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Ref Type Journal Article
PMID (27026201)
Authors Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, Soma M, Okamoto H, Oitate M, Arakawa S, Hirai T, Atsumi R, Nakada T, Hayakawa I, Abe Y, Agatsuma T
Title DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1.
URL
Abstract Text An anti-HER2 antibody-drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed.In vitro and in vivo pharmacologic activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models. The mechanism of action for the efficacy was also evaluated. Pharmacokinetics in cynomolgus monkeys and the safety profiles in rats and cynomolgus monkeys were assessed.DS-8201a exhibited a HER2 expression-dependent cell growth-inhibitory activity and induced tumor regression with a single dosing at more than 1 mg/kg in a HER2-positive gastric cancer NCI-N87 model. Binding activity to HER2 and ADCC activity of DS-8201a were comparable with unconjugated anti-HER2 antibody. DS-8201a also showed an inhibitory activity to Akt phosphorylation. DS-8201a induced phosphorylation of Chk1 and Histone H2A.X, the markers of DNA damage. Pharmacokinetics and safety profiles of DS-8201a were favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys, supporting DS-8201a as being well tolerated in humans. DS-8201a was effective in a T-DM1-insensitive PDX model with high HER2 expression. DS-8201a, but not T-DM1, demonstrated antitumor efficacy against several breast cancer PDX models with low HER2 expression.DS-8201a exhibited a potent antitumor activity in a broad selection of HER2-positive models and favorable pharmacokinetics and safety profiles. The results demonstrate that DS-8201a will be a valuable therapy with a great potential to respond to T-DM1-insensitive HER2-positive cancers and low HER2-expressing cancers. Clin Cancer Res; 22(20); 5097-108. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Trastuzumab deruxtecan Trastuzumab deruxtecan 0 35
Drug Name Trade Name Synonyms Drug Classes Drug Description
Trastuzumab deruxtecan Enhertu DS-8201|DS8201a|T-DXd|DS-8201|fam-trastuzumab deruxtecan-nxki|DS-8201a HER2 (ERBB2) Antibody 72 HER2 (ERBB2) Antibody-Drug Conjugate 27 Enhertu (trastuzumab deruxtecan) is an antibody-drug conjugate (ADC) comprising an anti-ERBB2 (HER2) antibody linked to a derivative of the topoisomerase inhibitor DX-8951, which delivers the cytotoxic agent to ERBB2 (HER2)-expressing tumor cells, potentially resulting in decreased growth of tumors, including tumors with low ERBB2 (HER2) expression (PMID: 27026201). Enhertu (fam-trastuzumab deruxtecan-nxki) is FDA approved for use in patients with ERBB2 (HER2)-positive breast cancer who have received two or more anti-HER2 therapies previously, in patients with ERBB2 (HER2)-low (IHC 1+ or IHC 2+/ISH -) breast cancer received prior chemotherapy, in patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal (GEJ) adenocarcinoma who have received prior trastuzumab-based therapy, and in patients with non-small cell lung cancer harboring ERBB2 (HER2) activating mutations who have received prior systemic therapy (FDA.gov).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References