Clinical Lymphoma, Myeloma & Leukemia, Vol.22, Suppl.2 - October 2022

S91 E XABS-198-ABC L Bispecific A n tibodies for Aggressi v e B-Cell L y m pho m a Rory Be nn ett, MBChB 1 , a n d Michael D icki n so n MBBS (Ho n s), D Med Sci, F RACP, F RCPA 1, * 1 Peter MacCallum Cancer Centre, 305 Grattan Street, Parkville, Victoria 3000, Australia *Correspo n di n g author: michael.dickinson@petermac.org Keywords Lymphoma, therapy, bispecific antibody, immunotherapy, clinical trials Introduction CD20/CD3 bispecific T-cell engaging antibodies lead to HLA- independent, cytotoxic T-cell mediated lymphoma cell death. We will review emerging safety and efficacy data from current publications and presentations. Clinical Pharmacology Unlike their CD19-targeting predecessor, blinatumomab, the CD20/3 bispecific antibodies (BsAb) in clinical development are predominantly IgG-like full-length antibodies. This structure and modifications to the Fc domain deliver a longer half-life and the ability to dose intermittently. Cytokine release syndrome (CRS) is a key consequence of T-cell activation and in trials has been dose-limiting. Recognising that CRS is both dose-dependent and reduced by low-dose priming, step-up dosing is used to mitigate CRS together with corticosteroid pre-medication. Additionally, a single dose of obinutuzumab is used before glofitamab. The uniquely subcutaneous route of delivery of epcoritamab influences the kinetics of CRS compared to the IV BsAb. Epcoritamab and odrenextamab are given continuously until disease progression, while glofitamab is a fixed-duration therapy. Clinical Efficacy Phase 1 trials show the clear activity of this class across the histological subtypes of large B-cell lymphoma and mantle cell lymphoma. Available data are summarised in Table 1 . To date, two drugs, epcoritamab and glofitamab, have available pivotal phase 2 data in large B-cell lymphoma (both n=~155). Both demonstrate approximately a 40% complete remission in the treatment of third and subsequent-line LBCL and are efficacious after the failure of CAR-T cell therapy. They are distinguished by the number of dosing visits in the first 24 weeks, route of administration, and duration of treatment. Extended follow-up from the dose-escalation phases of both agents, together with 9- and 12- month median follow-up data from the pivotal phase 2 cohorts of epcoritamab and glofitamab, respectively, confirm that complete remission is associated with durable responses and potentially cure. Although the CR rate is lower in the data from odronextamab so far, multi- year complete remissions have been observed. All three agents deliver complete remissions to patients previously exposed to CAR T, providing a clue to future sequencing possibilities. BsAb demonstrate efficacy against R/R mantle cell lymphoma (MCL). These patients were included in aNHL cohorts in the majority of trials, including the odronextamab phase 1 trial, where overall and complete responses of 50% and 33% were observed in 12 MCL patients, respectively. Preliminary data of evaluable MCL patients from the NP301 7 9 trial demonstrated overall and complete responses of 81% and 66. 7 %, respectively, with efficacy seemingly independent of prior BTK-inhibitor exposure. 1 Toxicity In all trials, while the incidence of reported CRS was common, optimisation of dosing and steroid schedules have made these treatments deliverable on a predominantly ambulatory basis. With ondronextamab and glofitamab, CRS was seen most commonly during dose step-up, but for epcoritamab it is seen most commonly at the time of the first target dose. CRS can be efficiently managed with early and judicious use of steroids. Serious neurological toxicities are rare but reported with all agents. Combination Therapies Under Evaluation Novel frontline combinations under evaluation for DLBCL or HGBL include glofitamab+R-CHOP or RCHP-polatuzumab (NCT04980222), and glofitamab (NCT0346 7 3 7 3, NCT04914 7 41) or mosunetuzumab (NCT036 77 141) with either R/O-CHOP or polatuzumab+R-CHP. Bispecifics are being combined with standard salvage therapies such as R-ICE (glofitamab, NCT05364424), gemcitabine/oxaliplatin (glofitamab NCT04408638, or mosunetuzumab NCT04313608); polatuzumab vedotin (glofitamab. NCT03533283 and or mosunetuzumab, NCT036 77 154); and lenalidomide or the CElMoDs (NCT05169515, NCT05335018, NCT02568553). The EPCORE NHL-2 study (NCT0466334 7 ) has multiple combination arms in different settings. Data from arm 1 of this study using first-line epcoritamab+R-CHOP for high-risk DLBCL has demonstrated an overall response rate of 96%. 2 A cohort of transplant-eligible R/R DLBCL patients who received salvage epcoritamab+R-DHAX/C with subsequent ASCT or epcoritamab monotherapy demonstrated OR and CR rates of 82.6% and