M. Nakamura,1 C. Diack,2 N. Ohishi,1 C. Xu,3 A. Phipps,4 C. Rossin,3 A. Muehlig,3 T. Kawanishi,1 T. Ohtomo,1 R. Lee,3 Y. Chen3; 1Chugai, Tokyo, Japan, 2F. Hoffmann-La Roche, Basel, Switzerland, 3Roche TCRC, New York, NY, 4F. Hoffmann-La Roche, Welwyn Garden City, United Kingdom

BACKGROUND: Codrituzumab (GC33) is a recombinant, humanized mAb that binds to glypican-3 (GPC3), an oncofetal protein highly expressed in hepatocellular carcinoma (HCC). Preclinical data suggests that GC33 triggers FcγRIIIa (CD16) mediated antibody-dependent cell cytotoxicity (ADCC) and/or antibody-dependent cell phagocytosis. Although the Phase II study failed to demonstrate the efficacy in the overall patient population, subpopulation analyses indicate that patients with high levels of CD16 and high drug exposures may benefit from GC33 treatment. The objectives of this investigation were to identify clinically relevant factors that may affect the overall survival (OS) and to annotate their effects in a quantitative fashion.
METHODS: The analysis included various clinical parameters collected from 181 patients with advanced HCC enrolled in the Phase II study. Exposures of GC33 were estimated by population PK covariate model with non-linear elimination pathway. The following covariates were explored: immune biomarkers including the levels of CD16 and CD4, GC33 exposures, and the potential prognostic biomarkers on HCC e.g., tumor size (sum of the longest diameters, SLD), soluble GPC3 and C-reactive protein.
RESULTS: Weibull model was selected as a base hazard model. The baseline tumor size was included in the hazard model independent of the drug effect. The drug effect was found to be a function of the levels of CD16 and GC33 exposures, which supports the ADCC mechanism of GC33.
CONCLUSION: The final model indicates that adequate drug exposures along with a favored immune environment are associated with a prolonged OS. This quantitative model should be further validated with emerging data to guide future study design.