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UNITED STATES
SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, D.C. 20549
____________________

FORM 8-K
 
CURRENT REPORT

Pursuant to Section 13 or 15(d) of the
Securities Exchange Act of 1934
 
Date of report (Date of earliest event reported):  May 29, 2020
 
MACROGENICS, INC.

(Exact Name of Registrant as Specified in Charter)

Delaware001-3611206-1591613
(State or Other Jurisdiction
of Incorporation)
(Commission
File Number)
(IRS Employer
 Identification No.)
9704 Medical Center Drive,
Rockville, Maryland		20850
(Address of Principal Executive Offices)(Zip Code)


Registrant's telephone number, including area code:  (301) 251-5172
 
Not applicable 
(Former Name or Former Address, if Changed Since Last Report)
 
Securities registered pursuant to Section 12(b) of the Act:
Title of each classTrading Symbol(s)Name of each exchange on which registered
Common Stock, par value $0.01 per shareMGNXNasdaq Global Select Market

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
[  ] Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
[  ] Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
[  ] Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
[  ] Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐



Item 8.01Other Events

On May 29, 2020, at the American Society of Clinical Oncology (“ASCO”) 2020 Virtual Annual Meeting, the following data were presented:

•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. The slides used at this presentation are filed as Exhibit 99.1 to this Form 8-K.
•Preliminary Dose Escalation Results from a Phase 1/2, First-in-Human Study of MGC018 (Anti-B7-H3 Antibody-Drug Conjugate) in Patients with Advanced Solid Tumor. The slides used at this presentation are filed as Exhibit 99.2 to this Form 8-K.
•SOPHIA Analysis by Chemotherapy (Ctx) Choice: A Phase 3 (P3) Study of Margetuximab (M) + Ctx vs Trastuzumab (T) + Ctx in Patients (pts) with Pretreated HER2+ Metastatic (met) Breast Cancer (MBC). The slides used at this presentation are filed as Exhibit 99.3 to this Form 8-K.


Item 9.01Financial Statements and Exhibits
(d) Exhibits.
Exhibit NumberDescription of Exhibit


SIGNATURE

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

Date: May 29, 2020
MACROGENICS, INC.
By:
/s/ Jeffrey Peters
Jeffrey Peters
Vice President and General Counsel


