G. Meneses-Lorente,1 K. Smart,1 A. Broeske,2 D. Rüttinger,2 C. Mueller,2 A. Phipps,1 A. Walz,3 C. Ries,2 M. Baehner,2 M. Cannarile2; 1Roche Products Limited, Welwyn Garden City, United Kingdom, 2Roche Diagnostics GmbH, Penzberg, Germany, 3F. Hoffmann-La Roche Ltd, Basel, Switzerland

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 RG7155, a CSF-1R inhibitor that depletes tumor associated macrophages, has been optimized in Phase I based upon TMDD and PK/PD of five biomarkers.
METHODS: In a monotherapy Phase I study, solid tumor or PVNS patients (n=34) received RG7155 doses from 100 to 3000 mg every 2 or 3 weeks (q2w/q3w).
RESULTS: Although an MTD was not achieved, the pharmacokinetics of RG7155 demonstrated target mediated drug disposition (TMDD) with saturation of the non-linear clearance at doses ≥ 900 mg q2w. Coupled to TMDD, concentrations of the CSF-1 ligand increased with RG7155 exposure. Reduction in CSF-1R+ and CD68+/CD163+ macrophages taken from both paired tumor and surrogate skin biopsies, along with reduction in peripheral blood monocytes (CD14+/CD16+) were also observed following RG7155 treatment. After PK/PD analysis, the increase in ligand and decrease in target cells plateaued at concentrations associated with RG7155 TMDD saturation and enabled an average concentration for maximum pharmacodynamic effect to be modeled. The saturation of the non-linear elimination component in the TMDD model was used as a surrogate for receptor occupancy assuming that the target is highly accessible. Based on all the PK/PD and preliminary efficacy, ≥90% target saturation is necessary to achieve maximum depletion of tumor promoting macrophages.
CONCLUSION: Based on the PK/PD analysis highlighting the need for ≥90% target saturation, the dose and schedule of RG7155 have been optimized for both indication and concomitant therapy options, at doses substantially below the highest investigated.