0000000000620589
AUTHOR
Andrea Pirzkall
Abstract 3363: Pharmacodynamic (PD) assessment of drug activity in tumor tissue from patients (pts) enrolled in a Phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR dual action antibody, in pts with locally advanced or metastatic epithelial tumors.
Abstract Background Members of the human epidermal growth factor receptor (HER) family of oncogenes are often co-expressed and heterodimerized, suggesting that simultaneous blockade of multiple HER family receptors may be more effective than targeting single receptors. MEHD is a dual-action human IgG1 antibody that can bivalently bind to HER3 and EGFR and block ligand binding to either. FDG-PET imaging is a recognized method of assessing PD modulation with EGFR inhibitors in the clinic. HER3 and EGFR signaling via the MAPK and PI3K pathways can be monitored in tissue by examining phosphorylation of downstream markers. Methods A Phase 1, multicenter, open-label study was conducted to evaluat…
A Phase Ib Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Cobimetinib and Duligotuzumab in Patients with Previously Treated Locally Advanced or Metastatic Cancers with Mutant KRAS
Abstract Lessons Learned Cobimetinib and duligotuzumab were well tolerated as single agents and in combination with other agents. The cobimetinib and duligotuzumab combination was associated with increased toxicity, most notably gastrointestinal, and limited efficacy in the patient population tested. Background KRAS-mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual-action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). Blockade of EGFR/HER3 and inhibitio…
Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors
Abstract Purpose: IDO1 induces immune suppression in T cells through l-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer. Patients and Methods: The study consisted of a 3+3 dose-escalation stage (n = 66) and a tumor-specific expansion stage (n = 92). Navoximod was given orally every 12 hours continuously for 21 consecu…
Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors.
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. …
Abstract CT-08: A Phase 1 study of MEHD7945A (MEHD), a first-in-class EGFR/HER3 dual action antibody, in patients (pts) with locally advanced or metastatic epithelial tumors
Abstract Background Dysregulated human epidermal growth factor receptor tyrosine kinase (HER RTK) signaling is an important driver of tumor growth, metastasis, and survival. Extensive HER RTK co-expression and heterodimerization suggest that simultaneous blockade of multiple RTKs may be more effective than targeting individual RTKs, and may help prevent or delay development of resistance mechanisms. MEHD is a novel dual-action human IgG1 antibody. Each antigen-binding fragment blocks ligand binding to both EGFR and HER3, which is meant to inhibit the activity of the major ligand-dependent HER dimers in cancer. MEHD also elicits antibody-dependent cell-mediated cytotoxicity, and has single-a…
Human pharmacokinetic (PK) characterization of the novel dual-action anti-HER3/EGFR antibody MEHD7945A (MEHD) in patients with refractory/recurrent epithelial tumors.
2567 Background: MEHD is a novel dual-action human IgG1 antibody that blocks ligand binding to HER3 and EGFR, and elicits antibody-dependent cell-mediated cytotoxicity (ADCC). MEHD demonstrates single-agent activity in a broad panel of tumor models, including models resistant to anti-HER3 or anti-EGFR treatment alone. The objective of this analysis was to characterize the PK of MEHD associated with body weight (BW)-based dosing used in a phase I study in patients with epithelial tumors and to evaluate the potential for using fixed dosing in future studies. Methods: Preliminary non-compartmental and population PK analyses were performed using patient data from the dose-escalation stage [1, …
A phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR dual-action antibody, in patients (pts) with refractory/recurrent epithelial tumors: Expansion cohorts.
2568 Background: Dysregulated human epidermal growth factor receptor tyrosine kinase (HER RTK) signaling is an important driver of tumor growth, metastasis, and survival. Extensive co-expression and heterodimerization suggest that simultaneous blockade of multiple HER RTKs may be more effective than blockade of a single RTK. MEHD is a novel dual-action human IgG1 antibody. Each antigen-binding fragment blocks ligand binding to HER3 or EGFR, and intended to inhibit signaling from all major ligand-dependent HER dimers. MEHD has single-agent activity in multiple tumor models including models resistant to anti-HER3 or anti-EGFR. Methods: This Phase I study evaluated safety, tolerability, pharm…