asco2020_mgd013phase1
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

 
asco2020_mgc018phase1
Preliminary Dose Escalation Results from a Phase 1/2, First-in-Human Study of Abstract #308859 MGC018 (Anti-B7-H3 Antibody-Drug Conjugate) in Patients with Advanced Solid Tumors John Powderly1, Sekwon Jang2, Juniper Scribner3, Deryk Loo3, Chet Bohac3, Alexander Spira4, Manish Sharma5 NCT03729596 1Carolina BioOncology, Huntersville, NC; 2Inova Schar Cancer Institute Fairfax, VA; 3MacroGenics, Inc., Rockville, MD; 4Virginia Cancer Specialists, Fairfax, VA; 5START Midwest, Grand Rapids, MI bohacg@macrogenics.com Background Study Design and Objectives Grade ≥ 3 Related Adverse Events Tumor Responses with MGC018 System Organ Class 0.5 mg/kg 1.0 mg/kg 2.0 mg/kg 3.0 mg/kg All ■■Phase 1 study evaluates safety, dose-limiting toxicities (DLT), and maximum Preferred Term (N=3) (N=6) (N=7) (N=7) (N=23) High B7-H3 Expression Levels in Solid Tumors tolerated dose (MTD) of MGC018 in a dose escalation 3+3+3 design AT LEAST ONE EVENT 2 (66.7) 2 (33.3) 7 (100) 3 (42.9) 14 (60.9) ■■Reduction of pleural-based tumor in NSCLC patient following progression Blood and lymphatic system disorders 0 0 2 (28.6) 2 (28.6) 4 (17.4) ■■MGC018 dosed intravenously every 21 days (q3w) Neutropenia 0 0 2 (28.6) 2 (28.6) 4 (17.4) after 5L of prior therapy Lymphopenia 0 0 1 (14.3) 1 (14.3) 2 (8.7) ■■6 dose escalation cohorts planned (0.5 to 5.0 mg/kg) Baseline (May 23, 2019) Week 6 (July 26, 2019) Potential Indications B7-H3 Positive* 2+ or Above Gastrointestinal disorders 0 1 (16.7) 0 0 1 (4.3) ■■Tumor response by investigator per RECIST v1.1 evaluated every 6 weeks for Gastrointestinal inflammation 0 1 (16.7) 0 0 1 (4.3) st Investigations 1 (33.3) 2 (33.3) 4 (57.1) 2 (28.6) 9 (39.1) 2 Doses of MGC018 1 4 cycles and every 12 weeks thereafter (2.0 mg/kg) Head and Neck Cancer 19/19 100% 19/19 100% Lymphocyte count decreased 0 1 (16.7) 2 (28.6) 1 (14.3) 4 (17.4) Blood alkaline phosphatase increased 0 0 1 (14.3) 1 (14.3) 2 (8.7) Decrease in pleural lesion ■■ read by Investigator Cohort expansion will enroll at the RP2D to assess safety and tumor response Neutrophil count decreased 0 1 (16.7) 1 (14.3) 0 2 (8.7) Kidney Cancer 77/78 99% 75/78 96% Platelet count decreased 0 0 1 (14.3) 1 (14.3) 2 (8.7) Primary Objective Lipase increased 1 (33.3) 0 0 0 1 (4.3) Glioblastoma 65/66 98% 63/66 95% White blood cell count decreased 0 1 (16.7) 0 0 1 (4.3) ■■ Safety and MTD (or maximum administered dose) Note image not exact Anterior-Posterior slice as May 23, 2019 Respiratory, thoracic and mediastinal disorders 1 (33.3) 0 0 0 1 (4.3) Thyroid Cancer 34/35 97% 33/35 94% Pneumonitis 1 (33.3) 0 0 0 1 (4.3) Secondary Objectives Line of Duration of Therapy Best Mesothelioma 41/44 93% 39/44 89% Skin and subcutaneous tissue disorders 0 0 3 (42.9) 1 (14.3) 4 (17.4) Treatment Cycles ■■PK and immunogenicity Palmar-plantar erythrodysaesthesia syndrome 0 0 1 (14.3) 1 (14.3) 2 (8.7) Tx (Months) Response Rash maculo-papular 0 0 2 (28.6) 0 2 (8.7) Melanoma 132/146 90% 94/146 64% ■■Antitumor activity Stasis dermatitis 0 0 1 (14.3) 0 1 (4.3) 1 Carboplatin+Paclitaxel+Bevacizumab 4 2 SD Prostate Cancer 88/99 89% 51/99 52% Key Eligibility Criteria 2 Nivolumab 40 16 SD 3 MK-7162 (IDO1 inhibitor) 3 2 SD Pancreas Cancer 69/78 88% 45/78 58% Inclusion 4 APG-1252 (Bcl-2 inhibitor) 2 1 PD Bladder Cancer 134/156 86% 123/156 79% ■■Patients with histologically proven, relapsed or refractory, unresectable Overall Summary of Treatment-Emergent Adverse Events 5 Pembrolizumab (MK-3475) 2 1 PD 0.5 mg/kg 1.0 mg/kg 2.0 mg/kg 3.0 mg/kg All locally advanced or metastatic solid tumors of any histology Patients Reporting at Least One Adverse Event Lung Cancer 324/379 85% 300/379 79% (N=3) (N=6) (N=7) (N=7) (N=23) ■■Patients for whom no therapy with demonstrated clinical benefit is available 6 MGC018 2 2 SD (≈24%) Breast Cancer 189/249 76% 156/249 63% Adverse Event 3 (100) 6 (100) 7 (100) 7 (100) 23 (100) ■ ■ Tumor tissue available to evaluate B7-H3 IHC (B7-H3 expression not Treatment-Related Adverse Event ¹ 3 (100) 4 (66.7) 7 (100) 7 (100) 21 (91.3) ■ Ovarian Cancer 59/79 75% 36/79 46% required for eligibility) Adverse Event ≥ Grade 3 ² 3 (100) 4 (66.7) 7 (100) 4 (57.1) 18 (78.3) ■ Greater than 50% PSA decline following ■ Patient 2: 99% PSA reduction *B7-H3 positivity reflects any grade staining (1-3+) via FFPE tumor microarray (cytoplasmic, membrane, and vasculature staining); Treatment-Related Adverse Event ≥ Grade 3 ² 2 (66.7) 2 (33.3) 7 (100) 3 (42.9) 14 (60.9) MGC018 in heavily pre-treated mCRPC with substantial improvement B7-H3 is expressed on tumor as well as tumor vasculature. Exclusion Serious Adverse Event 1 (33.3) 1 (16.7) 3 (42.9) 0 5 (21.7) in metastatic bone lesions of Duration ■■ Patient Line of MGC018 Abnormal laboratory parameters (hematologic, renal, and/or liver function) Event that Resulted in Study Discontinuation 1 (33.3) 1 (16.7) 3 (42.9) 0 5 (21.7) Treatment of Therapy (Dose) Therapy Response thoracic/lumbar spine, ribs, ■■Untreated or symptomatic central nervous system metastasis Event that Resulted in Drug MGC018 Withdrawal 1 (33.3) 1 (16.7) 3 (42.9) 1 (14.3) 6 (26.1) (months) sternum, and pelvis Event that Resulted in Drug MGC018 Dose Reduction 0 0 1 (14.3) 2 (28.6) 3 (13.0) Patient #1 1 Docetaxel 4 ■■ MGC018 Antibody-Drug Conjugate with Duocarmycin- Treatment with any systemic chemotherapy within 3 weeks 2 mg/kg 2 Enzalutamide 24 November 13, 2019 Event that Resulted in Drug MGC018 Interrupted 1 (33.3) 0 2 (28.6) 5 (71.4) 8 (34.8) SD (-29%); One target lesion 3 Prostvac 5 (radiotherapy within 2 weeks) (lymph node), 59% PSA based Linker Payload Fatal Adverse Event (pneumonitis) 1 (33.3) 0 0 0 1 (4.3) 4 Abiraterone 6 ■■ abdominal Decline Clinically significant cardiovascular or pulmonary disease Adverse Event of Special Interest (AESI) – Infusion Reaction 0 0 2 (28.6) 5 (71.4) 7 (30.4) adenopathy & 5 Nivolumab 6 seco vc- -DUBA O bone lesions MGC018 1 2 6 MGC018 4 HN OH Includes events with causality assessments of ‘Possible’, ‘Probable’ or ‘Definite’. Based on CTCAE criteria version 4.0.3. CL *Amendment applied to allow dose modification. 