EX-99.1 2 asco2020_mgd013phase1.htm ASCO 2020 MGD013 PHASE 1
A Phase 1, 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 Jason J. Luke,1 Manish R. Patel,2 Erika Hamilton,3 Bartosz Chmielowski,4 Susanna Ulahannan,5 Hedy Kindler,6 Shakeela Bahadur,7 Philip Clingan,8 Girish Mallesara,9 Andrew Weickhardt,10 Scott Currence,11 Linzhi Xu,11 Sanjeev Kaul,12 Francine Chen,11 Paul A. Moore,11 Ezio Bonvini,11 Bradley J. Sumrow,11 George Blumenschein13 1UPMC Hillman Cancer Center, Pittsburgh, PA; 2Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL; 3Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; 4Division of Hematology & Medical Oncology, Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA; 5SCRI Nashville/OUHSC Oklahoma City, Oklahoma City, OK; 6Division of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL; 7Banner MD Anderson Cancer Center, Gilbert, AZ; 8Southern Medical Day Care Centre, Wollongong, NSW, Australia; 9Calvary Mater Newcastle Hospital, Waratah, NSW, Australia; 10Austin Health, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; 11MacroGenics, Inc., Rockville, MD; 12Bio-ClinPharm Consulting, LLC. Cranbury, NJ; 13Department of Thoracic Head & Neck Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX. Jason J. Luke, MD, FACP @jasonlukemd

Presenter Disclosure Information Jason J. Luke, MD, FACP • Data and Safety Monitoring Board: TTC Oncology • Scientific Advisory Board: 7 Hills, Actym, Alphamab Oncology, Kanaph, Mavu (now part of AbbVie), Onc.AI, Pyxis, Springbank, Tempest • Consultancy: Abbvie, Akrevia, Algios, Array, Astellas, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Ideaya, Incyte, Janssen, Merck, Mersana, Novartis, PTx, RefleXion, Regeneron, Silicon, Tesaro, Vividion • Research Support: (all to institution for clinical trials unless noted) AbbVie, Agios (IIT), Array (IIT), Astellas, Bristol-Myers Squibb, CheckMate (SRA), Compugen, Corvus, EMD Serono, Evelo (SRA), Five Prime, FLX Bio, Genentech, Immatics, Immunocore, Incyte, Leap, MedImmune, MacroGenics, Necktar, Novartis, Palleon (SRA), Merck, Springbank, Tesaro, Tizona, Xencor • Travel: Akrevia, Bayer, Bristol-Myers Squibb, EMD Serono, Incyte, Janssen, Merck, Mersana, Novartis, Pyxis, RefleXion • Patents (both provisional): Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Jason J. Luke, MD, FACP @jasonlukemd 2

Rationale for Dual Targeting of PD-1 and LAG-3 • Checkpoint molecules are leveraged by tumors or APCs to evade the immune system • PD-1 and LAG-3 receptors are expressed on “exhausted” T-cells • Interactions with corresponding ligands negates anti-tumor T cell activity • Synergy of anti-PD-1 + anti-LAG-3 mAbs in animal tumor models • Combination trials of anti-PD-1 plus anti-LAG-3 are ongoing • MGD013, an investigational DART protein, targets PD-1 and LAG-3 with a single molecule MGD013 anti-PD-1 • Greater synergistic T-cell activation (IFN-γ) anti- anti- with MGD013 compared with combination LAG-3 LAG-3 of individual constituents • DART bispecific platform: • Stable diabody format PD-1 × LAG-3 • Multiple configurations & applications Tetravalent Bispecific DART Molecule Jason J. Luke, MD, FACP @jasonlukemd 3

