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313 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
  1. Manish Patel1,
  2. Jason Luke2,
  3. Erika Hamilton3,
  4. Bartosz Chmielowski4,
  5. George Blumenschein5,
  6. Hedy Kindler6,
  7. Shakeela Bahadur7,
  8. Cesar Santa-Maria8,
  9. Janine Koucheki9,
  10. Jichao Sun9,
  11. Sanjeev Kaul10,
  12. Francine Chen9,
  13. Xiaoyu Zhang9,
  14. John Muth9,
  15. Patrick Kaminker9,
  16. Paul Moore9,
  17. Bradley Sumrow9 and
  18. Susanna Ulahannan11
  1. 1Florida Cancer Specialists/Sarah Cann, Sarasota, FL, USA
  2. 2UPMC Hillman Cancer Center, Pittsburgh, PA, USA
  3. 3Sarah Cannon Research Institute, Nashville, TN, USA
  4. 4University of California Los Angeles, Los Angeles, CA, USA
  5. 5MD Anderson Cancer Center, Houston, TX, USA
  6. 6University of Chicago, Chicago, IL, USA
  7. 7Banner MD Anderson Cancer Center, Gilbert, AZ, USA
  8. 8Sidney Kimmel Comprehensive Cancer Ctr, Baltimore, MD, USA
  9. 9MacroGenics, Inc., Rockville, MD, USA
  10. 10Bio-ClinPharm Consulting, LLC, Cranbury, NJ, USA
  11. 11SCRI Nashville/OUHSC, OKC, OK, USA


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. In vitro studies have demonstrated upregulation of LAG-3/PD-L1 expression on immune cells after margetuximab exposure, along with enhanced lytic activity of immune cells primed by margetuximab in the presence of tebotelimab.

Methods This study characterizes safety, PK/PD, and preliminary antitumor activity of tebotelimab plus margetuximab in patients with advanced HER2+ malignancies. A one-step 3+3 dose escalation phase of tebotelimab (300 and 600 mg) combined with margetuximab 15 mg/kg, both every 3 weeks, was followed by cohort expansion of patients with breast, gastric or gastroesophageal, and other HER2+ tumors.

Results At data-cutoff, 31 patients (2.0 median lines of prior therapy; 64.5% with prior HER2-directed therapy) were treated. Median duration of treatment is 10.3 weeks with 17 patients remaining on treatment. No maximum tolerated dose was defined. Treatment-related adverse events (TRAEs) occurred in 23/31 (74.2%) patients, most commonly diarrhea (n=6), nausea, ALT increased (n=5, each), AST increased, and myalgia (n=4, each). The rate of Grade 3 TRAEs was 19.4%, with no Grade 4–5 TRAEs observed. Immune-related AEs were consistent with events observed with anti-PD-1 antibodies and were manageable with supportive treatment. Among 20 response-evaluable patients (i.e., received on-treatment scan), 8 objective responses (6 confirmed) per RECIST v1.1 have been observed, including a confirmed complete response (cholangiocarcinoma) and 7 partial responses (breast [2], microsatellite stable colorectal cancer [2], esophageal adenocarcinoma [1], ovarian cancer [1], and microsatellite stable gastroesophageal junction carcinoma).1 Immunohistochemistry (IHC) of available baseline tumor specimens (n=17) demonstrated low PD-L1 expression with combined positive scores of either 0 (n=16) or 1 (n=1, colorectal cancer). 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.

Trial Registration NCT03219268

Ethics Approval This study was approved by each Institution’s Ethics Board prior to enrollment of subjects.


  1. Luke J, 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 Oncol38: 2020 (suppl; abstr 3004).

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