HER2-overexpressing/amplified breast cancer as a testing ground for antibody-drug conjugate drug development in solid tumors.

HER2-overexpressing/amplified breast cancer as a testing ground for antibody-drug conjugate drug development in solid tumors. Clin Cancer Res. 2019 Oct 03;: Authors: Pegram MD, Miles D, Tsui CK, Zong Y Abstract Efficacy data from the KATHERINE clinical trial comparing ado-trastuzumab emtansine (T-DM1) to trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer with residual disease after neoadjuvant therapy (hazard ratio for invasive disease or death, 0.50; P<0.001). This establishes foundational precedent for antibody drug conjugates (ADCs) as effective therapy for treatment of subclinical micrometastasis in an adjuvant (or post-neoadjuvant) early-stage solid tumor setting. Despite this achievement, general principles from proposed systems pharmacokinetic modeling for intracellular processing of ADCs indicate potential shortcomings of T-DM1: 1) Cmax limited by toxicities, 2) slow internalization rate, 3) resistance mechanisms due to defects in intracellular trafficking (loss of lysosomal transporter solute carrier family 46 member 3, [SLC46A3]), and increased expression of drug transporters MDR1 and MRP1, and 4) lack of payload bystander effects limiting utility in tumors with heterogeneous HER2 expression. These handicaps may explain the inferiority of T-DM1-based therapy in the neoadjuvant and first-line metastatic HER2+ breast cancer settings, and lack of superiority...
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research