47OPhase 1 study of bispecific HER2 antibody-drug conjugate MEDI4276 in patients with advanced HER2-positive breast or gastric cancer

Background: MEDI4276 is a HER2-bispecific antibody targeting two different epitopes on HER2, with site-specific conjugation via maleimidocaproyl linker to a potent tubulysin-based microtubule inhibitor. MEDI4276 demonstrates enhanced cellular internalization and cytolysis of HER2+ tumor cells in vitro, including T-DM1 resistant cells. Methods: This was a phase 1 dose escalation trial in patients with advanced HER2+ breast or gastric cancer that was relapsed or refractory to standard therapy. MEDI4276 was infused intravenously over 60-90 minutes at 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.75, or 0.9 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; secondary endpoints included antitumor activity (RECIST 1.1; ORR, PFS, and OS), pharmacokinetics (PK), and immunogenicity. Results: As of 13 November 2017, 43 patients (median age 60 years [range: 36-76]; 69.8% female] were enrolled and treated: n = 3 in all groups except 0.4 (n = 6), 0.6 (n = 11), and 0.75 (n = 8) mg/kg. Maximum tolerated dose was exceeded at 0.9 mg/kg; dose-limiting toxicities (DLTs) were grade 3 liver function test (LFT) increases (n = 2; reversible) and grade 3 diarrhea (n = 1). Two other DLTs of grade 3 or 4 LFT increases were reported (0.4 and 0.6 mg/kg). Thirty-eight patients (88%) had drug-related adverse events (AE) of any grade; most common were nausea (58%), fatigue (42%), elevated AST (37%), vomiting (37%), and elevated ALT (35%). Twelve patients (28%) had drug-related AEs of grade 3-4 severity; most common were grade 3 elevated AST (19%) and grade 3 elevated ALT (12%). Drug-related grade 3 peripheral neuropathy was observed in 1 patient (2%) at 0.6 mg/kg and in 2 patients (5%) at 0.75 mg/kg. Four patients (9%) had ≥1 drug-related AE leading to treatment discontinuation. In the as-treated population, there was 1 CR (0.5 mg/kg; breast), 1 PR (0.6 mg/kg; breast), and 12 (28%) patients with SD. MEDI4276 exhibited non-linear PK, rapid clearance and negligible deconjugation. Conclusions: MEDI4276 has clinical activity, but with increased toxicity at higher doses. Updated results will be presented. Clinical trial identification: NCT02576548 Legal entity responsible for the study: MedImmune, LLC Funding: MedImmune Disclosure: M. Pegram: Consulting work for AstraZeneca, parent company of study sponsor (MedImmune), for non-branded educational sessions, within the past year. A.R. Tan: The author's institution has received research funding from MedImmune. A.M. Storniolo: Stock in Gilead, Celgene, Amgen - immediate family member Honoraria from Pfizer – author. N. Elgeioushi, S. Marshall, S. Abdullah: MedImmune employment and stock interests or options in its parent company, AstraZeneca. All other authors have declared no conflicts of interest.