MGD013 Phase 1 Trial Design • Primary objectives: – Safety, tolerability DLTs, MTD, MAD Dose Escalation in Previously Treated MGD013 Monotherapy Combination Cohort – Advanced Solid Tumors Cohort Expansiona Expansionab – Alternate dose (600 mg Q2W) Flat Dosing Q2W: 1200 mg Single Patient Cohorts† Ovarian • Secondary objectives: followed by 3+3 design 800 mg Pharmacokinetics HER2+ Solid – 400 mg TNBC – Immunogenicity Tumors 120 mg MTD/MAD/ – Preliminary activity alternate dose NSCLC 30 mg † • Exploratory PD objectives: 10 mg Other Select MGD013 (300 or 600 mg) + † Advanced – Receptor/ligand expression 3 mg Separate HCC Escalation: Margetuximab‡ 15 mg/kg   Solid/heme 120 mg 400 mg 600 mg d (both Q3W) – Serum biomarkers 1 mg† 3+3 designc Tumors – Gene expression profiling DLT = dose-limiting toxicity; MAD = maximum administered dose; MTD = maximum tolerated dose; IHC = immunohistochemistry; Q2W = every 2 weeks. ClinicalTrials.gov identifier: NCT03219268. ‡ Margetuximab is an investigational Fc- optimized mAb targeting HER2. a Monotherapy and combination expansion cohorts are ongoing. b Combination cohort involved a one-step dose escalation followed by expansion. c Separate hepatocellular carcinoma (HCC) 3+3 dose escalation initiated after corresponding dose levels cleared in primary Dose Escalation. d Other expansion cohorts enrolling patients with SCCHN, SCLC, HCC, cholangiocarcinoma, cervical cancer, gastric/gastroesophageal junction carcinoma, and DLBCL. Data cutoff: April 25, 2020. Jason J. Luke, MD, FACP @jasonlukemd 4

Baseline Demographics Monotherapy Combination Dose Escalation Cohort Expansion Cohort Expansion 1 -1200 mg Q2W 600 mg Q2W MGD013 + Margetuximab (n=53) (n=205) (n=21) Median age (range), years 64 (24, 84) 60 (27, 84) 62 (29, 83) Gender, n (%) Male 32 (60.4) 74 (36.1) 7 (33.3) Female 21 (39.6) 131 (63.9) 14 (66.7) ECOG PS, n (%) 0 22 (41.5) 60 (29.3) 12 (57.1) 1 31 (58.5) 145 (70.7) 9 (42.9) Median prior lines of therapy 2 (1, 9) 2 (1, 9)a 2 (1, 7) (range) Prior Checkpoint Inhibitor Yes 23 (43.4) 55 (26.8) 1 (4.8) No 30 (56.6) 139 (67.8) 20 (95.2) a Monotherapy Cohort Expansion median prior lines of therapy derived from n=200 patients (5 patients without this information available). Data cutoff: April, 25, 2020. Jason J. Luke, MD, FACP @jasonlukemd 5

Pharmacokinetics and Receptor Occupancy Linear PK (400-1200 mg dose range) and sustained receptor occupancy (≥120 mg) Pharmacokinetics (1-1200 mg) Receptor (PD-1) Occupancy (120 mg Q2W) 100 80 60 CD4 40 20 CD4 Occupancy (% ) 0 1 15 29 43 57 71 85 99 113 Days 100 80 60 40 CD8 20 CD8 Occupancy (% ) 0 Estimated t = 274 hours (~11 days) 1 15 29 43 57 71 85 99 113 1/2 Days pembro ctrough = published serum trough concentration of pembrolizumab at 2 mg/kg Q3W (23.6 μg/mL) [CDER, KEYTRUDA (pembrolizumab) Clinical Pharmacology and Biopharmaceutics Review(s). 2014] Jason J. Luke, MD, FACP @jasonlukemd 6

