tebotelimab (MGD013)

P2/3; Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 .

The PD-1 × LAG-3 bispecific molecule tebotelimab is safe as a monotherapy and in combination with margetuximab.

P1, N=353, Completed, MacroGenics | Active, not recruiting --> Completed

Tebotelimab demonstrated preliminary but promising antitumor activity and a tolerable safety profile in pts with untreated, unresectable, recurrent or metastatic, mucosal melanoma.

Tebotelimab demonstrated a manageable safety profile in pts with aHCC. Antitumor activity, mainly as disease stabilization, was observed in both the CPI-naïve setting and the CPI-experienced setting. No additional clinical trials are planned at this time.

P2, N=62, Terminated, MacroGenics | Trial completion date: Apr 2024 --> Jul 2022 | Recruiting --> Terminated | Trial primary completion date: Apr 2024 --> Jul 2022; Based on internal review of safety data

P1, N=60, Terminated, Zai Lab (Shanghai) Co., Ltd. | N=164 --> 60 | Trial completion date: Dec 2024 --> Mar 2022 | Recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Mar 2022; This termination decision is a business decision and is not due to any safety concerns.

P1, N=92, Terminated, Zai Lab (Shanghai) Co., Ltd. | Trial completion date: Aug 2022 --> Mar 2022 | Active, not recruiting --> Terminated; rapid changes in the treatment mode of melanoma worldwide and in China and the development strategy change

P1, N=353, Active, not recruiting, MacroGenics | Trial completion date: Jul 2022 --> Jun 2023 | Trial primary completion date: May 2022 --> Mar 2023

P2/3 | N=81 | Active, not recruiting | Sponsor: MacroGenics | Recruiting --> Active, not recruiting | N=798 --> 81 | Trial completion date: May 2026 --> Dec 2023 | Trial primary completion date: May 2024 --> Dec 2023

P1, N=92, Active, not recruiting, Zai Lab (Shanghai) Co., Ltd. | Recruiting --> Active, not recruiting | N=160 --> 92

P1, N=353, Active, not recruiting, MacroGenics | Recruiting --> Active, not recruiting

P1, N=352, Recruiting, MacroGenics | Trial primary completion date: Jul 2021 --> May 2022

Background Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care 1st-line therapy for advanced HER2+ GEJ/GC patients. This was 2- to 3-fold greater than in historical controls with checkpoint inhibitors alone. This registration-directed trial assesses efficacy, safety, and tolerability of M+checkpoint inhibition CTX in metastatic/locally advanced, treatment-na ve, HER2+ GEJ/GC patients.

P1, N=164, Recruiting, Zai Lab (Shanghai) Co., Ltd. | N=59 --> 164 | Trial completion date: Sep 2022 --> Dec 2024 | Trial primary completion date: Aug 2022 --> Dec 2024

Background: Margetuximab (M) has demonstrated anti-tumor activity in patients with advanced HER2+ gastric cancer and PFS superiority to trastuzumab (T) in pre-treated metastatic HER2+ breast cancer patients (1). M, through an Fc-dependent mechanism, can upregulate checkpoint molecules on NK-cells, CD8 T cells and tumor cells, thereby sensitizing them to immune checkpoint blockade. In turn, PD-1 and LAG-3 blockade by tebotelimab enhances M-mediated NK cell cytolytic activity in vitro.

P2, N=80, Recruiting, MacroGenics | Not yet recruiting --> Recruiting

Research Funding: MacroGenics, Inc Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care 1st-line therapy for advanced HER2+ GEJ/GC patients. Part 2 of cohort B consists of control (T+CTX) vs 1 experimental arm (M+CTX) + either retifanlimab or tebotelimab, depending on results from part 1; with 250 patients each. The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival.

P1, N=160, Recruiting, Zai Lab (Shanghai) Co., Ltd.

Standard-of-care, first-line therapy for patients with advanced human epidermal growth factor receptor 2 (HER2)-positive gastric/gastroesophageal junction adenocarcinoma is chemotherapy plus trastuzumab, a monoclonal antibody (mAb) targeting HER2...Here, we describe the design and rationale of the randomized, open-label, Phase II/III MAHOGANY trial evaluating margetuximab plus retifanlimab with/without chemotherapy and margetuximab plus tebotelimab with chemotherapy in first-line unresectable metastatic/locally advanced gastroesophageal junction adenocarcinoma. Primary end points include objective response rate, overall survival and safety/tolerability. Clinical trial registration: NCT04082364 (ClinicalTrials.gov).

P2, N=80, Not yet recruiting, MacroGenics

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). 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.

Background Tebotelimab, also known as MGD013, is an investigational, Fc bearing bispecific tetravalent DART molecule designed to bind PD-1 and LAG-3 and sustain/restore the function of exhausted T cells.1 Margetuximab, an investigational Fc-engineered anti-HER2 monoclonal antibody, has similar HER2 binding and antiproliferative properties to trastuzumab, but with enhanced Fc-mediated effector function. Investigations into other potential correlative biomarkers, including LAG-3 and PD-1 by IHC and gene expression profiling by NanoString, remain ongoing. Conclusions Tebotelimab in combination with margetuximab has demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity, with a preliminary overall response rate (ORR) of 40% (8/20) [including unconfirmed responses] among late-line patients with various advanced HER2+ malignancies.

Background Tebotelimab, also known as MGD013, is an investigational, Fc bearing bispecific tetravalent DART molecule designed to bind PD-1 and LAG-3 and sustain/restore the function of exhausted T cells.1 Margetuximab, an investigational Fc-engineered anti-HER2 monoclonal antibody, has similar HER2 binding and antiproliferative properties to trastuzumab, but with enhanced Fc-mediated effector function. Investigations into other potential correlative biomarkers, including LAG-3 and PD-1 by IHC and gene expression profiling by NanoString, remain ongoing. Conclusions Tebotelimab in combination with margetuximab has demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity, with a preliminary overall response rate (ORR) of 40% (8/20) [including unconfirmed responses] among late-line patients with various advanced HER2+ malignancies.

P2/3, N=0, Withdrawn, MacroGenics | N=750 --> 0 | Trial completion date: Oct 2025 --> Oct 2022 | Not yet recruiting --> Withdrawn | Trial primary completion date: Oct 2025 --> Oct 2020

Background Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is the standard of care 1st-line therapy for advanced HER2+ GEJ/GC patients (pts). Legal entity responsible for the study MacroGenics, Inc. Funding Macrogenics, Inc.

LAG-3 expression was detected on TILs across a broad range of solid tumors and DLBCL, with varying level of intensity or association with PD-1 expression. Correlative assessments of LAG-3/PD-1 expression with clinical responses to MGD013, an investigational bispecific DART(R) molecule targeting LAG-3/PD-1 (NCT03219268), will be undertaken. Research Funding: MacroGenics, Inc.

No abstract available

In a cohort of pts with HER2+ tumors treated with MGD013 in combination with margetuximab (investigational anti-HER-2 antibody), 3 PRs have been observed (breast [n=2], colorectal [n=1]; 1 cPR, 2 uPRs) and 2 pts with SD among 6 RE pts. MGD013, a novel molecule designed to coordinately block PD-1 and LAG-3, has demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity. Research Funding: MacroGenics, Inc.

P1, N=375, Recruiting, MacroGenics | N=255 --> 375

Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care palliative 1st-line therapy for advanced HER2+ GEJ/GC patients (pts). The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival. Research Funding: MacroGenics, Inc