1 Docetaxel 6 N OH Patient #2 N N 2 Abiraterone 4 SD (Ongoing); HN ■■ 3 mg/kg O O Results 3 treatment-related serious adverse events occurred in 3 patients: 3 Enzalutamide 12 99% PSA Proteolytic Cleavage Bone only Cleavable Peptide O O and Release of Toxin N O pneumonitis in a patient with concurrent bacterial pneumonia; disease 4 Radium 223 6 Decline O O N O O N N O OH N N O H 5 MGC018 3 N O N N I O Duocarmcyin Humanized H O H Self-elimination Module non-infectious gastroenteritis; and stasis dermatitis in a patient with s O O Payload IgG1 1 Docetaxel 8 NH DUBA Enrollment Status Patient #3 H N O chronic venous insufficiency 2 Provenge 2 SD (Ongoing); 2 3mg/kg ■ 3 Enzalutamide 6 67% PSA B7-H3 mAb Patients Screened N=29 ■ One DLT; Grade 4 neutropenia resolved to baseline Bone only disease 4 Abiraterone 9 Decline Drug-antibody ratio 2.68 Screen fail N=4 ■■No febrile neutropenia observed 5 MGC018 1.5 MGC018 February 7, 2020 Patient #4 1 Abiraterone Unknown SD (Ongoing); ■ Patients Enrolled N=25 3 mg/kg 2 Nivolumab + Unknown ■ MGC018 is an anti-B7-H3 antibody-drug conjugate (ADC) with a 74% PSA Bone only Rucaparib 3 Decline duocarmycin payload disease MGC018 1.5 1 Docetaxel 4 ■■vc-seco-DUocarmycin-hydroxyBenzamide Azaindole (DUBA) is a fully Cohort 1 (0.5 mg/kg) Cohort 2 (1mg/kg) Cohort 3 (2 mg/kg) Cohort 4 (3 mg/kg) Cohort 5 (4 mg/kg) Cohort 6 (5 mg/kg) Best Percent Change of Target Lesions by MGC018 Dose N=3 N=6 N=7 N=7 N=TBD (Enrolling) N=TBD 1 Patient #5 2 Provenge 12 SD (Ongoing); synthetic DNA alkylating agent Level and Tumor Type in the Evaluable Population 3mg/kg 3 Enzalutamide 7 78% PSA Colon CA Pancreatic NSCLC mCRPC* mCRPC* Bone only 4 Abiraterone 7 ■■ Decline DUBA cytotoxic activity is cell-cycle independent 50 disease 5 Docetaxel 4 Uveal Melanoma Esophageal Colon CA Colon CA mCRPC* ■■ CRC 6 MGC018 1.5 DUBA retains potency in multidrug-resistant cell lines 40 NSCLC SCLC Rectal CA Renal Cell TBD Patient 1 had 59% PSA reduction with near partial response, and several ■■ CRC Cleavable peptide linker – facilitates bystander effect patients with ongoing stable disease. Colon CA Pancreatic CA Colon CA CRC 30 Esophageal ■■ Induces immunogenic cell death in preclinical models Sarcoma Best PSA Reduction Ovarian CA mCRPC mCRPC* 20 160 DUBA Linker Payload provided and conjugated by Byondis. Pancreas Patient 1 141.8 Patient 2 Sarcoma mCRPC mCRPC* CRC 10 140 Patient 3 May 1, 2020 CRC Uveal Patient 4 Melanoma 120 *On study mCRPC mCRPC* 114.0 Patient 5* 0 111.4 Ovarian NSCLC 100 RCC ■■ SCLC Anti-Tumor Activity of MGC018 in Human Cancer 25 patients enrolled as of 06 May 2020 -10 80 67% Reduction 67.0 ■■ 60.2 PDX Models 23 patients included in safety and efficacy assessment of Cohorts 1–4 60 -20 59% Reduction NSCLC 47.0 46.4 Prostate Cancer PDX Breast Cancer PDX Head and Neck Cancer PDX ■■ 40 18 patients (1 with metastatic castration-resistant prostate cancer [mCRPC]) Change from Baseline (%) -30 Prostate* 78% Reduction CTG-2441 CTG-0869 CTG-0790 24.9 with measurable disease evaluated per RECIST v1.1 20 17.2 ) 1500 2500 2500 74% Reduction 3 -40 4.5 99% Reduction ■■ 0 0.5 2000 2000 6 patients with mCRPC with bone only disease Baseline 3612 16 19 24 -50 Cohort: 0.5 mg/kg 1.0 mg/kg 2.0 mg/kg 3.0 mg/kg Weeks 1000 1500 1500 ¹Patients who received at least one dose and had at least one post-baseline tumor evaluation. *mCRPC Pt #1. *Patient 5 Scaled for Charting Purposes: Baseline PSA 1,114 ng/mL Data were extracted on 06MAY2020. dropped to 249 ng/mL on Week 6 1000 1000 Safety Summary 500 500 500 Tumor Volume (mm Related Adverse Events ≥ 