Translational PKPD Biomarker Analysis: KRASG12C Inhibitor GDC-6036 in Lung Cancer

KRAS G12C is a common oncogenic driver mutation in solid tumors, including non-small cell lung cancer. GDC-6036 is an oral, highly potent, selective KRAS G12C inhibitor that irreversibly locks the protein in an inactive state to turn off its oncogenic signaling. GDC-6036 demonstrated dose-dependent tumor growth inhibition (TGI) in lung tumor xenograft models in mice. The anti-tumor activity was dependent upon the extent of GDC-6036 covalent target engagement, inhibition of KRAS pathway, and intrinsic dependence on KRAS G12C. A novel 2D LC-MS/MS assay was developed for the quantitative assessment of KRAS G12C target engagement in solid tumors and extended to an ongoing Phase I study in patients with advanced-stage cancers with KRAS G12C mutation. The speaker will discuss how the totality of in vitro target inhibition, cell proliferation, mouse in vivo PK/PD-TGI, clinical PK and target engagement data was integrated in informing dose selection of GDC-6036 in clinical development.