First-in-Human, Phase 1 Dose-Escalation Study of Biparatopic Anti-HER2 Antibody-Drug Conjugate MEDI4276 in Patients with HER2+ Advanced Breast or Gastric Cancer. Molecular cancer therapeutics Pegram, M. D., Hamilton, E. P., Tan, A. R., Storniolo, A. M., Balic, K., Rosenbaum, A. I., Liang, M., He, P., Marshall, S., Scheuber, A., Das, M., Patel, M. R. 2021


MEDI4276 is a biparatopic tetravalent antibody targeting 2 nonoverlapping epitopes in subdomains 2 and 4 of the HER2 ecto-domain, with site-specific conjugation to a tubulysin-based microtubule inhibitor payload. MEDI4276 demonstrates enhanced cellular internalization and cytolysis of HER2+ tumor cells in vitro. This was a first-in-human, dose-escalation clinical trial in patients with HER2+ advanced or metastatic breast cancer (BC) or gastric cancer. MEDI4276 doses escalated from 0.05-0.9 mg/kg (60-90-minute IV infusion Q3W). Primary endpoints were safety and tolerability; secondary endpoints included antitumor activity (objective response, progression-free survival, and overall survival), pharmacokinetics, and immunogenicity. Forty-seven patients (median age 59 years; median of 7 prior treatment regimens) were treated. The maximum tolerated dose was exceeded at 0.9 mg/kg with 2 patients experiencing dose-limiting toxicities (DLT) of grade 3 liver function test (LFT) increases, 1 of which also had grade 3 diarrhea, which resolved. Two additional patients reported DLTs of grade 3 LFT increases at lower doses (0.4 and 0.6 mg/kg). The most common (all grade) drug-related adverse events (AEs) were nausea (59.6%), fatigue (44.7%), aspartate aminotransferase (AST) increased (42.6%), and vomiting (38.3%). The most common grade 3/4 drug-related AE was AST increased (21.3%). Five patients had drug-related AEs leading to treatment discontinuation. In the as-treated population, there was 1 complete response (0.5 mg/kg; BC), and 2 partial responses (0.6 and 0.75 mg/kg; BC)-all had prior trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). MEDI4276 has demonstrable clinical activity but displays intolerable toxicity at doses >0.3 mg/kg.

View details for DOI 10.1158/1535-7163.MCT-20-0014

View details for PubMedID 34045233