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.

Abstract

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, pharmacokinetics (PK), and pharmacodynamic (PD) activity of intravenous MEHD every 2 weeks (q2w). Tumor PD assessments were pre- and post-dose FDG-PET and IHC for pS6, pPRAS40 or pERK in tumor biopsies. Tumor CT assessments were performed q8w. No dose-limiting toxicity (DLT) was observed in six 3+3 cohorts from 1-30 mg/kg (n=30). We report results from 4 tumor-specific cohorts receiving 14 mg/kg MEHD (recommended Phase II dose). Results: As of 21 Nov 2011, 36 pts (CRC=12, NSCLC=9, SCCHN=10, pancreatic=5), median age 62.5 (35–87), all PS 0-1, median # prior regimens 3.5 (1-8), received a median of 4 doses (1-9) of MEHD; 18 pts remain on study. PK data are consistent with human anti-EGFR antibodies. No related Grade (G) ≥3 adverse events (AEs) have been observed. Common related G1/2 AEs included rash/dermatitis (53%), diarrhea (36%), fatigue (22%), paronychia (19%), dry skin, nausea, and decreased appetite (all 17%), asthenia and stomatitis/oral pain (all 14%). Related AEs ≤ 24 h after first infusion included G1/2 headache (42%), fever (33%), and chills (17%), and decreased in intensity and frequency with later infusions. Early PD data indicate target inhibition in 8/36 pts (SCCHN=2, NSCLC=2, CRC=4), and best response by RECIST includes 2 PR (both SCCHN), 6 pts with SD ≥ 8 weeks (NSCLC=2, CRC=4), 7/8 previously treated with EGFR inhibitors. Conclusions: MEHD at 14 mg/kg q2w has an encouraging safety profile and evidence of anti-tumor activity. Phase II studies are planned.