MGD013 Dose Escalation: Results Best % Reduction of Target Lesions * Immune-Related Adverse Events of Special Interest (AESIs) RECIST Evaluable Population (n=42)* No. (%) of Patients All Grades > Grade 3 (N=53) (N=53) Rash 7 (13.2) 1 (1.9) Hypothyroidism 6 (11.3) 0 Immune-mediated hepatitis 2 (3.8) 2 (3.8) : Previous Checkpoint Inhibitor Pancreatitis 1 (1.9) 1 (1.9) Colitis 1 (1.9) 1 (1.9) Adrenal insufficiency 1 (1.9) 1 (1.9) Hyperthyroidism 1 (1.9) 0 * Based on patients with baseline and post-treatment tumor measurements. Data cutoff: April, 25, 2020 • Well-tolerated with manageable irAEs • Safety consistent with anti-PD-(L)1 toxicity profile Confirmed Partial Responses (n=1, each): • TNBC (10 mg) • MTD not exceeded or defined at up to 1200 mg Q2W • Mesothelioma (800 mg) • Dose limiting toxicities: Refractory to anti-PD-1 treatment • Gastric Cancer (1200 mg) • Immune-mediated hepatitis (1200 mg – primary dose escalation); resolved without sequelae • 18 patients with SD as best overall response (DCR = 48.8%) • Lipase increase with radiographic evidence of pancreatitis (600 mg – HCC escalation); dose level subsequently cleared Jason J. Luke, MD, FACP @jasonlukemd 7

MGD013 Monotherapy Cohort Expansion: Safety No. (%) of Patients All Grades > Grade 3 Overall AE Totals (N=205) (N=205) AE (irrespective of causality) 178 (86.8) 86 (42.0) Treatment-related AE 118 (57.6) 37 (18.0)a SAE (irrespective of causality) 63 (30.7) 47 (22.9) Treatment-related SAE 18 (8.8) 11 (5.4) AE leading to discontinuation 18 (8.8) 16 (7.8) AESIs in ≥ 2 Patients Rash 17 (8.3) 6 (2.9) Hypothyroidism 16 (7.8) 0 (0.0) IRR or CRS 13 (6.3) 5 (2.4) Diarrhoea 11 (5.4) 1 (0.5) Lipase increased 11 (5.4) 7 (3.4) Hyperthyroidism 10 (4.9) 1 (0.5) Arthralgia 9 (4.4) 0 (0.0) Pneumonitis 4 (2.0) 1 (0.5) Myalgia 4 (2.0) 0 (0.0) Peripheral neuropathy 3 (1.5) 1 (0.5) Hepatitis 3 (1.5) 2 (1.0) Adrenal insufficiency 2 (1.0) 0 (0.0) * Includes MedDRA Preferred Terms of Rash and Maculopapular Rash. ** Includes MedDRA Preferred Terms of Pruritus and Generalized Pruritus. a Grade 4 drug-related AEs include: lipase increased (n=3), neutrophil count decreased, and IRR (n=1, each). No Grade 5 TRAEs have been reported. AESI = adverse events of special interest. Data cutoff: April, 25, 2020. Jason J. Luke, MD, FACP @jasonlukemd 8

MGD013 Monotherapy Cohort Expansion: Activity Anti-tumor activity observed in multiple tumor types Triple-negative Breast Cancer Epithelial Ovarian Cancer Non-small Cell Lung Cancer TNBC EOC NSCLC, CPI-Naïve NSCLC, post-PD-1 Evaluable Patients 23 23 14 15 ORR (Confirmed) 4.3% (1/23) 8.7% (2/23) 14.3% (2/14) 0% (0/15) ORR (Confirmed + Unconfirmed) 17.4% (4/23) 8.7% (2/23) 21.4% (3/14) 13.3% (2/15) SD 34.8% (8/23) 43.5% (10/23) 50.0% (7/14) 53.3% (8/15) DCR 39.1% (9/23) 52.2% (12/23) 64.3% (9/14) 53.3% (8/15) Data cutoff: April, 25, 2020 Jason J. Luke, MD, FACP @jasonlukemd 9

Complete Response after Single MGD013 Administration 27-year-old male with DLBCL progressive disease after CAR-T cell therapy MGD013 Screening Complete Response - Day 24 • Relapsed subsequent to DA-R-EPOCH and JCAR017 • Pre-treatment biopsy: High levels of LAG-3 & PD-L1 • Received MGD013, 600 mg x 1 • Admitted on Day 11 for management of Grade 2 CRS • CR on Day 24 (per Lugano classification) • No evidence of CAR-T in circulation PD-1/LAG-3 Co-expression • Allogeneic SCT performed • Currently in remission: • 11 months post-MGD013 • 9 months post-transplant PD-1 LAG3 DAPI PD-1 (magenta) and LAG-3 (green) co-localized staining Jason J. Luke, MD, FACP @jasonlukemd 10

