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114 Time of CAR-T Failure Is a Strong Predictor of Outcome for Bispecific Antibody Therapy in Relapsed/Refractory Large B-Cell Lymphoma

Program: Oral and Poster Abstracts
Type: Oral
Session: 906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: 'In with the Old, In with the New': Outcomes of Conventional and Novel Therapeutic Paradigms in Aggressive Lymphoid Malignancies
Hematology Disease Topics & Pathways:
Research, Adult, Lymphomas, Clinical Research, B Cell lymphoma, Patient-reported outcomes, Diseases, Therapy sequence, Real-world evidence, Aggressive lymphoma, Treatment Considerations, Lymphoid Malignancies, Study Population, Human
Saturday, December 7, 2024: 10:45 AM

Evgenii Shumilov1*, Rebecca Wurm-Kuczera, MD2*, Vladan Vucinic, MD3*, Maximilian Seib1*, Udo Holtick4*, Paolo Mazzeo5,6*, Julia Katharina Scholz, MD7*, Hristo Boyadzhiev8,9*, Thomas Melchardt, MD10*, Alexander Hölscher, MD11*, Christian R Schultze-Florey, MD12*, Giuliano Filippini Velazquez, MD13*, Anna Ossami Saidy14*, Vadim Lesan15*, Ulf Schnetzke16*, Andrea Kerkhoff, MD1*, Ulrike Bacher17*, Susanne Ghandili, MD18*, Enver Aydilek5*, Niklas Gebauer19*, Thomas Weber20*, Gerald Wulf5*, Bertram Glass, MD14*, Lorenz Thurner, MD15, Florian Heidel, MD12, Christoph Schmid, MD13*, Andreas Viardot, MD, PhD21, Mathias Hänel, MD22, Sascha Dietrich11*, Thomas Pabst8, Francis A. Ayuk, M.D.23*, Bastian von Tresckow24, Björn Chapuy25, Christiane Pott, MD26*, Fabian Mueller, MD27* and Georg Lenz1

1Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
2Department of Hematology, Oncology, and Cancer Immunology, Charité -University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
3Department for Hematology, Cell Therapy, Hemostaseology and Infectious Diseases, University of Leipzig, Leipzig, Saxony, Germany
4Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf; German CLL Study Group, University of Cologne, Cologne, Germany
5Department of Hematology and Medical Oncology, University Hospital Goettingen, Goettingen, Germany
6Department of Hematology and Medical Oncology, INDIGHO laboratory, University Medical Center Goettingen, Goettingen, Germany
7Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Erlangen, Germany
8Department of Medical Oncology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland
9Habichtswald Hospital, Kassel, Germany
103rd Medical Dept. with Haematology, Medical Oncology, Haemostaseology, Rheumatology and Infectiology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
11Department of Hematology, Oncology and Immunology, University Hospital of Duesseldorf, Duesseldorf, Germany
12Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
13Department of Hematology, University Hospital Augsburg, Augsburg, Germany
14Department of Hematology and Cell Therapy, Helios Klinikum Berlin-Buch, Berlin, Germany
15Department of Internal Medicine I (Oncology, Hematology, Clinical Immunology, and Rheumatology), Saarland University Medical School, Homburg, Germany
16Hematology and Medical Oncology, University Hospital Jena, Jena, Germany
17Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
18Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
19Department for Hematology and Oncology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
20Department of Internal Medicine IV, Haematology and Oncology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
21Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
22Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany
23Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
24Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer consortium (DKTK partner site Essen), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
25Department of Hematology, Oncology and Cancer Immunology, Charité - University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
26Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein, Kiel, Germany
27Department of Internal Medicine 5 - Hematology and Oncology, University Hospital of Erlangen, Erlangen, Germany

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 (>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 (>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.

