Time of CAR-T Failure Is a Strong Predictor of Outcome for Bispecific Antibody Therapy in Relapsed/Refractory Large B-Cell Lymphoma
Authors: Shumilov Evgenii , Wurm-Kuczera Rebecca , Vucinic Vladan , Seib Maximilian , Holtick Udo , Mazzeo Paolo , Scholz Julia Katharina , Boyadzhiev Hristo , Melchardt Thomas , Hölscher Alexander , Schultze-Florey Christian R , Velazquez Giuliano Filippini , Ossami Saidy Anna , Lesan Vadim , Schnetzke Ulf , Kerkhoff Andrea , Bacher Ulrike , Ghandili Susanne , Aydilek Enver , Gebauer Niklas , Weber Thomas , Wulf Gerald , Glass Bertram , Thurner Lorenz , Heidel Florian , Schmid Christoph , Viardot Andreas , Hänel Mathias , Dietrich Sascha , Pabst Thomas , Ayuk Francis A. , von Tresckow Bastian , Chapuy Björn , Pott Christiane , Mueller Fabian , Lenz Georg 
Published: December 2024

Introduction
Patients (pts) with relapsed or refractory (r/r) large B-cell lymphoma (LBCL) after CD19 chimeric antigen receptor (CAR)-T cell therapy are challenging to treat. CD20xCD3 T-cell-engaging bispecific antibodies (BsAbs) have emerged as a promising therapeutic option for these pts. In the pivotal trials, glofitamab and epcoritamab demonstrated notable efficacy, with an overall response rate (ORR) of at least 50% and a complete response rate (CR) of at least 34% after CAR-T cell therapy. However, data on the efficacy and safety of BsAbs post-CAR-Ts in the real-world setting are scarce.
Methods
To assess the efficacy and feasibility of BsAbs in the post CAR-T population, we conducted a retrospective, multicenter, multinational analysis, enrolling 85 pts with r/r LBCL treated with BsAbs across 20 centers in Germany, Austria, and Switzerland. Pts were eligible for the study if they had experienced CAR-T cell failure. We defined early ((within first 3 months (mo)), intermediate (4-6 mo) and late (&gt;6 mo) CAR-T cell failure and assessed efficacy (ORR, CR, PR, mPFS, mOS) and feasibility of BsAbs in the real-world setting depending on these time points. Furthermore, information on treatment between CAR-T and following BsAb was collected.
Results
The study cohort included de novo diffuse large B-cell lymphoma (DLBLC) (55/85), transformed indolent lymphoma (18/85), high grade B-cell lymphoma (HGBCL) ((10/85; MYC & BCL2/BCL6 rearrangements (5/10); not otherwise specified (NOS) (4/10); or 11q deletion (1/10)), primary mediastinal B-cell lymphoma (PMBCL) (1/85) and T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) (1/85). Before receiving BsAbs, 43 (51%) pts presented with early (mo 1-3), 24 (28%) with intermediate (mo 4-6), and 18 (21%) pts with late (&gt;6 mo) relapse post-CAR-Ts. Moreover, 51 out of 85 pts (60%) received BsAbs directly after CAR-T failure (immediate BsAb group), while 34 (40%) had a median of one therapy (range 1-4) prior to BsAbs (non-immediate BsAb group). Glofitamab (75/85) was the most commonly administered BsAb followed by epcoritamab (9/85) and mosunetuzumab (1/85).
Overall, 42% of pts responded to BsAbs, with 23% achieving CR and 19% partial response (PR). The ORR varied based on the timing of BsAbs application (47% immediate vs. 35% non-immediate, p=0.282) and CAR-T cell failure (30% vs. 50% vs. 61% in early, intermediate and late relapse post-CAR-Ts, p=0.019). The highest CR rate was observed in pts with late CAR-T failure (44%), followed by intermediate (25%) and early (14%) groups (p=0.037). The median progression-free survival (mPFS) was 3.27 mo, while the median overall survival (mOS) was 6.83 mo. Estimated mPFS was significantly better in the immediate than in the non-immediate BsAb group (4.37 mo vs. 2.48 mo, p=0.026) while mOS did not differ significantly (7.73 mo vs 5.10 mo, p=0.100). Additionally, mPFS and mOS differed significantly in early (2.13 and 4.10 mo), intermediate (3.73 and 7.73 mo) and late (10.46 mo and not reached) CAR-T failure groups, accordingly (p≤0.004).
In the multivariate analysis, sensitivity to the last treatment prior BsAbs (PFS - [HR=2.31, p=0.004]; OS - [HR=2.81, p=0.006]), the timepoint of CAR-T failure (PFS - [HR=1.48, p=0.05]; OS - [HR=1.94, p=0.011]), additional therapies between CAR-T and BsAb (PFS - [HR=1.86, p=0.039]) and LDH levels before application of BsAb considered as continuous variable (p=0.049 for PFS) were the strongest predictors of survival after initiation of BsAbs.
The frequency of cytokine release syndrome (CRS) was 31%, with grades 3-4 documented in 3%. Severe immune effector cell-associated neurotoxicity syndrome (ICANS) occurred only in one patient (1%) (grade 3). Infections were documented in 36% of pts, with grades 3 in 11% and three pts with grade 5 (all associated with COVID-19).
Conclusions
In summary, BsAbs show efficacy and manageable safety profiles in r/r LBCL pts following CAR-T failure in real-world settings. However, efficacy of BsAb is significantly impaired in early CAR-T refractory pts underscoring the necessity of novel therapeutic approaches in these pts.