RT Journal Article
SR Electronic
T1 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
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP A193
OP A193
DO 10.1136/jitc-2020-SITC2020.0313
VO 8
IS Suppl 3
A1 Patel, Manish
A1 Luke, Jason
A1 Hamilton, Erika
A1 Chmielowski, Bartosz
A1 Blumenschein, George
A1 Kindler, Hedy
A1 Bahadur, Shakeela
A1 Santa-Maria, Cesar
A1 Koucheki, Janine
A1 Sun, Jichao
A1 Kaul, Sanjeev
A1 Chen, Francine
A1 Zhang, Xiaoyu
A1 Muth, John
A1 Kaminker, Patrick
A1 Moore, Paul
A1 Sumrow, Bradley
A1 Ulahannan, Susanna
YR 2020
UL http://jitc.bmj.com/content/8/Suppl_3/A193.1.abstract
AB 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 NCT03219268Ethics Approval This study was approved by each Institution’s Ethics Board prior to enrollment of subjects.ReferenceLuke 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).