Among patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who have progressed after CAR-T cell therapy, the bispecific antibody odronextamab demonstrated a generally manageable safety profile and durable responses, according to findings from the post-CAR-T expansion cohort of the ELM-1 study published in Blood.
The objective response rate (ORR) and complete response (CR) rate were 48.3% and 31.7%, respectively, after a median follow-up of 16.2 months. The median duration of response (DOR) was 14.8 months, and the median duration of CR was not reached; the median progression-free survival (PFS) and overall survival (OS) were 4.8 months and 10.2 months, respectively. Moreover, these responses were similar across patients regardless of prior CAR-T products used and time to relapse on CAR T.
“Odronextamab monotherapy demonstrated encouraging efficacy and generally manageable safety, supporting its potential as an off-the-shelf option for post-CAR-T patients,” lead study author, Dr. Max Topp, a professor and head of Hematology, Department of Hematology at Universitätsklinikum Würzburg, in Würzburg, Germany, and colleagues wrote in the journal.
CD19-directed CAR-T cell therapy is a treatment option for R/R DLBCL which has shown substantial efficacy in pivotal trials, leading to certain agents' approvals in the United States and Europe. However, despite the efficacy of CD19-targeted CAR-T cell therapy, approximately half of patients with R/R DLBCL will experience relapse, with a median overall survival (OS) of five months post-progression. Additionally, many patients do not receive further treatment following CAR-T, underscoring a significant unmet need in this population.
One potential mechanism of resistance or relapse is CD19 antigen loss, which occurs in approximately 30% of patients at disease progression after CAR-T cell therapy. This challenge has spurred interest in treatments targeting alternative B-cell antigens, though no standard of care has been established for these patients. In the Phase 1 ELM-1 study, odronextamab monotherapy demonstrated efficacy and manageable safety in heavily pretreated patients with R/R DLBCL and other B-cell malignancies.
At the 2024 ASH Annual Meeting, investigators presented the primary analysis of the dedicated post-CAR T expansion cohort of ELM-1.
Delving Into the Methods Used in ELM-1
ELM-1 is a phase 1, single-arm, multicenter study evaluating odronextamab monotherapy in patients with R/R CD20-positive B-cell non-Hodgkin lymphoma. The prespecified post-CAR-T expansion cohort included patients aged 18 years or older with DLBCL who experienced disease progression after CAR-T cell therapy and had recovered from associated toxicities. Prior CAR-T was not required to be the most recent treatment before enrollment.
Eligible patients had received at least one prior anti-CD20 therapy and had adequate hematologic and organ function. Exclusion criteria included primary central nervous system (CNS) lymphoma or known/suspected CNS involvement.
Patients received intravenous (IV) odronextamab in 21-day cycles, with a step-up dosing strategy in Cycle 1 to mitigate the risk of cytokine release syndrome (CRS). Odronextamab was administered at 160 milligrams (mg) on Days 1, 8 and 15 of Cycles 2 to 4, then at 320 mg every two weeks until disease progression or unacceptable toxicity. Patients achieving a CR lasting nine months or longer transitioned to 320 mg every four weeks.
The primary end point of the study was the ORR. Secondary end points included DOR, PFS, OS, safety, pharmacokinetics and immunogenicity. Exploratory end points assessed biomarkers, including T-cell and B-cell dynamics and cytokine profiles.
“The post-CAR-T expansion cohort of ELM-1 is the first study to prospectively evaluate the efficacy and safety of odronextamab in patients with R/R DLBCL progressing after CAR T therapy,” Topp and colleagues wrote. “Additionally, to our knowledge, this is the first analysis demonstrating T-cell fitness during treatment with a CD20×CD3 bispecific antibody.”
More Results and Safety Generated in the Analysis
Between May 17, 2020, and April 19, 2023, 60 patients with R/R DLBCL who progressed after CAR-T cell therapy were enrolled in the study. Among them, 55 patients (91.7%) completed at least one cycle of odronextamab, and 31 patients (51.7%) completed four or more cycles. The most common reason for treatment discontinuation was disease progression (55%), followed by physician or patient decisions (26.7%) and side effects (11.7%). At the data cutoff on Jan. 22, 2024, the median duration of treatment exposure was 12.07 weeks, with two patients remaining on treatment.
The median follow-up was 16.2 months, with a median time to response of 1.8 months. Responses were observed across high-risk subgroups and regardless of the type of prior CAR-T therapy. Notably, patients with a CR had significantly longer PFS and OS compared with those achieving only a PR. Those who relapsed within 90 days of prior CAR T had shorter PFS and OS than those who relapsed later.
All patients experienced at least one treatment-emergent side effect, with 90% experiencing a treatment-related side effect. Grade 3 (severe) or higher treatment-emergent side effects were reported in 76.7% of patients, most commonly neutropenia (16.7%) and anemia (13.3%). Cytokine release syndrome (CRS) occurred in 48.3% of patients but was limited to grades 1 or 2, with a median onset of 17.7 hours and a median duration of two days. Neurologic side effects occurred in 50% of patients, with encephalopathy being the most common grade 3 event. No cases of immune effector cell-associated neurotoxicity syndrome or tumor lysis syndrome were reported. Infections were observed in 50% of patients, with grade 3 or higher infections occurring in 20%. One treatment-related grade 5 (death) event of COVID-19 pneumonia was reported.
“Responses were durable, regardless of time since prior CAR-T, and T cell fitness was maintained during odronextamab treatment. Given the lack of treatment options in this patient population, the results of this study support the potential use of odronextamab as an off-the-shelf treatment option after CAR-T,” investigators concluded.
Reference:
"Odronextamab monotherapy in R/R DLBCL after progression with CAR T-cell therapy: Primary analysis of the ELM-1 study," By Dr. Max S. Topp, et al. Blood.
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