rate (CR)] of 60%. We have 2 biospecifics approved in the treatment of diffuse large B-cell lymphoma with response rates of 40% to 50% and CR rates of 20% to 30% in an even more high-risk disease scenario, and we have other antibodies that are pending approval.

These are off-the-shelf treatments with more favorable toxicity profiles than other T-cell-engaging treatments such as autologous CAR T-cell therapy. [We must understand] the ceiling for bispecifics and just how high they can go, how early they can go in therapeutic paradigms and in earlier lines of therapy, and whether we can identify their best partners be the immunologic or cytotoxic to further leverage this powerful class of treatments.

Can you discuss some of the follow-up data observed with mosunetuzumab?

Mosunetuzumab the first bispecific approved in the treatment of relapse follicular lymphoma as a monotherapy. At [the 2023 American Society of Hematology Annual Meeting], we presented our updated findings as we continue to follow these patients to learn more about the durability of this therapy. The results presented here were very encouraging. We see prolongation in both the progression-free survival, PFS, as well as the duration of response with a median PFS for these heavily pretreated patients was just about 2 years. The median duration of response was 3 years. This is very important data.

What should a community oncologist know about mosunetuzumab?

This is further ammunition to support our broader deployment of mosunetuzumab in a number of care settings. In addition to the updates on activity, we also importantly found no new safety signals as we follow the cohort over time, again, reaffirming that this is treatment that is appropriate for community-based settings.

Which specific types of lymphomas have shown the most promising response bispecific therapies based on current data?

So far, we have the greatest breadth of data in the treatment of follicular lymphoma and diffuse large B-cell lymphoma. Those are the 2 diseases in which we have FDA approvals currently. That's not the end of the story, of course, and we have extensive work ongoing in other histologies. We have a registrational trial ongoing for the evaluation of glofitimab in relapsed or refractory mantle cell lymphoma. I expect that over these next years and future [meetings], we will see a lot of other bispecific data in other settings as well.

How does the safety profile of bispecifics compare with other options? Are there any potential long-term risks one should know about?

When comparing a toxicity profile of a treatment, it is sometimes hard to know which is the best comparator. If one thinks about bispecific antibodies, as I do, as a T-cell-engaging therapy, then the toxicity evaluation of a drug or that class should be in that context, comparing bispecifics to CAR T-cell therapies, which of course have a spectrum of toxicities, but consistent across the board in terms of the nature of such toxicities.

We see that bispecific antibodies have less of all of that. Lower rates of cytokine release syndrome, lower rates of high-grade cytokine release syndrome, and far lower rates of immunologic adverse events called ICANS, compared with CAR T-cell therapies. Are there risks of late effects? Certainly. And as these data mature, we are continuing to look for emerging safety signals and to follow the persistence of those toxicities. Updated data for mosunetuzumab showed that the median duration of B-cell ablation was approximately 18 months, but that there is ongoing immune recovery, which is encouraging and not always seen after autologous CAR T-cell therapy.

How effective are they in combination with other therapies?

There are a number of combination protocols that are being conducted and starting to see early data readouts. We have combinations of some of these drugs with other immunologic approaches, such as immunomodulatory drugs, and we have data combining them with other cytotoxic approaches, both chemotherapy and antibody drug conjugates. These drugs do appear to be combinable and finding the optimal partners and optimal lines of therapy and histologies for such combinations is high priority work.

What are your predictions for the future of bispecific antibodies and personalized medicine?

I am tremendously optimistic about bispecific antibodies. They offer us the potential for off-the-shelf, safe, and effective immunotherapies in contexts where patients have been failed by more traditional approaches. I am excited to see where that field takes us, how many patients can reach these treatments, and how many patients can benefit from them.

I think that the most exciting development in personalized medicine in B-cell lymphomas has been in developing best-in-class abilities to detect minimal or measurable residual disease [MRD]. Impressive data for a novel MRD detection technology may pave the way for us to use such an approach to truly develop personalized response adapted therapeutic approaches in high-risk patients.