G. Meneses-Lorente,1 C. McIntyre,1 W. Jacob,2 M. Zajac,1 I. James,2 M. Thomas,3 M. Weisser,2 J. Hsu4; 1Roche Products Limited, Welwyn Garden City, United Kingdom, 2Roche Diagnostics GmbH, Penzberg, Germany, 3Roche Pharma AG, Grenzach-Wyhlen, Germany, 4Roche TCRC, Inc, New York, NY

BACKGROUND: Dose optimization of monoclonal antibodies using a PK/PD approach often proves difficult due to absence of MTD or quantifiable biomarkers. The dose and schedule of RG7116, a HER3 inhibiting, glyco-engineered monoclonal antibody, has been optimized in a Phase I study based upon TMDD and HER3 receptor down regulation.
METHODS: In a Phase I study, (n=137) patients with advanced or metastatic carcinoma expressing HER3 protein received RG7116 doses from 100 to 2000 mg q2w in monotherapy, and from 400 mg to 2000 mg in combination with either cetuximab (initial dose 400 mg/m2 qw and subsequent doses 250 mg/m2 qw) or erlotinib (150 mg po qd). A q3w regimen was also explored in combination with erlotinib.
RESULTS: Although an MTD was not reached, the pharmacokinetics of RG7116 demonstrated TMDD with saturation of the non-linear clearance at doses ≥ 400 mg q2w both in monotherapy and in combination with either cetuximab or erlotinib. Coupled to TMDD, full HER3 downregulation was observed in skin and tumor biopsies at doses ≥ 400 mg q2w. The saturation of the non-linear elimination component in the TMDD model was used as a surrogate for receptor occupancy and indicated that ≥ 95% target saturation was achieved with doses ≥ 400 mg and was sustained over the course of a q2w dosing cycle and doses ≥ 800 mg for a dosing interval of q3w. Based on all PK, target saturation and HER3 data, a dose of 800 mg q3w was recommended for future combinations with cytotoxic agents or targeted therapies that are administered q3w.
CONCLUSION: Based on the TMDD model and HER3 downregulation, the dose and schedule of RG7116 have been optimized for concomitant therapy options, at doses substantially below the highest investigated.