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