Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in locally advanced or metastatic epithelial tumors

Dejan Juric, Rodrigo Dienstmann, Andres Cervantes, Manuel Hidalgo, Wells Messersmith, George R. Blumenschein, Josep Tabernero, Desamparados Roda, Antonio Calles, Antonio Jimeno, Xiaodong Wang, Sandra Sanabria Bohorquez, Cecilia Leddy, Catherine Littman, Amy V. Kapp, David S. Shames, Elicia Penuel, Lukas C. Amler, Andrea Pirzkall, Jose Baselga

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32 Citations (Scopus)

Abstract

© 2015 AACR. Purpose: The novel dual-Action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A. Experimental Design: Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1-30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3. Results: No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n 1/4 30) or expansion (n 1/4 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in≥20% of patients≥24 hours after the first infusion included grade 1/2 headache, fever, and chills, which were managed with premedication and/or symptomatic treatment. Pharmacodynamic data indicated target inhibition in 25% of evaluable patients. Best response by RECIST included 2 confirmed partial responses in squamous cell carcinomas of head and neck (SCCHN) patients with high tumor tissue levels of the HER3 ligand heregulin; 14 patients had stable disease ≥8 weeks, including SCCHN (n1/4 3), colorectal cancer (n1/4 6), and non-small cell lung cancer (n 1/4 3). Conclusions: MEHD7945A was well-Tolerated as single agent with evidence of tumor pharmacodynamic modulation and antitumor activity in SCCHN. Phase II studies were initiated with flat (nonweight-based) dosing at 1,100 mg q2w in SCCHN and colorectal cancer.
Original languageEnglish
Pages (from-to)2462-2470
JournalClinical Cancer Research
Volume21
Issue number11
DOIs
Publication statusPublished - 1 Jun 2015

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