10%, All Grades B7-H3 IHC Data 0 0 0 010203040 -5 0510 15 20 25 30 0102030405060 System Organ Class 0.5 mg/kg 1.0 mg/kg 2.0 mg/kg 3.0 mg/kg All Percent Change of Target Lesions by Tumor Type ■■18 of 23 patients had tissue samples evaluable for B7-H3 expression Study Day Study Day Study Day Preferred Term (N=3) (N=6) (N=7) (N=7) (N=23) NSCLC ■■ Vehicle MGC018 3 mg/kg Ctrl ADC 3 mg/kg AT LEAST ONE EVENT 3 (100) 4 (66.7) 7 (100) 7 (100) 21 (91.3) 80 H-score: Median 200 (range 82–279) Uveal Melanoma Blood and lymphatic system disorders 0 1 (16.7) 2 (28.6) 3 (42.9) 6 (26.1) Prostate ■■ 300 300 300 70 Vasculature score: Median 2+ (range 0–3+) 3+ 3+ 3+ Neutropenia 0 1 (16.7) 2 (28.6) 3 (42.9) 6 (26.1) SCLC 250 2+ 250 250 * 2+ 2+ Lymphopenia 0 0 1 (14.3) 2 (28.6) 3 (13.0) 60 Sarcoma 200 1+ 200 200 * 1+ 1+ Gastrointestinal disorders 0 4 (66.7) 2 (28.6) 2 (28.6) 8 (34.8) CRC 150 0 150 150 50 * 0 0 Nausea 0 2 (33.3) 2 (28.6) 1 (14.3) 5 (21.7) Ovarian H-Score H-Score H-Score 100 100 100 Vomiting 0 1 (16.7) 2 (28.6) 1 (14.3) 4 (17.4) 40 RCC Conclusions 50 50 50 Pancreas General disorders and administration site conditions 2 (66.7) 2 (33.3) 2 (28.6) 5 (71.4) 11 (47.8) Esophageal 0 0 0 30 CTG-2428 CTG-2440 CTG-2427 CTG-2441 CTG-2208 CTG-0869 CTG-0012CTG-1941 CTG-0152CTG-0790CTG-0434CTG-0149 Fatigue 1 (33.3) 1 (16.7) 2 (28.6) 4 (57.1) 8 (34.8) First new lesion ■■ Chills 1 (33.3) 1 (16.7) 2 (28.6) 1 (14.3) 5 (21.7) MGC018 has an acceptable safety profile to date with manageable Staining with goat anti-B7-H3 polyclonal Ab R&D Systems, Inc. 20 Pyrexia 1 (33.3) 0 2 (28.6) 0 3 (13.0) hematologic and skin toxicity Injury, poisoning and procedural complications 0 0 2 (28.6) 5 (71.4) 7 (30.4) 10 Infusion related reaction 0 0 2 (28.6) 5 (71.4) 7 (30.4) 0 ––1 DLT occurred at 2 mg/kg, resolved to baseline Investigations 1 (33.3) 3 (50.0) 4 (57.1) 4 (57.1) 12 (52.2) ■■ Neutrophil count decreased 0 1 (16.7) 1 (14.3) 3 (42.9) 5 (21.7) -10 Preliminary evidence of anti-tumor activity with radiologic improvement in Lymphocyte count decreased 0 1 (16.7) 2 (28.6) 1 (14.3) 4 (17.4) -20 Rationale Platelet count decreased 0 0 1 (14.3) 2 (28.6) 3 (13.0) heavily pretreated patients: Skin and subcutaneous tissue disorders 0 3 (50.0) 5 (71.4) 5 (71.4) 13 (56.5) -30 ––NSCLC Skin hyperpigmentation 0 3 (50.0) 1 (14.3) 3 (42.9) 7 (30.4) ■■ -40 B7-H3 is highly expressed in multiple solid tumors, with limited expression Palmar-plantar erythrodysaesthesia syndrome 0 0 3 (42.9) 2 (28.6) 5 (21.7) ––mCRPC with rapid PSA reduction Pruritus 0 1 (16.7) 1 (14.3) 2 (28.6) 4 (17.4) -50 in normal tissue Change in Target Lesions from Baseline (%) Rash maculo-papular 0 0 2 (28.6) 1 (14.3) 3 (13.0) ■■Enrollment ongoing at 4 mg/kg q3w 0510 15 20 25 30 35 40 45 50 ■■ ¹Includes events with causality ratings of ‘Possible’, ‘Probable’ or ‘Definite’. ²Subjects are counted once for each Preferred Term reported. MGC018 is a novel ADC that delivers a potent duocarmycin payload to ■■ (Note: 1 pt at 1.0 mg/kg and 3.0 mg/kg experienced angioedema; both AEs were Grade 2 and resolved to baseline.) Weeks Since Treatment Initiation Planned dose expansion in mCRPC dividing and non-dividing B7-H3-expressing cells Presented at the ASCO20 Virtual Scientific Program, May 29–31, 2020

