S224: high complete response rate with tnb-486, a novel cd19xcd3 t-cell engager, in relapsed/refractory follicular lymphoma: interim results from an ongoing phase 1 study

Background: Follicular lymphoma (FL) is incurable with a relapsing/remitting pattern and decreasing progression-free survival (PFS) interval per recurrence. In the relapsed/refractory (R/R) setting, patients (pts) failing chimeric antigen receptor T-cell therapy (CAR T) or CD20 bispecific T-cell engagers (TCE) have few options. In addition, CD19 CAR T is limited by access and toxicities, while CD20 TCE are limited by CD20 antigen loss. TNB-486 is a novel bispecific CD19xCD3 TCE that induces T-cell–mediated cytotoxicity with reduced cytokine release via a low-affinity αCD3 moiety. Aims: We present interim data from a phase 1 dose-escalation study of TNB-486 (NCT04594642). Methods: Third-line+ R/R FL pts (grade [G] 1–3a) were enrolled (prior CD19 therapy allowed). Escalating fixed TNB-486 doses (0.03–2.4 mg) without priming were evaluated prior to implementing single (day [D] 1) and double priming doses (D1 & 8) prior to target dose (D15). TNB-486 was given IV every 2 weeks in 28-d cycles (C) for up to 2 y. Response was assessed with RECIL 2017 by central image review. Adverse events (AEs) and cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by CTCAE v5.0 and 2019 ASTCT criteria. Results: As of Dec 31, 2022, 17 pts received TNB-486 at target doses 0.03–10 mg (median age 68 y [range 33–86]; 53% male; 65% stage III/IV; 25% CD20-negative disease; median prior lines of therapy [LOT] 3 [range 2–9]). Prior therapies included αCD20 Ab (100%), alkylator (76%), IMiD (47%), CD20 TCE (12%), CD19 CAR T (12%), and autologous stem cell transplant (ASCT) (6%); 53% progressed or started 2nd LOT within 24 months (mo) of initiating 1st LOT (POD24). Median time on study was 7 mo (range 1–22). Eleven pts were response evaluable for efficacy at target doses ≥2.4 mg. Objective response rate (ORR) and complete response (CR) rate were 91% (Figure). ORR/CR for pts with CD20-negative disease, prior CD20 TCE, and POD24 was 100%. One pt with 9 prior LOT including ASCT and CAR T, had progression of disease. One pt progressed at C6 after achieving CR with preserved CD19 expression. All others remain in remission to date. The 6-mo PFS rate was 91%. No G3+ CRS occurred (59% G1, 12% G2). Neurologic events consistent with ICANS were reported in 24%, all G1–2 except 1 with a G3 event (confusion). All CRS/neurotoxicity (NT) were transient, resolving in a median of 1.5 d (range 1–5). G3+ treatment-related AEs in >10% of pts included decreased lymphocytes (35%) and neutropenia (12%). No treatment-related deaths or AEs leading to discontinuation occurred (1 pt died and 1 discontinued due to COVID-19). One pt received double step-up priming dosing to date with no CRS/NT. Pharmacokinetic/pharmacodynamic data analysis is ongoing. Summary/Conclusion: TNB-486 induces high complete remission rates during early phase dose escalation. With limited follow-up, responses appear durable in heavily pretreated FL pts, with a manageable safety profile. Dose escalation is ongoing to identify the RP2D.Keywords: CD19, Follicular lymphoma, Bispecific, B cell lymphoma