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.
Authors: Juric Dejan , Dienstmann Rodrigo , Cervantes Andres , Hidalgo Manuel , Messersmith Wells , Blumenschein George , Baselga Jose , Tabernero Josep , Roda Desamparados , Calles Antonio , Jimeno Antonio , Amler Lukas , Stern Howard , Sanabria Sandra , Penuel Elicia , Pirzkall Andrea 
Published: August 2014

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 evaluate the safety, pharmacokinetics, and anti-tumor activity of MEHD administered intravenously every 2 weeks at doses ranging from 1 to 30 mg/kg during escalation (n=30), and at 14 mg/kg during expansion (n=36). FDG-PET scans and optional tumor biopsies (bxs) were obtained at baseline and cycle 2, day 2 (C2D2). Tumor bxs were evaluated by immunohistochemistry (IHC) for S235/236-p-S6, T246-p-PRAS40, and T202/Y204-p-MAPK. EGFR and KRAS mutation (mt) status was determined by PCR. Paired frozen bxs were utilized for exploratory assessment by reverse-phase protein arrays (see Penuel et al. abstract).

Results

Evidence of PD modulation by imaging or IHC was observed in 14 pts including 7 CRC (KRAS mt-2, wt-5), 3 NSCLC, 2 SCCHN, 1 ovarian, and 1 anal cancer. Tumor FDG-uptake was decreased by at least 20%, indicating a partial metabolic response (PMR), in 9/56 evaluated pts (16%). Tumor bxs were obtained at baseline and C2D2 from 32 pts (12 escalation, 20 expansion). Sufficient viable tumor for IHC was present in both bxs from 17/32 evaluated pts. IHC signal was decreased for one or more of the 3 markers in the C2D2 bxs of 6/17 pts (35%), 5 CRC (KRAS mt-2, wt-3), 1 NSCLC. Best response by CT-RECIST includes PR in 2 patients with SCCHN, both with PMR and both tumors expressing high heregulin, with duration of response of 10 and 12+ months.

Conclusions

Evidence of PD modulation is demonstrated by a PMR rate of 16% and reduced pathway activity by IHC in 35% of pts with evaluable biopsies. These data suggest MEHD is biologically active in pts and downregulates intracellular signaling activity consistent with HER3 and/or EGFR inhibition in tumor tissue and is further supported by evidence of anti-tumor activity. Phase II studies in SCCHN and CRC are ongoing.

Citation Format: Dejan Juric, Rodrigo Dienstmann, Andres Cervantes, Manuel Hidalgo, Wells Messersmith, George Blumenschein, Jose Baselga, Josep Tabernero, Desamparados Roda, Antonio Calles, Antonio Jimeno, Lukas Amler, Howard Stern, Sandra Sanabria, Elicia Penuel, Andrea Pirzkall. 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]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3363. doi:10.1158/1538-7445.AM2013-3363