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

Abstract

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.

Clinical landscape of LAG-3-targeted therapy

“…PD-1/LAG-3 co-blockade caused increased cytokine secretion and enhanced T-cell responses compared to PD-1 or LAG-3 single blockade. 93 Seven clinical trials are evaluating MGD013 monotherapy and combinations. [94][95][96][97] Preliminary data show encouraging responses and acceptable pharmacokinetics.…”

“…96,98 A phase I study tested MGD013 in patients with relapsed or refractory DLBCL, demonstrating good pharmacodynamics, safety profiles and antitumor activities with and without prior CAR-T-cell treatment. 93 FS118. FS118 is a first-in-class human tetravalent, full-length human IgG1, anti-LAG-3/PD-L1 bispecific antibody developed by F-star Therapeutics.…”

LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors

“…The data demonstrate that the simultaneous genetic ablation of PD-1, LAG-3, and TIM-3 expression induced a more sustained anti-tumor activity compared to non-edited T cells resulting in reduced tumor growth as well as increased survival. 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 [ 133 ].…”

Promising Immunotherapeutic Modalities for B-Cell Lymphoproliferative Disorders

“…There are only preliminary data from a small cohort of RR DLBCL (ORR 27% (3/11), CR 18% (2/11), PR 9% (1/11)) at the moment. Treatment-related AEs were reported in more than half of patients (64.7%) with one grade ≥3 pneumonia [ 83 ]. As this is the dual immune checkpoint inhibitor, autoimune treatment related toxicity should be closely monitored.…”