Abstract B03: Pharmacodynamic biomarker evaluation in phase I clinical trials of selective PI3K and PI3K/mTOR inhibitors
Authors: Nakanishi Yoshito , Spoerke Jill M. , Derynck Mika , Lauchle Jennifer O. , Koeppen Hartmut , Fredrickson Jill , Ware Joseph , Hampton Garret , Yan Yibing , Lackner Mark R. 
Published: October 2015

Abstract
Background: The PI3K/Akt pathway is frequently altered in cancer by multiple mechanisms including PI3K activating mutations, PTEN loss, RTK activation, and other oncogenic mutations. GDC-0941 and GDC-0980 are selective PI3K and dual PI3K/mTOR inhibitors, respectively, which are currently in clinical development. Pharmacodynamic changes in biomarkers in response to dose and exposures were analyzed from sequential biopsies from phase I studies of GDC-0941 and GDC-0980. The purpose was to evaluate pathway inhibition at tolerable doses, as well as look for associations between modulation of phosphorylation and gene expression of downstream PI3K factors and interactions with cancer immune cell infiltration.
Methods: Pre- and post-treatment biopsies were collected from a subset of patients who were treated with escalating doses of GDC-0941 (NCT00876122, NCT00876109) or GDC-0980 (NCT00854126). In addition to previously described phospho-S6, phospho-AKT, and phospho-PRAS40 analysis by immunohistochemistry (IHC), CyclinD1, phospho-ERK, Ki-67, and markers of T-cell infiltration (CD8, PD-L1) were also assessed by IHC. Gene expression analysis was also performed with the nCounter® Analysis System (NanoString Technologies) to determine if pathway modulation can be assessed more quantitatively across a broader set of markers, and to determine whether feedback upregulation of pathway components was observed in treated patient samples. Genes analyzed included PI3K pathway, apoptosis/cell cycle, and tumor immunity related genes.
Results: Pharmacodynamic biomarker assays were conducted on 23 paired samples from the GDC-0941 study and 22 paired samples from the GDC-0980 study. Post-dose samples were obtained within hours of anticipated Cmax of both drugs. Reduction of phospho-S6, phospho-AKT, and phospho-PRAS40 were observed in a dose and exposure dependent manner. Upregulation of immune-related proteins was not observed after two weeks dosing with GDC-0941 or GDC-0980, which could be impacted by inhibition of T-cell signaling through PI3K. We report here the pharmacodynamic gene expression analysis, as measured by the NanoString nCounter® system, in patients from whom tissue was available, and analysis of the extent to which these the pharmacodynamic biomarkers are associated with each other. Based on PK modeling and PD, the doses achieved in Phase I studies enable future studies to be conducted at doses associated with tumor xenograft shrinkage (J Clin Oncol 29: 2011 [suppl; abstr 3052, 3021], Mol Cancer Ther 2009;8[12 Suppl]:B137).
Conclusions: Pharmacodynamic assays confirmed effective broad pathway knockdown of multiple signaling components at safe and tolerated clinical doses of GDC-0941 and GDC-0980. What remains unclear is duration and magnitude of pathway inhibition required will translate to clinical efficacy and translatability across tumor types that may have different PI3K pathway dependencies and alterations. These data supports further clinical testing to evaluate efficacy in these different patient subsets.
Citation Format: Yoshito Nakanishi, Jill M. Spoerke, Mika Derynck, Jennifer O. Lauchle, Hartmut Koeppen, Jill Fredrickson, Joseph Ware, Garret Hampton, Yibing Yan, Mark R. Lackner. Pharmacodynamic biomarker evaluation in phase I clinical trials of selective PI3K and PI3K/mTOR inhibitors. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B03.