Abstract
Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of HER2 amplified breast cancers has improved meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for HER2 amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.
Highlights
The human epidermal growth factor receptor 2 (HER2), known as erbB-2, or proto-oncogene Neu, is a receptor tyrosine-protein kinase encoded by the ERBB2 (HER2) gene on chromosome 17q12 [1]
T-DM1 is a second-generation antibody-drug conjugate (ADC) consisting of the monoclonal HER2 directed IgG1 antibody trastuzumab, a non-cleavable thioether linker attached to random lysins and 3 to 4 maytansoinoid emtansine, called DM1 [14]
monomethyl auristatin E (MMAE) is linked to hertuzumab using a protease-sensitive valine-citrulline dipeptide sequence, which was designed for optimal stability in human plasma and efficient cleavage by human cathepsin B
Summary
The human epidermal growth factor receptor 2 (HER2), known as erbB-2, or proto-oncogene Neu, is a receptor tyrosine-protein kinase encoded by the ERBB2 (HER2) gene on chromosome 17q12 [1]. In two landmark adjuvant trastuzumab trials including patients with HER2-amplified or overexpressing breast cancer according to local site laboratories, a cohort of patients with neither HER2-amplification nor HER2 overexpression by central testing was identified. These HER2-low cohorts seemed to benefit from trastuzumab in a retrospective unplanned subgroup analysis [11,12]. The efficacy of an adjuvant trastuzumab treatment in HER2-low (immunohistochemistry (IHC) 1+ or 2+ but not HER2 amplified) breast cancer patients was prospectively investigated in the phase 3 trial NSABP B-47 [13]. A high drug-to-antibody ratio increases antitumoral efficacy despite a low HER2 antigen
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