Sequencing of Bispecific Antibodies vs CAR T-Cell Therapies is Dependent on Several Factors in DLBCL, Multiple Myeloma

As bispecific antibodies gain traction in the diffuse large B-cell lymphoma (DLBCL) treatment paradigm, patient characteristics such as frailty, fitness, and disease risk influence how Francisco Hernandez-Ilizaliturri, MD, selects and sequences treatment with bispecific antibodies and CAR T-cell therapies.

Version 2.2024 of the NCCN Clinical Practice Guidelines in Oncology for B-Cell Lymphomas, which were released in April 2024, include axicabtagene ciloleucel (Yescarta) and lisocabtagene maraleucel (Breyanzi) as recommended second-line therapies, and bispecific antibodies, such as epcoritamab-bysp (Epkinly), are recommended in the third- and subsequent-line settings.¹

“Bispecific antibodies are another form of T-cell engager therapy, and their activity has been proven in clinical trials not only in relapsed/refractory large-cell lymphoma, but also in follicular lymphoma, [and] to a lesser degree in other types of lymphomas,” Hernandez-Ilizaliturri said in an interview with OncLive®. “Some of them are approved for patients with relapsed/refractory large-cell lymphoma, so in this context we are trying to weigh the choice of CAR T-cell therapy [vs a] bispecific antibody.”

In the interview, Hernandez-Ilizaliturri detailed how he selects and sequences treatments for patients with DLBCL, and also provided insights into the multiple myeloma space regarding how the FDA approvals of the CAR T-cell therapies ciltacabtagene autoleucel (cilta-cel, Carvykti) and idecabtagene vicleucel (ide-cel, Abecma) have provided more options for patients in earlier lines of treatment. Hernandez-Ilizaliturri is the director of Lymphoma Research, head of the Lymphoma Translational Research Laboratory, a professor of oncology, and an associate professor in the Department of Immunology at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

OncLive: How do the expanded indications of cilta-cel in the second-line setting and ide-cel in the third-line setting affect the use of CAR T-cell therapy in multiple myeloma?

Hernandez-Ilizaliturri: The approval of CAR T-cell therapy in multiple myeloma highlights the principle that these novel forms of immunotherapy can be applied to cancers beyond B-cell lymphomas. They provide therapeutic strategies for patients who are young—when they have good kidney function—[and] need to have disease control.

The activity [observed] in the 2 clinical trials with each of the CAR T-cell therapy products also highlights the need to develop new treatments because in contrast with what we see with B-cell lymphoma, the duration of the activity is not as long. Sometimes we should not wait too long to implement these treatments because the more damaged the immune system is in a patient from prior treatments, the less likely it is that these kinds of immunotherapies are going to [be effective] for a long time.

[The data] also stressed the need to learn how those myeloma cells may be further affecting CAR T-cell function, so we can develop a better way to apply this technology to have better clinical activity. [These are] encouraging data that are going to change the way that we practice, but it opens a lot of questions and is forcing industry to partner with academic centers to develop better CAR T-cell products for myeloma.

What factors do you consider when selecting CAR T-cell therapy or approved bispecific antibodies in DLBCL?

In general, we have longer follow-[up] data with CAR T-cell therapy; we can be comfortable assuming that CAR T-cell therapy can cure [approximately] 30% to 40% of patients with relapsed or refractory LBCL. Whereas the follow-up of patients treated with bispecific antibodies is not long enough to see if patients are being cured with this intervention. For a patient who is younger and fit, it may be better to start with a CAR T-cell therapy product because there is longer follow-up data and we have become more proficient in treating acute toxicities—that mitigates some of the concerns about that treatment.

If a patient is frailer, a bispecific antibody may be more suitable. [Treatment selection] also has to do with the geographic location of the patient and their access to CAR T-cell therapy. One of the benefits of bispecific antibodies is that they can be administered close to the patient’s home, as long as the physician is comfortable using the bispecific antibody and monitoring the adverse effects.

How do you sequence bispecific antibodies and CAR T-cell therapies in DLBCL?

It’s encouraging that bispecific antibodies have shown activity in patients previously treated with CAR T-cell therapy. A way to sequence these treatments would be to first start with CAR T-cell therapy and then [administer] a bispecific antibody in patients with high-grade lymphoma. This may change, as there are some interesting emerging data [regarding] combining bispecific antibodies with rituximab [Rituxan] or CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] in patients with high-risk DLBCL or large cell lymphoma.

There are data looking at combining the bispecific antibody [epcoritamab] with R-CHOP [rituximab plus CHOP] and the ORR [was] 100% [in 31 patients with high-risk DLBCL treated in the phase 1/2 EPCORE NHL-2 (NCT04663347) trial]. There are ongoing randomized trials in the first-line setting combining a bispecific antibody with R-CHOP vs R-CHOP in DLBCL [as well].

We don’t know if bispecific antibodies will move into the first-line setting at [some] point, but in the relapsed/refractory setting the most logical treatment sequence will be to do CAR T-cell therapy followed by a bispecific antibody; that thought process may be different in follicular lymphoma because patients tend to be elderly, have medical problems, and, in general, the disease is not pacing too aggressively. [Therefore], patients may be more suited to receive a bispecific antibody first and followed by CAR T-cell therapy, but this is a moving field. We have to be open-minded [with] the capacity of these 2 technologies to see how we’re going to learn to sequence them better in the future.

Reference

NCCN. Clinical Practice Guidelines in Oncology. B-Cell Lymphomas, version 2.2024. Accessed July 12, 2024. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf