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
Authors: Dejan Juric, Rodrigo Dienstmann, Wells Messersmith, Andres Cervantes, George Blumenschein, Jose Baselga, Josep Tabernero, Antonio Jimeno, Antonio Calles, Desamparados Roda, Yan Xin, Amy V. Kapp, G. Scott Chandler, Andrea Pirzkall, Manuel Hidalgo
Journal: Cancer Research (2012)

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-agent activity in a broad panel of tumor models, including those resistant to anti-EGFR or anti-HER3 treatment alone. Methods A Phase 1, multicenter, open-label study was conducted to evaluate the safety, pharmacokinetics (PK), and anti-tumor activity of MEHD administered intravenously every 2 weeks (q2w) in pts with refractory or relapsed epithelial tumors, and to define a recommended Phase 2 dose (RP2D). The study consists of 3+3 dose-escalation cohorts with a 28-day window to evaluate dose-limiting toxicity (DLT), and expansion at the RP2D. Here we report results from the dose-escalation cohorts. Results Twenty-five pts (median age 62, range 44-80), all PS 0-1, with a median of 4 (range 1-11) prior treatments, received a median of 4 doses (range 2-11) of MEHD in 6 dose-escalation cohorts (1-30 mg/kg). No DLTs or Grade (G) β4 adverse events (AEs) attributed to MEHD have been reported; related G3 AEs were limited to diarrhea (2 pts) and nausea (1 pt). G1/2 related AEs were generally consistent with known anti-EGFR toxicity and included rash/dermatitis (12 G1), dry skin (1 G2, 3 G1), pruritus (5 G1), paronychia (2 G2, 1 G1), stomatitis/oral pain (1 G2, 5 G1). Other related G1/2 AEs occurring in &amp;gt;10% of pts included fatigue (4), nausea (3), and vomiting (3). Related AEs suggestive of infusion-related reaction (occurring within 24 hours of infusion) were reported in 16 pts, all of whom received doses β10 mg/kg. These included G1/2 headache, fever, and chills, which generally diminished in intensity and frequency after the first infusion, and were managed with pre-medication and symptomatic treatment. Clearance of MEHD decreased in a dose-dependent manner, approaching linearity and achieving PK targets at doses &amp;gt;10 mg/kg q2w. Decreases in tumor S6, PRAS40, and ERK phosphorylation were observed in 4/8 pts with tumor biopsies at 10-15 mg/kg, and metabolic responses by FDG-PET were observed in 2 pts. Conclusions MEHD was well-tolerated with a favorable safety profile in pts with advanced tumors treated at doses up to 30 mg/kg q2w. Tumor PD modulation was observed. PK results support a RP2D of either q2w (14 mg/kg) or q3w (21 mg/kg). An expansion phase at the q2w RP2D is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr CT-08. doi:1538-7445.AM2012-CT-08