tebotelimab (MGD013) / MacroGenics - LARVOL DELTA

Immune Checkpoint Inhibitors Reverse the Mesenchymal Stromal Cell-Mediated Immunosuppression in Acute Myeloid Leukemia Microenvironment (ASH 2024) - "With the established 3D model, the effect of CPI (bispecific anti-PD-1 x anti-LAG-3 DART®molecule, MGD013/tebotelimab; anti-LAG-3 IgG4 antibody; and anti-PD-1 IgG4 antibody, nivolumab) on AML killing and T-cell activity were assessed and compared to a palivizumab-based IgG4 antibody as a control. Conclusion : MSCs play a major role in influencing CD8+ T cell-mediated killing of AML cells through the suppression of CD8+ T cell activity, potentially involving the LAG-3 immune checkpoint mechanism. LAG-3 immune checkpoint inhibitor showed effective response in reversing T-cell suppression within the AML microenvironment and warrants further investigation as an immunotherapeutic in AML."

Checkpoint inhibition • IO biomarker • Stroma • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33 • CD34 • CD73 • CD8 • ENG • HAVCR2 • HLA-C • IFNG • PD-L1 • PTPRC • THY1 • TNFA

Treatment outcomes in previously treated patients with advanced/metastatic HER2+ biliary tract cancer: A systematic review (ESMO-GI 2024) - "Nine therapies (pertuzumab + trastuzumab [P+T], pyrotinib, SHR-A1811, TAS0728, T-deruxtecan [T-DXd], tebotelimab + margetuximab, T+FOLFOX [T+F], tucatinib + T and zanidatamab [zani]) were assessed... HER2 targeted therapies demonstrated promising benefit in patients with previously treated advanced/metastatic HER2+ BTC."

Clinical • Metastases • Review • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2

MAHOGANY: Combination Margetuximab, Retifanlimab, Tebotelimab, and Chemotherapy Phase 2/3 Trial in HER2+ Gastric/GEJ Cancer (clinicaltrials.gov) - P2/3 | N=82 | Active, not recruiting | Sponsor: MacroGenics | Trial completion date: Mar 2024 ➔ Jun 2025

Combination therapy • Metastases • Trial completion date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI • PD-L1

MAHOGANY: Combination Margetuximab, Retifanlimab, Tebotelimab, and Chemotherapy Phase 2/3 Trial in HER2+ Gastric/GEJ Cancer (clinicaltrials.gov) - P2/3 | N=82 | Active, not recruiting | Sponsor: MacroGenics | Trial completion date: Dec 2023 ➔ Mar 2024 | Trial primary completion date: Dec 2023 ➔ Mar 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI • PD-L1

Tebotelimab Is Safe and Effective Across Multiple Cancer Types. (PubMed, Cancer Discov) - "The PD-1 × LAG-3 bispecific molecule tebotelimab is safe as a monotherapy and in combination with margetuximab."

Journal • Oncology • LAG3 • PD-1

Cancer Drug That Targets Two Immune-evading Tumor Tactics Performs Well in Early Clinical Trial (Eurekalert) - P=NA | N=269 | '"No approved cancer drugs are like this. It is truly a novel development in the field,' said lead author Jason Luke, M.D...'The patients in our trial had cancers that were not responding to other therapies, so to see double-digit response rates is encouraging.''

Clinical data

The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial. (PubMed, Nat Med) - P1 | "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 ."

Journal • P1 data • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • LAG3

Tebotelimab, a PD-1/LAG-3 bispecific antibody, in patients with untreated, unresectable, recurrent or metastatic, mucosal melanoma: An open-label, single-arm, Phase 1 study (AACR 2023) - P1 | "Tebotelimab demonstrated preliminary but promising antitumor activity and a tolerable safety profile in pts with untreated, unresectable, recurrent or metastatic, mucosal melanoma."