 
asco2020_sophiabychemo
SOPHIA Analysis by Chemotherapy (Ctx) Choice: A Phase 3 (P3) Study of Margetuximab (M) + Ctx vs Abstract #1040 Trastuzumab (T) + Ctx in Patients (pts) with Pretreated HER2+ Metastatic (met) Breast Cancer (MBC) Santiago Escriva-de-Romani, MD1, Seock-Ah Im, MD, PhD2, Fatima Cardoso, MD3, Javier Cortes, MD, PhD4, Giuseppe Curigliano, MD, PhD5, William J. Gradishar, MD, FASCO, FACP6, Mark D. Pegram, MD7, Gail S. Wright, MD, FACP, FCCP8, Christelle Levy, MD9, Michelino De Laurentiis, MD, PhD10, Jean-Marc Ferrero, MD11, Shakeela W. Bahadur, MD12, Sung-Bae Kim, MD13, Katarína Petráková, MD, PhD14, David A. Riseberg, MD15, Denise Yardley, MD16, Sutton Edlich17, Shengyan Hong, PhD17, Edwin Rock, MD, PhD17, Hope S. Rugo, MD18, on behalf of the SOPHIA Study Group rocke@macrogenics.com 1Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Barcelona, Spain; 2Seoul National University Hospital, Cancer Research Institute, and College of Medicine, Seoul, Korea; 3Champalimaud Clinical Center/Champalimaud Foundation, Breast Unit, Lisbon, Portugal; 4IOB Institute of Oncology, Quironsalud Group, Madrid, Vall d’Hebron Institute of Oncology, Barcelona, Spain; 5University of Milano, European Institute of Oncology, IRCSS, Division of Early Drug Development, Milan, Italy; 6Northwestern University, Division of Hematology/Oncology, Chicago, Illinois, USA; 7Stanford Women’s Cancer Center, Breast Cancer Oncology Program, Palo Alto, California, USA; 8Florida Cancer Specialists & Research Institute, New Port Richey, FL, USA; 9Centre François Baclesse, Institut Normand du Sein, Caen, France; 10National Cancer Institute “Fondazione Pascale,” Department of Breast and Thoracic Oncology, Naples, Italy; 11Centre Antoine Lacassagne, Department of Medical Oncology, Nice, France; 12Bannerer MD Anderson Cancer Center, Breast Cancer Program, Gilbert, Arizona, USA; 13Asan Medical Center, Department of Oncology, Seoul, Korea; 14Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Brno, Czech Republic; 15Mercy Medical Center, Division of Medical Oncology and Hematology, Baltimore, Maryland, USA; 16Sarah Cannon Research Institute and Tennessee Oncology PLLC, Nashville, TN, USA; 17MacroGenics, Inc., Rockville, Maryland, USA; 18University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA Background/Methods Figure 1. Progression-Free Survival Results by Chemotherapy y 1.0 y 1.0 ■■Despite advances, pretreated HER2+ MBC remains incurable with ongoing Capecitabine Eribulin 0.9 Treatment Group Events/Total Median (95% CI) HR (95% CI) 0.9 Treatment Group Events/Total Median (95% CI) HR (95% CI) Margetuximab plus Chemo 29/71 8.28 (5.55-11.50) 0.773 (0.473-1.262) Margetuximab plus Chemo 35/66 5.95 (3.81-8.05) 0.662 (0.416-1.053) need for new therapies. Investigational M has similar HER2 binding and 0.8 