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RESEARCH PRODUCT

A first-in-human trial of RG7116, a glycoengineered monoclonal antibody targeting HER3, in patients with advanced/metastatic tumors of epithelial cell origin expressing HER3 protein.

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2522 Background: The Human Epidermal Growth Factor Receptor 3 (HER3) is a key heterodimerization partner for other HER family members thereby acting as a downstream signal amplifier. This is a first in human study evaluating the safety of RG7116, a humanized anti-HER3 monoclonal antibody with potent HER3 signal inhibition. Due to a glycoengineered Fc-part this antibody displays enhanced antibody-dependent cellular cytotoxicity as compared to conventional antibodies. Methods: Patients (pts) with advanced or metastatic carcinomas with centrally confirmed HER3 protein expression were included. A “3+3” dose escalation design was performed starting at 100 mg flat dosing in a q2w regimen. In addition to single agent RG7116 (Part A), RG7116 plus cetuximab (Part B) and RG7116 plus erlotinib (Part C) combinations are evaluated. The results of Part A are presented. Results: Twenty-five pts have been enrolled in 6 cohorts (100 to 2000 mg). No DLTs were observed. Pts had a median (range) of 3 (2 to 6) prior chemotherapy lines. Nine infusion-related reactions (IRRs) Gr 1 to 3 occurred in 7 pts. Three drug-related AEs Gr 3 were reported, 1 IRR, 1 GGT increase, and 1 neutropenia. Only 1 patient was tested positive for human anti human antibodies (HAHA). The PK of RG7116 was non-linear from 100 mg up to 400 mg, possibly as a result of target-mediated drug disposition. Both Cmax and AUC showed a greater than doseEproportional increase over the same dose range, accompanied by a decline in total clearance. Dose proportionality was observed from 800 mg onwards. PD effects were observed from the first dose level onwards with HER3 membranous protein down-regulation in skin and from 200 mg onwards in ontreatment tumor samples. Five pts (1 NSCLC, 2 CRC, 1 SCCHN, 1 BC) had a best response of SD. Confirmed SD (>16 weeks) was observed in 2 pts. One BC patient achieved a PR in 18 FDG-PET and significant shrinkage of non-target tumor lesions on CT scan. Conclusions: RG7116 is the first glycoengineered monoclonal anti-HER3 antibody in clinical development. RG7116 monotherapy was well tolerated, and demonstrated preliminary signs of clinical activity. Clinical trial information: NCT01482377.