Clinical • IO biomarker • Metastases • P1 data • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • LAG3 • PD-1 • PD-L1

Zai Lab to Highlight New Data from its Oncology Portfolio at 2023 AACR Annual Meeting (Yahoo Finance) - "Zai Lab Limited...will present new data including a translational and biomarker data analysis from its internal oncology discovery program ZL-1211 at the upcoming 2023 American Association for Cancer Research (AACR) Annual Meeting in Orlando on April 14-19, 2023....This presentation will feature results generated from clinical patient samples using these assays to support the mechanism of action for ZL-1211.Several potential predictive biomarkers from preclinical in vitro and in vivo analyses will be highlighted in the presentation....In addition, Zai will be presenting a second poster presentation about tebotelimab, a PD-1/LAG-3 bispecific antibody."

Biomarker • Trial status • Melanoma • Mucosal Melanoma • Oncology • Skin Cancer • Solid Tumor

A Study of MGD013 in Patients With Unresectable or Metastatic Neoplasms (clinicaltrials.gov) - P1 | N=353 | Completed | Sponsor: MacroGenics | Active, not recruiting ➔ Completed

Metastases • Trial completion • Biliary Cancer • Breast Cancer • Cervical Cancer • Cholangiocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hematological Disorders • Hematological Malignancies • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • LAG3 • PD-1 • PD-L1

An open-label, single-arm, dose escalation and expansion phase 1 study of tebotelimab (MGD013) plus niraparib in patients with locally advanced or metastatic gastric cancer who failed prior treatments. (ASCO-GI 2023) - P1 | "Tebotelimab plus niraparib preliminarily demonstrated an acceptable safety profile in pts with metastatic GC, however with limited antitumor activity. No further clinical trials are planned. Clinical trial information: NCT04178460."

Clinical • IO biomarker • Metastases • P1 data • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • LAG3 • PD-1 • PD-L1

[VIRTUAL] A phase 1 evaluation of tebotelimab, a bispecific PD-1 x LAG-3 DART® molecule, in combination with margetuximab in patients with advanced HER2+ neoplasms (SITC 2020) - P1 | "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."

Clinical • Combination therapy • IO Biomarker • P1 data • Biliary Cancer • Cholangiocarcinoma • Colorectal Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor • HER-2 • LAG3 • PD-1 • PD-L1

[VIRTUAL] Immunohistochemistry analyses of LAG-3 expression across different tumor types and co-expression with PD-1. (ASCO 2020) - P1 | "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."

IO Biomarker • Biliary Cancer • Breast Cancer • Cervical Cancer • Cholangiocarcinoma • Diffuse Large B Cell Lymphoma • Gastric Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Head and Neck Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Lymphoma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Thoracic Cancer • Triple Negative Breast Cancer • HER-2 • LAG3 • PD-1

Tebotelimab, a PD-1/LAG-3 bispecific antibody, in patients with advanced hepatocellular carcinoma who had failed prior targeted therapy and/or immunotherapy: An open-label, single-arm, phase 1/2 dose-escalation and expansion study. (ASCO-GI 2023) - P1/2 | "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."

Clinical • Metastases • P1/2 data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • LAG3 • PD-1

[VIRTUAL] 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 (ASH 2020) - "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."

Clinical • IO biomarker • P1 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immune Modulation • Infectious Disease • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Pneumonia • Respiratory Diseases • Transplantation • CD19 • CD8 • GZMB • IFNG • IL2 • IL6 • LAG3 • PD-L1

Phase 2 trial of enoblituzumab plus retifanlimab or tebotelimab in first-line treatment of patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). (ASCO 2022) - P2 | "In a phase 1/2 study, the combination of enoblituzumab with pembrolizumab was well tolerated (Aggarwal C, et al. All pts will be followed for survival after the last dose of study drug. The first pt was enrolled in March 2021, and 28 pts are on treatment as of January 19, 2022."

Clinical • IO biomarker • P2 data • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • FCGR3A • HLA-DRB1 • IFNG • LAG3 • PD-L2

[VIRTUAL] Phase II trial of enoblituzumab plus retifanlimab or tebotelimab in first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M SCCHN) (ESMO 2021) - P2 | "In a phase I study of enoblituzumab plus pembrolizumab, study drug was well tolerated. In the tebotelimab cohort, safety data will be reviewed for dose limiting toxicities through Cycle 2 Day 7 on the 1st 12 pts. All patients will be followed for survival after receipt of the last dose of study drug."

