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 >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 >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