Trastuzumab plus Chemo 37/72 5.52 (4.17-8.28) Reference 0.8 Trastuzumab plus Chemo 39/70 4.17 (3.38-5.55) Reference Unstratified Logrank p-value: 0.3019 + Censor Unstratified Logrank p-value: 0.0797 + Censor antiproliferative effects as T. Relative to T, M Fc engineering increases 0.7 0.7 binding affinity for both variants of activating Fc receptor (FcR) CD16A and 0.6 0.6 decreases affinity for inhibitory FcR CD32B, coordinately activating innate 0.5 0.5 and adaptive immunity 0.4 0.4 0.3 0.3 ■■SOPHIA (NCT02492711), an open-label P3 trial, enrolled pts with HER2+ 0.2 0.2 MBC after pertuzumab and 1–3 lines of prior treatment (Tx) for MBC. 0.1 0.1 0.0 0.0 Randomization was 1:1 to M (15 mg/kg IV q3w + Ctx) or T (6 [8 for loading Progression-free Survival Probabilit Progression-free Survival Probabilit 0246810 12 14 16 18 20 22 24 26 0246810 12 14 16 18 20 22 24 26 dose] mg/kg IV q3w + Ctx), stratified by met sites (≤2, >2), Tx lines for met Patients-at-Risk Time from Initial Randomization (months) Patients-at-Risk Time from Initial Randomization (months) Margetuximab plus Chemo 71 49 34 16 14 9 3 3 3 2 1 1 0 Margetuximab plus Chemo 66 42 31 18 11 2 1 111 110 disease (≤2, >2), and Ctx choice, including capecitabine (Cap), eribulin (Eri), Trastuzumab plus Chemo 72 55 37 18 15 7 1 1 1 1 1 1 10 Trastuzumab plus Chemo 70 41 22 6 3 1 0 gemcitabine (Gem), or vinorelbine (Vin). Primary endpoints were central y 1.0 Gemcitabine y 1.0 Vinorelbine blinded PFS and OS, assessed sequentially using the stratified log-rank test 0.9 Treatment Group Events/Total Median (95% CI) HR (95% CI) 0.9 Treatment Group Events/Total Median (95% CI) HR (95% CI) Margetuximab plus Chemo 15/33 5.39 (4.07-11.01) 0.580 (0.285-1.180) Margetuximab plus Chemo 51/96 5.62 (4.24-6.97) 0.898 (0.596-1.352) 0.8 Trastuzumab plus Chemo 17/33 3.52 (1.45-7.16) Reference 0.8 Trastuzumab plus Chemo 42/95 5.13 (3.42-6.67) Reference ■■ Unstratified Logrank p-value: 0.1279 + Censor Unstratified Logrank p-value: 0.6058 + Censor M + Ctx prolonged PFS over T + Ctx (Table 1). Second interim OS results 0.7 0.7 from Sept 2019 favor M without significance (hazard ratio [HR], 0.89; 0.6 0.6 95% CI 0.69–1.13; nominal P=0.326) 0.5 0.5 0.4 0.4 Results 0.3 0.3 0.2 0.2 ■■Investigator chemotherapy choices, PFS hazard ratios (HRs), and safety 0.1 0.1 0.0 0.0 Progression-free Survival Probabilit Progression-free Survival Probabilit results by chemotherapy are shown in Table 1 and Figure 1 0 246810 12 14 16 18 20 22 24 26 0 2468101214161820222426 ■■ Patients-at-Risk Time from Initial Randomization (months) Patients-at-Risk Time from Initial Randomization (months) Patients receiving Eri and Gem had the lowest PFS HRs, favoring M over T, Margetuximab plus Chemo 33 24 16 5 3 2 1 1 1 0 Margetuximab plus Chemo 96 67 47 20 15 8 3 101 although no statistical significance