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

Research output: Contribution to journalArticle

Abstract

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 (US)
Pages (from-to)2462-2470
Number of pages9
JournalClinical Cancer Research
Volume21
Issue number11
DOIs
StatePublished - Jun 1 2015
Externally publishedYes

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Pharmacokinetics
Safety
Antibodies
Neoplasms
Colorectal Neoplasms
Neuregulin-1
Ligands
Antibodies, Monoclonal, Humanized
Chills
Premedication
Head and Neck Neoplasms
Non-Small Cell Lung Carcinoma
Nausea
Headache
Disease Progression
Squamous Cell Carcinoma
Diarrhea
Research Design
Fever
Immunoglobulin G

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in locally advanced or metastatic epithelial tumors. / Juric, Dejan; Dienstmann, Rodrigo; Cervantes, Andres; Hidalgo, Manuel; Messersmith, Wells; Blumenschein, George R.; Tabernero, Josep; Roda, Desamparados; Calles, Antonio; Jimeno, Antonio; Wang, Xiaodong; Bohorquez, Sandra Sanabria; Leddy, Cecilia; Littman, Catherine; Kapp, Amy V.; Shames, David S.; Penuel, Elicia; Amler, Lukas C.; Pirzkall, Andrea; Baselga, Jose.

In: Clinical Cancer Research, Vol. 21, No. 11, 01.06.2015, p. 2462-2470.

Research output: Contribution to journalArticle

Juric, D, Dienstmann, R, Cervantes, A, Hidalgo, M, Messersmith, W, Blumenschein, GR, Tabernero, J, Roda, D, Calles, A, Jimeno, A, Wang, X, Bohorquez, SS, Leddy, C, Littman, C, Kapp, AV, Shames, DS, Penuel, E, Amler, LC, Pirzkall, A & Baselga, J 2015, 'Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in locally advanced or metastatic epithelial tumors', Clinical Cancer Research, vol. 21, no. 11, pp. 2462-2470. https://doi.org/10.1158/1078-0432.CCR-14-2412
Juric, Dejan ; Dienstmann, Rodrigo ; Cervantes, Andres ; Hidalgo, Manuel ; Messersmith, Wells ; Blumenschein, George R. ; Tabernero, Josep ; Roda, Desamparados ; Calles, Antonio ; Jimeno, Antonio ; Wang, Xiaodong ; Bohorquez, Sandra Sanabria ; Leddy, Cecilia ; Littman, Catherine ; Kapp, Amy V. ; Shames, David S. ; Penuel, Elicia ; Amler, Lukas C. ; Pirzkall, Andrea ; Baselga, Jose. / Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in locally advanced or metastatic epithelial tumors. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 11. pp. 2462-2470.
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T1 - Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in locally advanced or metastatic epithelial tumors

AU - Juric, Dejan

AU - Dienstmann, Rodrigo

AU - Cervantes, Andres

AU - Hidalgo, Manuel

AU - Messersmith, Wells

AU - Blumenschein, George R.

AU - Tabernero, Josep

AU - Roda, Desamparados

AU - Calles, Antonio

AU - Jimeno, Antonio

AU - Wang, Xiaodong

AU - Bohorquez, Sandra Sanabria

AU - Leddy, Cecilia

AU - Littman, Catherine

AU - Kapp, Amy V.

AU - Shames, David S.

AU - Penuel, Elicia

AU - Amler, Lukas C.

AU - Pirzkall, Andrea

AU - Baselga, Jose

PY - 2015/6/1

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N2 - 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.

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