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
dc.contributor.author | Pegram, Mark D. | |
dc.contributor.author | Hamilton, Erika P. | |
dc.contributor.author | Tan, Antoinette R. | |
dc.contributor.author | Storniolo, Anna Maria | |
dc.contributor.author | Balic, Kemal | |
dc.contributor.author | Rosenbaum, Anton I. | |
dc.contributor.author | Liang, Meina | |
dc.contributor.author | He, Peng | |
dc.contributor.author | Marshall, Shannon | |
dc.contributor.author | Scheuber, Anita | |
dc.contributor.author | Das, Mayukh | |
dc.contributor.author | Patel, Manish R. | |
dc.contributor.department | Medicine, School of Medicine | |
dc.date.accessioned | 2024-04-03T08:20:59Z | |
dc.date.available | 2024-04-03T08:20:59Z | |
dc.date.issued | 2021 | |
dc.description.abstract | MEDI4276 is a biparatopic tetravalent antibody targeting two 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-positive tumor cells in vitro This was a first-in-human, dose-escalation clinical trial in patients with HER2-positive advanced or metastatic breast cancer or gastric cancer. MEDI4276 doses escalated from 0.05 to 0.9 mg/kg (60- to 90-minute intravenous infusion every 3 weeks). 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 seven prior treatment regimens) were treated. The maximum tolerated dose was exceeded at 0.9 mg/kg with two patients experiencing dose-limiting toxicities (DLTs) of grade 3 liver function test (LFT) increases, one of whom 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 one complete response (0.5 mg/kg; breast cancer), and two partial responses (0.6 and 0.75 mg/kg; breast cancer)-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. | |
dc.eprint.version | Final published version | |
dc.identifier.citation | Pegram MD, Hamilton EP, Tan AR, et al. 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. Mol Cancer Ther. 2021;20(8):1442-1453. doi:10.1158/1535-7163.MCT-20-0014 | |
dc.identifier.uri | https://hdl.handle.net/1805/39706 | |
dc.language.iso | en_US | |
dc.publisher | American Association for Cancer Research | |
dc.relation.isversionof | 10.1158/1535-7163.MCT-20-0014 | |
dc.relation.journal | Molecular Cancer Therapeutics | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.source | PMC | |
dc.subject | Immunoconjugates | |
dc.subject | Stomach neoplasms | |
dc.subject | Breast neoplasms | |
dc.subject | Immunological antineoplastic agents | |
dc.title | 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 | |
dc.type | Article |