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3022 A Phase 1, Open-Label Study of MGD013, a Bispecific DART® Molecule Binding PD‑1 and LAG‑3 in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster III
Hematology Disease Topics & Pathways:
Biological, Adult, Therapies, checkpoint inhibitors, immunotherapy, Study Population
Monday, December 7, 2020, 7:00 AM-3:30 PM

Jie Wang, MD1, Adam S. Asch, MD2, Nada Hamad, MBBS, BSc, MSc, FRACP FRCPA3, Andrew Weickhardt, MBBS(Hons) FRACP DMedSc4*, Monika Tomaszewska-Kiecana5*, Monika Dlugosz-Danecka, MD, PhD6*, Halyna Pylypenko, MD7*, Shakeela Bahadur, MD8*, Susanna Ulahannan, MD, MMed9*, Janine Koucheki10*, Jichao Sun, PhD10*, Hua Li10*, Francine Chen, MD11*, Xiaoyu Zhang10*, John Muth, MS10*, Patrick Kaminker, PhD10*, Paul Moore, PhD10* and Bradley James Sumrow, MD10*

1Duke Cancer Institute, Durham, NC
2Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
3Department of Haematology, St Vincent's Hospital, Sydney, Australia
4Austin Health, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
5BioVirtus, Jozefow, Poland
6Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland
7Regional Treatment and Diagnostics Haematology Centre, Department of Hematology, Cherkasy Regional Oncology Centre, Cherkasy, Ukraine
8Banner MD Anderson Cancer Center, Gilbert, AZ
9University of Oklahoma Health Sciences Center, Oklahoma City, OK
10MacroGenics, Inc., Rockville, MD
11MacroGenics, Inc., Brisbane, CA

Background: MGD013 is an investigational, first-in-class, Fc‑bearing bispecific tetravalent DART molecule designed to bind PD-1 and LAG-3 and sustain/restore the function of exhausted T cells (1). MGD013 demonstrates in vitro ligand blocking properties and improved T-cell responses beyond that observed with anti-PD-1 and anti-LAG-3 benchmark antibodies alone or in combination. PD-1 targeted therapy with nivolumab in patients (pts) with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) has yielded modest efficacy (2). LAG-3, highly expressed in DLBCL (3), has emerged as another therapeutic target of interest in this population with continued unmet need.

Methods: This study characterizes the safety, tolerability, dose-limiting toxicities, maximum tolerated dose, PK/PD, and antitumor activity of MGD013 in pts with advanced solid and hematologic malignancies. R/R DLBCL pts are being treated at the recommended Phase 2 dose of 600 mg every two weeks in Cohort Expansion.

Results: At data-cutoff, 17 DLBCL pts received MGD013 (2.5 median prior lines of therapy, 41.2% with prior CAR-T therapy). Treatment-related adverse events (TRAEs) occurred in 11/17 (64.7%) pts, with no same TRAE occurring in > 1 patient except pyrexia (n=3). One grade ≥ 3 TRAE occurred (pneumonia), and no events of tumor lysis syndrome were observed. Among 11 response-evaluable pts (i.e. received at least one on-treatment scan), 1 complete response (CR) and 3 partial responses (PRs) per the Lugano Classification were observed. Analyses of available pre-treatment tumor biopsy samples corresponding to responding pts demonstrated relatively high levels of LAG-3, PD-1, and PD-L1 by IHC. More comprehensive translational analyses were undertaken for the pt with CR, observed after a single MGD013 infusion in a 28-year-old male in relapse 6 months after CD19-directed CAR T-cell therapy. In contrast to a pre-CAR T biopsy specimen demonstrating no LAG-3 or PD-1 expression, IHC analysis of a lymph node specimen biopsied post-CAR T and prior to MGD013 treatment revealed high levels of both LAG-3 and PD-1 on both infiltrating T-cells and malignant B-cells. Consistent with CD19 CAR T resistance, no CD19 expression was evident. MHC class II and PD-L1 expression were observed, which when bound to LAG-3 and PD-1, respectively, form immune checkpoints that can decrease T cell function. Following MGD013 treatment, serum IFN-γ markedly increased to >140-fold above baseline. No significant changes were observed for IL-6 or IL-2. Expansion of circulating CD3+CD8+ and CD3+CD4-CD8- T-cell subsets and associated cytolytic markers (i.e., perforin, granzyme B) were observed following MGD013 treatment. The patient underwent allogeneic stem cell transplant (allo-SCT) and remains in remission 14 months post-MGD013 and 12 months post-allo-SCT. Further correlative biomarker analyses are underway in the ongoing clinical trial.

Conclusion: MGD013, a novel molecule designed to coordinately block PD-1 and LAG-3, has preliminarily demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity in R/R DLBCL pts with and without prior treatment with CAR T. Biomarker analyses confirmed expression of both PD-1 and LAG-3 axes in responding pts with evidence of pharmacodynamic responses consistent with the ability of MGD013 to enhance T-cell function.

References:

1. Luke JJ, Patel MR, Hamilton E, et al. A phase I, first-in-human, open-label, dose-escalation study of MGD013, a bispecific DART molecule binding PD‑1 and LAG‑3, in patients with unresectable or metastatic neoplasms. J Clin Oncol 38: 2020 (suppl; abstr 3004).

2. Keane C, Law SC, Gould C, et al. LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma. Blood Adv. 2020;4(7):1367-1377. doi:10.1182/bloodadvances.2019001390

3. Ansell SM, Minnema MC, Johnson P, et al., Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study. J Clin Oncol, 2019. 37(6): p. 481-489.

Disclosures: Wang: Verastem Oncology: Membership on an entity's Board of Directors or advisory committees; Curio Science: Honoraria; Putnam LLC: Honoraria. Asch: Astellas Pharma: Research Funding; Cartesian: Research Funding; Forty Seven: Research Funding; Juno: Research Funding; MacroGenics: Research Funding; MEI Pharma: Patents & Royalties: Provisional patent submitted (I), Research Funding. Hamad: Novartis: Honoraria; Abbvie: Honoraria. Weickhardt: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ulahannan: Merck Co. Inc: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics, Inc.: Research Funding; ArQule, Inc.: Research Funding; Evelo Biosciences, Inc.: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Klus Pharma, Inc.: Research Funding; Isofol: Research Funding; GlaxoSmithKline GSK: Research Funding; Mersana Therapeutics: Research Funding; Macrogenics: Research Funding; Celgene Corporation: Research Funding; Boehringer Ingelheim: Research Funding; Array: Membership on an entity's Board of Directors or advisory committees; Ciclomed LLC: Research Funding; AbbVie, Inc.: Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Exelxis: Membership on an entity's Board of Directors or advisory committees. Koucheki: MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sun: MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Li: MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Chen: MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Muth: MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Kaminker: MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Moore: MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sumrow: MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company.

*signifies non-member of ASH