Objective Responses Associated with LAG-3 Expression Inflammatory interferon-γ signature elevated in patients with clinical response Retrospective IHC Analyses Transcript Profiling (Baseline Tumor Biopsy) 30 30 LAG-3 vs PD-1 IFN-γ Gene Signature 20 PD SD PR 20 10 NSCLC P-NSCLC 10 LAG-3 Expression 0 Ovarian PD SD PR LAG-3 Score TNBC LAG-3 neg 0 BOR Individual patients ordered LAG-3 high to low PR SD 100 PD PD SD PR Unknown 75 50 PD SD PR 25 PD-L1 TPS/CPS PD-L1 negative Objective responses associated with high baseline LAG-3/PD-1 0 expression and IFN-γ gene signature (CXCL9, CXCL10, CXC11, STAT1) Individual patients ordered PD-L1 high to low Archival biopsies from TNBC, EOC, and NSCLC expansion cohorts analyzed for LAG-3 (N=46) or PD-L1 (N = 45) by IHC. LAG-3 score was determined by calculating mean value of LAG-3+ cells per 40x field across 5 LAG-3+ hot spots (Chen et al., e15086 ASCO 2020). PD-L1 expression was determined per Agilent PD-L1 (22C3) pharmDx kit; TPS (NSCLC) was The NanoString PanCancer IO 360™ assay was used to interrogate gene expression, including the abundance of 14 calculated as per interpretation manual and CPS (EOC, TNBC) calculated as follows: number of PD-L1 + cells (tumor and immune cell types and 32 immuno-oncology signatures from archival biopsies from EOC (N= 14) NSCLC (N= 25) and immune)/total number of viable tumor cells x 100. CPS <1 or TPS <1% was considered negative. TNBC (N=13 ) expansion cohorts Jason J. Luke, MD, FACP @jasonlukemd 11

Can Tumors Be Made More Responsive to PD-1 × LAG-3 Intervention? Enhancing effector-cell activation via Fc-engineered mAb Margetuximab Investigational Fc-engineered anti-HER2 mAb Margetuximab Enhances LAG-3 Expression by NK Cells • Same anti-HER2 properties as trastuzumab 3 - • Enhanced Fc-mediated effector functiona LAG • Superior PFS to trastuzumab in clinical study • SOPHIA: Head-to-head Phase 3 study in mBCb Control Ab Margetuximab Trastuzumab • Anti-tumor activity in advanced gastric cancer • In combination with anti-PD-1c a Nordstrom, et al., 2011 Breast Cancer Research, 13: R123 b Rugo, et al., ASCO 2019, Chicago, IL Human PBMC (Donor # 859) + N87 (HER2+) gastric cancer cells; E:T = 10:1; (IL-2, 20 U/mL) c Catenacci, et al., ASCO GI 2019, San Francisco, CA | Catenacci et al. 2020 Lancet Oncology, in press Control Ab 50ng/mL, margetuximab/trastuzumab, 5ng/mL;. FACS analyses (72h) on CD3-CD56+-gated NK cells Jason J. Luke, MD, FACP @jasonlukemd 12

Fc-engineered mAb plus PD-1 x LAG-3 DART: Combinatorial Biology PD-1 x LAG-3 (MGD013) Enhances Lytic Fc-engineered Margetuximab Activity of Immune Cells Primed by Up-regulates LAG-3/PD-L1 Expression Fc-engineered mAb (Margetuximab) NK Monocyte CD4 T CD8 T ADCC NK-cell Killing LAG-3 100 100 (-) 80 80 MGD013 PD-1 60 60 Live cellLive (%) 40 40 20 20 PD-L1 0 0 Control Ab Marge Control Ab Marge Control Ab Marge Control Ab Marge Upregulation of LAG-3 and PD-L1 on NK, monocytes and T cells ADCC (target: margetuximab opsonized N87, E:T=10) and NK-cell killing (target: K562, E:T=10) mediated by immune cells activated for 6 days by margetuximab +/- MGD013 in Human PBMC (Donor # 731) + N87 (HER2+) gastric cancer cells; E:T = 15:1 +/- margetuximab (no supplementary IL-2) the presence of N87 tumor cells. Jason J. Luke, MD, FACP @jasonlukemd 13

