First-in-Human, Phase 1 Dose-Escalation Study of Biparatopic Anti-HER2 Antibody–Drug Conjugate MEDI4276 in Patients with HER2-positive Advanced Breast or Gastric Cancer

Abstract

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 tubulysinbased 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 adotrastuzumab emtansine (T-DM1). MEDI4276 has demonstrable clinical activity but displays intolerable toxicity at doses >0.3 mg/kg.

Discovery of a novel human antibody VH domain with potent activity against mesothelin expressing cancer cells in both CAR T-cell and antibody drug conjugate formats

“…Several bi-paratopic antibodies have been reported in different tumor models [27-30]. In a breast cancer model, a bi-paratopic antibody shows enhanced avidity and cross linking activity to promote HER2 clustering and lysosomal degradation [27].…”

More than Toxins—Current Prospects in Designing the Next Generation of Antibody Drug Conjugates

“…These results were also re-capitulated in in vivo models. The experimental success of this agent, now termed MEDI4276, has led to its deployment in a phase I clinical trial concluded in August 2021 [40]. ZW49, is a similar HER2-targeting biparatopic ADC.…”

Targeted Approaches to HER2-Low Breast Cancer: Current Practice and Future Directions

“…Unfortunately, in the phase Ⅱ dose-escalation and expansion study ( identifier: NCT02576548), even though MEDI4276 demonstrated obvious clinical activity, it still showed unbearable toxicity when the dose was higher than 0.3 mg/kg. Common toxicities included nausea, fatigue and vomiting [ 65 ]. The clinical development of MEDI4276 was severely delayed due to high incidences of drug-related adverse reactions, and it was therefore halted.…”