CD20 xCD3 bispecific antibodies for large B cell lymphoma: latest updates from 2024 ASH annual meeting

Abstract

Bispecific antibodies (BsAbs) represent an innovative class of off-the-shelf T-cell redirecting agents and are considered among the most promising immunotherapeutic strategies for the treatment of lymphoma. Notably, anti-CD20 × CD3 BsAbs have exhibited substantial monotherapy efficacy in patients with heavily pretreated B-cell non-Hodgkin lymphoma (B-NHL), showing a tolerable toxicity profile predominantly associated with T-cell activation-related side effects. In this study, we summarized several latest reports on CD20 × CD3 bsAbs for the therapy of Large B Cell Lymphoma (LBCL), also in first line, from the ASH 2024 annual meeting (ASH 2024).

To the Editor,

This article presents a comprehensive overview of the most recent clinical data on CD20×CD3 BsAbs for LBCL, as showcased at the 2024 ASH Annual Meeting (Table 1).

Table 1 Characteristics of CD20×CD3 bispecifc antibodies

BsAbs in the setting of first line fit treatment patients

Patients with LBCL experience a relapse rate of 40% after first-line treatment, with OS and PFS rates decreasing as the IPI increases, suggesting the need for novel treatments to improve outcomes. Falchi et al. reported results from the EPOCORE-NHL 2 trial involving 47 previously untreated patients with LBCL (IPI ≥ 3) who received epcoritamab (epcor) [1] plus R-CHOP. At the median follow-up the ORR was 100%, with a CR rate of 87%. The estimated OS and PFS at 24 months were 87% and 74%, respectively. The most frequent treatment-related AEs were neutropenia (70%), anemia (68%), and CRS (60%), with CRS all being Grade 1–3 and occurring after the first full dose. ICANS was reported in 2 patients and resolved.

In a multicenter trial comparing glofitamab (glofit)-R-CHOP (arm A) and glofit-pola-R-CHP (arm B) for high-risk LBCL patients (IPI ≥ 3, NCCN-IPI ≥ 4, or HGBL with MYC and BCL2 and/or BCL6 rearrangements) [2], 80 patients were randomized. After induction, CR/PR rates were 70%/29% in arm A and 80%/18% in arm B. Grade ≥ 3 AEs occurred in 22/40 patients in each arm, with CRS Grade 1 in 7/40 (18%) in arm A and 8/40 (20%) in arm B. One Grade 2 CRS event occurred in each arm, with no Grade 3–5 CRS events.

BsAbs in the setting of first line unfit treatment patients

The EPCORE^® DLBCL-3 trial (Arm A) [3] enrolled 45 patients aged over 75 years, anthracycline-ineligible due to advanced age, comorbidities, or cardiac toxicity risk, all with newly diagnosed LBCL. These patients received epcor for a fixed duration of up to one year. Among 39 evaluable patients, the ORR was 74% (29/39) and the CR rate was 64% (25/39). The most common treatment-emergent AEs occurred in 20% of patients, with 68% of these being CRS. Despite advanced age and comorbidities, epcor demonstrated both efficacy and a favourable safety profile.

Another study explored the combination of epcor and R-mini-CHOP in first-line LBCL [4]. In arm 8 of the EPCORE™ NHL-2 study, 28 patients with a median age of 81 years and cardiological comorbidities were enrolled. The median follow-up was 16.8 months, with an ORR of 89% (25/28) and a CR rate of 82% (23/28). The most common treatment-related AEs were CRS (45%), all resolved except for one case.

Given R-CHOP’s high efficacy, BsAbs may be reserved for higher-risk or comorbid patients to enhance chemotherapy, without introducing new safety concerns.

BsAbs in the setting of R/R patients

R/R LBCL patients have poor prognosis, with 50% failing salvage chemotherapy and ASCT. CAR-T achieves long-term remission in 40%, with some ineligible due to fitness, access, or cost, or needing bridging therapy.

In the setting of R/R LBCL, three groups presented long-term follow-up data on monotherapy with BaAbs. Allan et al. [5] reported pooled data from the ELM 1 and 2 studies using odronextamab (odro) monotherapy in hard-to-treat R/R LBCL populations. Epcore-NHL 1 [6] presented 3-year data from 157 patients treated with epcor monotherapy. Dickinson [7] presented 3-year results from 155 patients treated with 12 cycles of glofit. These three trials demonstrated similar efficacy in terms of ORR and comparable CRS rates (Table 2).

Table 2 Overview of clinical trials using BsAbs in patients with LBCL in first line and in R/R setting

Riedell et al. [8] presented the first results from plamotamab, a novel CD20×CD3 BsAb administered subcutaneously in heavily pretreated NHL patients, including 14 with LBCL. The median number of prior lines was 4, compared to 3 for other BsAbs.

For combination therapies in R/R LBCL, Diefenbach et al. [9] explored the combination of glofit with R-ICE in patients eligible for ASCT or CAR-T therapy after one prior line. Gurion et al. [10] updated the Epcore-NHL-5 study, where 40 patients with R/R LBCL received epcor plus lenalidomide for 12 cycles, achieving an ORR/CR rate of 67.6%/65%, this combination aim to restore the immune synapse and enhance cytotoxicity.

Both glofit and mosunetuzumab (mosu) have been combined with the anti-CD79b antibody-drug conjugate polatuzumab vedotin (pola) in R/R LBCL patients [11–12]. In the Chavez trials, patients were randomized to the M-Pola arm vs. the rituximab (R)-Pola arm. The ORR and CR rates for these combinations were 84% and 61% for glofit, and 78% and 58% for mosu, respectively. These results suggest an advantage for combination therapy while maintaining a similar safety profile (Table 2).

CD20×CD3 BsAbs are a major advance in LBCL treatment. While their CR rates match CAR-T, more data on long-term outcomes and DoRs are needed. The easiest accessibility to these drugs could represent an advantage to CAR-T and ensure better compared to ASCT in R/R patients.