Proffered Paper Session 1 Proffered Paper session

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

Presentation Number
47O
Lecture Time
13:30 - 13:45
Speakers
  • Mark Pegram (Stanford, US)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
13:30 - 15:00
Authors
  • Mark Pegram (Stanford, US)
  • Erika Hamilton (Nashville, US)
  • Antoinette R. Tan (Charlotte, US)
  • Anna M. Storniolo (Indianapolis, US)
  • Nairouz Elgeioushi (Gaithersburg, US)
  • Shannon Marshall (Gaithersburg, US)
  • Shaad Abdullah (Gaithersburg, US)
  • Manish Patel (Sarasota, US)

Abstract

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.

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