Fc-engineered αHER2 plus PD-1 × LAG-3 DART (Margetuximab plus MGD013) Preliminary results in patients with relapsed/refractory HER2+ solid tumors • ORR = 42.9% (6/14 evaluable pts) • Includes unconfirmed objective responses • Well-tolerated PD PD PDPD • Responding patients remain on therapy PD PD PDPD PDPD SD Baseline PD-L1 & LAG-3 in # of Responding Patients (N = 6) SDSD cPR PD-L1 CPS: < 1 1 TBD # # PDPD uPR cPR N 4 1 1 cPR uCR cPR LAG-3 Score: < 5 5-15 TBD/NE N 3 1 2 # GEJ pt with apparent pseudo-progression (PD per RECIST), now with 37.5% reduction in target lesions (iPR per iRECIST). Jason J. Luke, MD, FACP @jasonlukemd 14

Durable Response in Patient Receiving MGD013 plus Margetuximab Resolution of chest wall disease with confirmed PR of overall tumor burden Metastatic HER2+ breast cancer in Baseline 67-year-old female • Previously progressed on: Day 15† – 1L pertuzumab/trastuzumab/anastrozole 2L TDM1/anastrozole – Day 28† – 3L TDM1 Baseline tumor burden: • Right breast, liver and lymph nodes Day 70 – PD-L1 CPS: <1; LAG-3 score: 0.8 • Patient remains on treatment in Cycle 15 Day 295 with improved clinical status and ongoing partial response – 1st tumor assessment: -46% – 2nd tumor assessment: -61% – 3rd tumor assessment: -65% – 4th tumor assessment: -66% Note: Images correspond to the patient’s right chest wall † Day 15 and Day 28 images obtained after one dose of the combination Jason J. Luke, MD, FACP @jasonlukemd 15

MGD013 (PD-1 × LAG-3 DART Molecule): Conclusions First-in-class bispecific checkpoint inhibitor • Designed to independently or coordinately block PD-1 and LAG-3 • Well tolerated at doses up to 1200 mg Q2W • RP2D: 600 mg Q2W or Q3W • Safety profile consistent with anti-PD-1 monotherapy Encouraging monotherapy activity in multiple tumor types • Baseline LAG-3 expression & IFN-γ signature associated with objective response Compelling preliminary combinatorial activity with margetuximab (Fc-engineered mAb) • >40% ORR observed in low PD-L1-expressing, relapsed/refractory HER2+ tumors • Compares favorably to low historical response rates to anti-HER2 ± CPI Evaluation of MGD013 as monotherapy and in combination with Fc-engineered mAbs (incl. margetuximab) is ongoing Jason J. Luke, MD, FACP @jasonlukemd 16

Investigators Australia Spain United States of America Philip Clingan Analia Azaro Pedrazzoli Charu Aggarwal Anthony Joshua Javier Cortes Castan Shakeela Bahadur Girish Mallesara Maria Jose De Miguel Luken George Blumenschein Andrew Weickhardt Bartosz Chmielowski Anthony El-Khoueiry Lipika Goyal Bulgaria Thailand Erika Hamilton Nadezhda Miteva Chaiyut Charoentum Hedy Kindler Jason Luke Krasimir Nikolov Arunee Dechapunkul Virote Sriuranpong Robin Norris Krasimir Oreshkov Manish Patel Cesar Santa-Maria Susanna Ulahannan Jie Wang Poland Ukraine Monika Dlugosz-Danecka Igor Bondarenko Iwona Lugowska Yevhen Hotko Rodryg Ramlau Anna Kryzhanivska Andriy Kurochkin Monika Tomaszewska-Kiecana Halyna Pylypenko Lucjan Wyrwicz Serhii Shevnia Jason J. Luke, MD, FACP @jasonlukemd 17

Acknowledgments Thank you to the patients and their families who participated or continue to participate in this study. Jason J. Luke, MD, FACP @jasonlukemd 18