of individual Ctx subgroups was seen Trastuzumab plus Chemo 33 12 9 4 3 1 1 0 Trastuzumab plus Chemo 95 54 31 16 10 4 1 101 ■■Table 1: There was variable toxicity among Ctx subgroups. Fewer subjects receiving Cap had Ctx related ≥Grade 3 Adverse Events (AEs) Table 2. Adverse Events Leading to Chemotherapy Discontinuation ■■ Grade (G) In this unblinded study, more pts on M than T in all subgroups discontinued Population1 Total ≥ Grade 3 Adverse Events Ctx alone due to AE; 8 on M and 7 on T also discontinued antibody G5 G4 G3 G2 G1 ■■Table 2: AEs leading to chemotherapy discontinuation were diverse; M + Ctx (n=264) 29 1 1 13 11 3 3 such AEs were considered probably or definitely related to antibody Cap (n=68) 8 1 1 2 4 – Aspiration pneumonia (G5), septic shock (G4), hydronephrosis (G3), colitis (G3) Eri (n=66) 9 – – 5 3 1 Left ventricular (LV) dysfunction, neuropathy, neutropenia, seroma3, spondylolisthesis therapy, including 2 on M (seroma, IRR) and 1 on T (pneumonia) Gem (n=35)2 6 – – 4 1 1 Asthenia, edema, stress, vasculitis Vin (n=95) 6 – – 2 3 1 Abdominal pain, infusion related reaction (IRR)3 Table 1. PFS and Safety Results by Chemotherapy T + Ctx (n=266) 17 – – 7 1 1 PFS, 265 events ≥ Grade 3 AEs Leading to Ctx Cap (n=71) 6 – – 5 1 - Fatigue, GI toxicity, leukemia, neuropathy, palmar-plantar erythrodysesthesia Population1 HR (95% CI)1 Ctx Related AEs2 Discontinuation2 Eri (n=68) 4 – – 3 1 - Intracranial hemorrhage, neuralgia, transaminase elevations Gem (n=32) 5 – – 3 1 1 Clostridium difficile infection, osteonecrosis of jaw, bilirubin elevation Intent-To-Treat (N=536) 0.76 (0.59-0.98) 41.7% M vs 40.6% T 11% M vs 6.4% T Vin (n=95) 2 – – 2 - - Intestinal obstruction, pneumonia3 1Safety data cutoff 10-Apr-2019: 530 subjects who received any study therapy.2 2 subjects had capecitabine selected but received gemcitabine. 3Considered probably or definitely related to antibody study therapy. Capecitabine (n=143) 0.77 (0.47-1.26) 25% M vs 28% T 11.8% M vs 8.5% T Eribulin (n=136) 0.66 (0.42-1.05) 45.5% M vs 48.5% T 13.6% M vs 5.9% T Conclusions Gemcitabine (n=66) 0.58 (0.29-1.18) 40% M vs 53.1% T 17.1% M vs 15.6% T ■■Margetuximab improved PFS over trastuzumab across all chemotherapy subgroups Vinorelbine (n=191) 0.90 (0.60-1.35) 51.6% M vs 40% T 6.3% M vs 2.1% T ■■Hazard ratio differences among chemotherapy subgroups may be driven by selection bias and/or tumor sensitivity to individual chemotherapies ■■ 1Primary PFS data cutoff 10-Oct-2018: 536 Intent-To-Treat subjects. Safety was acceptable and manageable in all chemotherapy subgroups 2Safety data cutoff 10-Apr-2019: 530 subjects who received any study therapy. We thank the patients who consented to this research and study teams at all participating study sites. Presented at the ASCO20 Virtual Scientific Program, May 29–31, 2020