Clinical • P2 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD276

Enoblituzumab Plus Retifanlimab or Tebotelimab in Head and Neck Cancer (clinicaltrials.gov) - P2 | N=62 | Terminated | Sponsor: 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

Combination therapy • Trial completion date • Trial primary completion date • Trial termination • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

MacroGenics Announces Closure of CP-MGA271-06 Study Evaluating Enoblituzumab plus Checkpoint Inhibition in Head and Neck Cancer (GlobeNewswire) - "MacroGenics...announced that effective as of July 7, 2022, the Company closed the Phase 2 study (CP-MGA271-06) evaluating the investigational regimen of enoblituzumab (Fc-optimized B7-H3-directed monoclonal antibody) in combination with either retifanlimab (anti-PD-1 monoclonal antibody) or tebotelimab (PD-1 × LAG-3 bispecific DART® molecule) in the first-line treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). The decision to discontinue the study was based on an internal review of safety data, which included the occurrence of seven fatalities potentially associated with hemorrhagic events in both arms of the study (of 62 total patients treated)....The Company...instructed investigators that no additional patients in the study were to be enrolled or receive further treatments as of July 7, 2022."

Trial termination • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A Study of MGD013 in Patients With Unresectable or Metastatic Neoplasms (clinicaltrials.gov) - P1 | N=353 | Active, not recruiting | Sponsor: MacroGenics | Trial completion date: Jun 2023 ➔ Feb 2023

Trial completion date • Biliary Cancer • Breast Cancer • Cervical Cancer • Cholangiocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hematological Disorders • Hematological Malignancies • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • LAG3 • PD-1 • PD-L1

MGD013 Monotherapy and Combination With Brivanib Dose Escalation and Expansion Study in Advanced Liver Cancer Patients (clinicaltrials.gov) - P1/2 | N=88 | Terminated | Sponsor: Zai Lab (Shanghai) Co., Ltd. | N=300 ➔ 88 | Trial completion date: Jun 2023 ➔ Apr 2022 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2022 ➔ Apr 2022; Due to the rapid shifting of liver cancer disease landscape and the company's adjustment of development strategy.

Combination therapy • Enrollment change • Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immune Modulation • Liver Cancer • Oncology • Solid Tumor

A Study of Niraparib Combined With MGD013 in Patients With Advanced or Metastatic Solid Tumor Who Failed Prior Treatment (clinicaltrials.gov) - P1 | N=60 | Terminated | Sponsor: 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.

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Biliary Cancer • Biliary Tract Cancer • Breast Cancer • Cholangiocarcinoma • Endometrial Cancer • Esophageal Cancer • Gallbladder Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • FGFR2 • HER-2 • HRD • IDH1 • LAG3 • PGR

[VIRTUAL] Margetuximab combined with anti-PD-1 (retifanlimab) or anti-PD-1/LAG-3 (tebotelimab) +/- chemotherapy in first-line therapy of advanced/metastatic HER2+ gastroesophageal junction or gastric cancer (ESMO-GI 2021) - P2/3 | "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."

Clinical • IO biomarker • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FCGR3A • HER-2 • LAG3 • PD-L2

Enoblituzumab + retifanlimab + tebotelimab: Data from P2 trial (NCT04634825) for squamous cell carcinoma of head and neck in H2 2022 (Macrogenics) - Corporate Presentation

P2 data • Oncology • Squamous Cell Carcinoma of Head and Neck

[VIRTUAL] Phase Ib study of niraparib plus tebotelimab in patients with advanced or metastatic gastric cancer after prior treatment failure (ESMO-GI 2021) - P1 | "The PARP inhibitor olaparib showed modest efficacy in the second-line treatment of gastric cancer...The PARP inhibitor niraparib has approved indications in ovarian cancer; phase I/II studies of niraparib + pembrolizumab in advanced triple-negative breast cancer or platinum-resistant ovarian cancer suggest promising safety and antitumor potential of combining niraparib with PD-1 inhibition...Conclusions MTD was not reached. The pre-specified highest dose level of tebotelimab 600 mg Q2W + niraparib 200 mg QD was DLT-free, exhibited antitumor activity, and is preliminarily recommended as RP2D for Dose Expansion in which an additional 35 patients are planned to be enrolled."

Clinical • P1 data • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • LAG3