Odronextamab confirmed manageable security and sturdy responses in R/R DLBCL sufferers progressing after CAR-T.
Amongst sufferers with relapsed/refractory (R/R) diffuse giant B-cell lymphoma (DLBCL) who’ve progressed after CAR-T cell remedy, the bispecific antibody odronextamab demonstrated a typically manageable security profile and sturdy responses, based on findings from the post-CAR-T enlargement cohort of the ELM-1 examine revealed in Blood.
The target response fee (ORR) and full response (CR) fee had been 48.3% and 31.7%, respectively, after a median follow-up of 16.2 months. The median length of response (DOR) was 14.8 months, and the median length of CR was not reached; the median progression-free survival (PFS) and total survival (OS) had been 4.8 months and 10.2 months, respectively. Furthermore, these responses had been comparable throughout sufferers no matter prior CAR-T merchandise used and time to relapse on CAR T.
“Odronextamab monotherapy demonstrated encouraging efficacy and usually manageable security, supporting its potential as an off-the-shelf possibility for post-CAR-T sufferers,” lead examine writer, Dr. Max Topp, a professor and head of Hematology, Division of Hematology at Universitätsklinikum Würzburg, in Würzburg, Germany, and colleagues wrote within the journal.
CD19-directed CAR-T cell remedy is a remedy possibility for R/R DLBCL which has proven substantial efficacy in pivotal trials, resulting in sure brokers’ approvals in america and Europe. Nevertheless, regardless of the efficacy of CD19-targeted CAR-T cell remedy, roughly half of sufferers with R/R DLBCL will expertise relapse, with a median total survival (OS) of 5 months post-progression. Moreover, many sufferers don’t obtain additional remedy following CAR-T, underscoring a major unmet want on this inhabitants.
Glossary:
CAR T-cell remedy: A approach to reprogram the immune system to higher battle most cancers by enhancing the power of T cells to acknowledge and assault most cancers cells.
Goal response fee (ORR): the proportion of sufferers who’ve a partial or full response to a remedy.
Full response (CR): the whole disappearance of all detectable indicators of a tumor or most cancers.
Median length of response (DOR): the size of time in a medical trial the place 50% of sufferers who achieved a tumor response skilled no illness development earlier than their most cancers progressed once more.
Development-free survival (PFS): the period of time a affected person lives with a illness like most cancers with out it getting worse.
General survival (OS): the size of time a affected person survives after being identified with a illness or beginning remedy.
Cytokine launch syndrome (CRS): systemic inflammatory response that happens when the immune system releases giant quantities of cytokines into the bloodstream.
One potential mechanism of resistance or relapse is CD19 antigen loss, which happens in roughly 30% of sufferers at illness development after CAR-T cell remedy. This problem has spurred curiosity in therapies concentrating on different B-cell antigens, although no normal of care has been established for these sufferers. Within the Section 1 ELM-1 examine, odronextamab monotherapy demonstrated efficacy and manageable security in closely pretreated sufferers with R/R DLBCL and different B-cell malignancies.
On the 2024 ASH Annual Assembly, investigators offered the first evaluation of the devoted post-CAR T enlargement cohort of ELM-1.
Delving Into the Strategies Utilized in ELM-1
ELM-1 is a part 1, single-arm, multicenter examine evaluating odronextamab monotherapy in sufferers with R/R CD20-positive B-cell non-Hodgkin lymphoma. The prespecified post-CAR-T enlargement cohort included sufferers aged 18 years or older with DLBCL who skilled illness development after CAR-T cell remedy and had recovered from related toxicities. Prior CAR-T was not required to be the newest remedy earlier than enrollment.
Eligible sufferers had obtained no less than one prior anti-CD20 remedy and had sufficient hematologic and organ perform. Exclusion standards included main central nervous system (CNS) lymphoma or recognized/suspected CNS involvement.
Sufferers obtained intravenous (IV) odronextamab in 21-day cycles, with a step-up dosing technique in Cycle 1 to mitigate the danger of cytokine launch syndrome (CRS). Odronextamab was administered at 160 milligrams (mg) on Days 1, 8 and 15 of Cycles 2 to 4, then at 320 mg each two weeks till illness development or unacceptable toxicity. Sufferers attaining a CR lasting 9 months or longer transitioned to 320 mg each 4 weeks.
The first finish level of the examine was the ORR. Secondary finish factors included DOR, PFS, OS, security, pharmacokinetics and immunogenicity. Exploratory finish factors assessed biomarkers, together with T-cell and B-cell dynamics and cytokine profiles.
“The post-CAR-T enlargement cohort of ELM-1 is the primary examine to prospectively consider the efficacy and security of odronextamab in sufferers with R/R DLBCL progressing after CAR T remedy,” Topp and colleagues wrote. “Moreover, to our information, that is the primary evaluation demonstrating T-cell health throughout remedy with a CD20×CD3 bispecific antibody.”
Extra Outcomes and Security Generated within the Evaluation
Between Might 17, 2020, and April 19, 2023, 60 sufferers with R/R DLBCL who progressed after CAR-T cell remedy had been enrolled within the examine. Amongst them, 55 sufferers (91.7%) accomplished no less than one cycle of odronextamab, and 31 sufferers (51.7%) accomplished 4 or extra cycles. The most typical cause for remedy discontinuation was illness development (55%), adopted by doctor or affected person choices (26.7%) and uncomfortable side effects (11.7%). On the knowledge cutoff on Jan. 22, 2024, the median length of remedy publicity was 12.07 weeks, with two sufferers remaining on remedy.
The median follow-up was 16.2 months, with a median time to response of 1.8 months. Responses had been noticed throughout high-risk subgroups and no matter the kind of prior CAR-T remedy. Notably, sufferers with a CR had considerably longer PFS and OS in contrast with these attaining solely a PR. Those that relapsed inside 90 days of prior CAR T had shorter PFS and OS than those that relapsed later.
All sufferers skilled no less than one treatment-emergent aspect impact, with 90% experiencing a treatment-related aspect impact. Grade 3 (extreme) or greater treatment-emergent uncomfortable side effects had been reported in 76.7% of sufferers, mostly neutropenia (16.7%) and anemia (13.3%). Cytokine launch syndrome (CRS) occurred in 48.3% of sufferers however was restricted to grades 1 or 2, with a median onset of 17.7 hours and a median length of two days. Neurologic uncomfortable side effects occurred in 50% of sufferers, with encephalopathy being the most typical grade 3 occasion. No circumstances of immune effector cell-associated neurotoxicity syndrome or tumor lysis syndrome had been reported. Infections had been noticed in 50% of sufferers, with grade 3 or greater infections occurring in 20%. One treatment-related grade 5 (dying) occasion of COVID-19 pneumonia was reported.
“Responses had been sturdy, no matter time since prior CAR-T, and T cell health was maintained throughout odronextamab remedy. Given the dearth of remedy choices on this affected person inhabitants, the outcomes of this examine help the potential use of odronextamab as an off-the-shelf remedy possibility after CAR-T,” investigators concluded.
Reference:
“Odronextamab monotherapy in R/R DLBCL after development with CAR T-cell remedy: Main evaluation of the ELM-1 examine,” By Dr. Max S. Topp, et al. Blood.
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