Disclosures: Shumilov: Gilead: Consultancy, Honoraria, Other: Travel and congress support; BMS: Consultancy, Honoraria; Incyte: Honoraria; Oncopeptides: Consultancy, Honoraria, Other: Travel and congress support; Stemline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and congress support; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi-Aventis: Consultancy, Honoraria, Other: Congress support. Vucinic: Gilead/Kite, Janssen, BMS Celgene, Novartis: Consultancy, Honoraria; Amgen: Honoraria, Other: Travel grant. Holtick: Roche: Honoraria. Scholz: Beigene, Abbvie, Janssen, Novartis: Other: travel support . Melchardt: Abbvie, Roche: Honoraria. Schultze-Florey: Janssen: Consultancy, Honoraria, Other: Travel support, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Other: Travel support; Pierre Fabre: Consultancy, Honoraria, Other: Travel support; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria; Abbvie: Other: Travel support. Lesan: Pierre Fabre: Other: Travel and Congress Grant. Schnetzke: Abbvie, Novartis, Kite Gilead, BMS, Janssen, Sobi, Takeda, Beigene: Consultancy, Honoraria, Other: travel support . Kerkhoff: Abbvie: Honoraria, Other: Travel- & congress-support; MSD: Honoraria; Takeda: Honoraria; AstraZeneca: Honoraria; BMS: Honoraria, Other: Travel- & congress-support; Amgen: Honoraria; Sobi: Other: Travel- & congress-support; EUSA: Other: Travel- & congress-support; BeiGene: Other: Travel- & congress-support; Roche: Honoraria. Aydilek: Kite Gilead: Honoraria. Gebauer: AstraZeneca: Honoraria; Takeda: Honoraria; Menarini Stemline: Honoraria; Beigene: Honoraria, Other: travel support ; Janssen: Honoraria, Other: travel support. Glass: Riemser, Roche: Other: grants ; Roche, Kite Gilead, BMS: Other: travel support ; Kite Gilead, Novartis, BMS, Roche, Miltenyi, Incyte: Honoraria. Heidel: Novartis, Celgene/BMS, CTI: Research Funding; BMS/Celgene, AOP, Novartis, CTI, Janssen, Abbvie, GSK, Merck, CTI, Kartos, Telios: Consultancy. Viardot: AbbVie, Amgen, Kite, Roche, Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; AbbVie, BMS, Kite, Novartis, Roche, Sobi: Honoraria. Hänel: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Falk Foundation: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; BristolMyersSquibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer Vital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BristolMyersSquibb/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria; Novartis: Honoraria. Dietrich: University Hospital Dusseldorf Germany: Current Employment; F. Hoffmann-La Roche Ltd, Kite: Research Funding; F. Hoffmann-La Roche Ltd, Kite, BMS, AbbVie: Honoraria. Ayuk: Abbvie: Honoraria; Novartis: Consultancy, Honoraria; BMS: Honoraria; Medac: Consultancy, Honoraria; Miltenyi Biomedicine: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding. von Tresckow: AbbVie, AstraZeneca, Gilead Kite, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, and Novartis: Other: Travel and congress support ; Esteve (Inst), Merck Sharp & Dohme (Inst), Novartis (Inst), and Takeda (Inst): Research Funding; AbbVie, AstraZeneca, BMS/Celgene, Gilead Kite, Incyte, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Novartis, Roche and Takeda: Honoraria; Allogene, Amgen, BMS/Celgene, Cerus, Gilead Kite, Incyte, IQVIA, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Miltenyi, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, Qualworld, Regeneron, Roche, Sobi and Takeda: Consultancy. Chapuy: Sobi, Roche: Other: travel support ; AbbVie, Ars tempi, Astra Zeneca, BMS, Incyte, Janssen, Gilead, KML, Roche, Sobi, Ono: Honoraria; AbbVie, Bristol Myers Squibb, Incyte, Janssen, Roche, and Sobi: Consultancy. Lenz: Roche, Gilead, BMS, Novartis, AstraZeneca, Abbvie, Incyte, Genmab, Constellation, ADC Therapeutics, Miltenyi, PentixaPharm, Sobi, Immagene, Genase, Hexal-Sandoz, Lilly, Beigene, MSD, Pierre Fabre: Consultancy; Acerta: Research Funding; Sobi: Honoraria, Speakers Bureau; Pierre Fabre: Honoraria; PentixaPharm: Honoraria; NanoString: Honoraria; MSD: Honoraria; Miltenyi Biotech: Honoraria; Lilly: Honoraria; Karyopharm: Honoraria; Incyte: Honoraria; Immagene: Honoraria; Hexal/Sandoz: Honoraria; Genmab: Honoraria; Genase: Honoraria; Constellation: Honoraria; BMS: Honoraria; BeiGene: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; ADC Therapeutics: Honoraria; Verastem: Research Funding; AQUINOX: Research Funding; ELVESCA: Current equity holder in private company; Roche, Gilead, BMS, Novartis, AstraZeneca, Abbvie, Incyte, Genmab, Constellation, ADC Therapeutics, Miltenyi, PentixaPharm, Sobi, Immagene, Genase, Hexal-Sandoz, Lilly, Beigene, MSD, Pierre Fabre: Membership on an entity's Board of Directors or advisory committees; AbbVie, BeiGene, Sobi, Roche, Gilead, BMS: Other: Travel; Bayer: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; MorphoSys: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Honoraria, Research Funding; AGIOS: Research Funding; AstraZeneca: Honoraria, Research Funding.

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