Odronextamab Shows Efficacy in DLBCL Post CAR T-Cell Therapy

Matthew Matasar, MD

Odronextamab (Ordspono) given as a monotherapy demonstrated encouraging efficacy and had a generally manageable safety profile when used for the treatment of patients with diffuse large B-cell lymphoma who progressed following treatment with chimeric antigen receptor (CAR) T-cell therapy.¹

ELM-1 (NCT02290951), is an ongoing, phase 1 study evaluating the safety and tolerability of odronextamab in patients with CD20-positive B-cell malignancies who have previously received CD20-directed antibody therapy. Patients aged 18 years and older with DLBCL and disease progression after CAR T-cell therapy received odronextamab given via intravenous infusion weekly in 21-day cycles during cycles 1 to 4. This was given along with steroid prophylaxis and step-up dosing in cycle 1, followed by 160 mg on day 1, 8, and 15 of cycles 2 to 4. After the fourth cycle, odronextamab maintenance treatment was given to patients at a dose of 320 mg once every 2 weeks until disease progression or unacceptable toxicity.

The primary end point of the study was objective response rate (ORR), as assessed by independent central review (ICR) according to the Lugano classification, and key secondary end points of the trial were duration of response (DOR), progression-free survival (PFS), and OS. Exploratory end points evaluated included immune biomarker assessment.

According to findings presented at the 2024 American Society of Hematology Annual Meeting, patients treated with odronextamab had an ORR of 48% and a CR rate of 32% by ICR, respectively. The median DOR was 14.8 months (95% CI, 2.8-not estimable [NE]) and median duration of CR was not reached (NR) in this arm (95% CI, 3.3-NE). Additionally, the median PFS was 4.8 months (95% CI, 2.6-5.4) and the median OS observed among patients was 10.2 months (95% CI, 4.6-15.8). Both the median PFS and OS in complete responders was NR.

The most common treatment-emergent adverse event (TEAE) was cytokine release syndrome (CRS), occurring in 48% of patients. Grade 3 or greater TEAEs were reported in 77% of patients, with the most frequent being neutropenia (17%), anemia (13%), and decreases in neutrophil and white blood cell counts (10% each). Five patients (8%) permanently discontinued odronextamab due to AEs, including COVID-19, pneumonia, encephalopathy, epilepsy, and gait disturbance (1 case each). One treatment-related death occurred (COVID-19 pneumonia).

Additionally, no cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were reported. Grade 3 or greater infections occurred in 12 patients (20%), with 2 attributed to COVID-19. No tumor flare or tumor lysis syndrome cases were observed.

In an interview with Targeted Oncology^TM, Matthew Matasar, MD, chief of the division of blood disorders at the Rutgers Cancer Institute and professor at the Rutgers Robert Wood Johnson Medical School, discussed what the findings from the primary analysis of the ELM-1 trial of odronextamab in DLBCL means for oncologists.

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Targeted Oncology: Could you just provide an overview of the ELM-1 study and its primary objectives?

Matasar: We have long understood that while CAR T cell therapy has changed the landscape of relapse and refractory large cell lymphoma, there definitely remains unmet need. Certainly, loss of CD19 can limit our ability to administer subsequent CD19-directed treatments, and we know in general that bispecific antibodies are active in the management of aggressive B-cell lymphomas. So the question being posed here in this sub-analysis from ELM-1 is the activity of odronextamab as monotherapy in the treatment of diffuse large B-cell lymphoma relapsing after CAR T-cell therapy.

How does odronextamab work in the context of DLBCL, and why was it selected for this patient population?

Odronextamab is a bispecific antibody targeting both CD20 on the surface of malignant B-cells and CD3 on healthy native T-cells. These bispecific antibodies, such as odronextamab, create an immune synapse, allowing for T-cell activation, proliferation, and T-cell-mediated B-cell killing. We have extensive data from odronextamab and other similar molecules that these bispecific antibodies can be effective in treating aggressive B-cell lymphoma, even after the failure of prior lines of therapy. So here, we pose the question of whether odronextamab could be an appropriate treatment for patients that have been failed by CD19-targeting CAR T-cell therapy, understanding that patients who have been failed by CD19 CAR represent an area of tremendous unmet need, and these are patients with, unfortunately, very poor prognosis in the absence of standard treatments.

What were the key findings from the primary analysis for these patients?

What we found in this primary analysis from the prospectively collected cohort of patients receiving odronextamab after failure of CD19 CAR is that indeed, odronextamab monotherapy can be very effective in this very high-risk patient population. Not only do we see excellent overall response rates and complete response rates, but we also see durability as well, with some patients extending benefit well beyond a year, with the median duration of response of almost 15 months. And for those achieving their complete response, the median duration of CR not yet having been reached.

What was the response rate observed, and how does this compare with other available treatment options for patients with DLBCL after CAR T-cell failure?

The overall response rate for the collective cohort was 48%, and the overall complete response rate was 32%. I think it is important to recognize, however, that this is not a homogenous patient population in the post–CAR-T setting, and we saw a very clear correlation between the duration of benefit from the antecedent CAR and the likelihood of benefit from odronextamab. For patients that were either 6 months or longer after CAR T-cell therapy before enrolling on ELM-1, the overall response rate was over 80%, and complete response rates of 50% to 70%—very active. Conversely, those patients that had gone on to ELM-1, having derived less than 3 months' benefit from the prior CAR, were much less likely to benefit from odronextamab, with an overall response rate of only 21% and a CR rate of only 10%.

Were there any notable safety concerns or adverse events observed in this study?

I would say encouragingly, the safety profile from odronextamab in this context was similar to that which we understand is associated with odronextamab or similar bispecific antibodies in aggressive B-cell lymphoma. Certainly, CRS was seen. It occurred in about half of patients. It was entirely restricted to grade 1 or grade 2 in severity. Only 20% of patients required tocilizumab as a protocol-dictated rescue, and all cases were self-limited with supportive measures. Additionally, we saw no cases of ICANS, really reinforcing that this treatment is potentially safe and effective in this patient population.

For the community oncology audience, what are the key takeaways from this research?

I would say the key takeaways are that even though we know that patients who are relapsing after CAR T-cell therapy represent a very high-risk group of people, treatments like odronextamab as a bispecific antibody can potentially offer tremendous benefit with a treatment that can be administered in a variety of care settings, including community-based and outpatient contexts.

What are the next steps for the study in terms of follow-up for patients who participated in the trial?

We are always curious as to just how deep the rabbit hole is going to be, and as we allow these data to mature, we are going to better understand whether bispecific antibodies like odronextamab may represent not just an excellent option for disease control, but whether they may in fact hold a period of potential for a subset of patients.

REFERENCE:

1. Matasar M, Topp MS, Allan JN, et al. Efficacy and safety of odronextamab monotherapy in patients (Pts) with diffuse large B-cell lymphoma (DLBCL) progressing after CAR T-cell therapy: Primary analysis from the ELM-1 study. Blood. 2024;144(supplement 1):866. doi:10.1182/blood-2024-199155