Abstract 4567: Biomarker evaluation in phase I clinical trials of selective PI3K and PI3K/mTOR inhibitors.
Authors: Spoerke Jill , Desai Rupal , Patel Rajesh , Fredrickson Jill , Wang Yulei , Levy Gallia , Gendreau Steve , Lauchle Jennifer , Derynck Mika , Raja Rajiv , Koeppen Hartmut , Hampton Garret , Yan Yibing , Lackner Mark R. 
Published: August 2014

Abstract
Background: The PI3K/Akt pathway is frequently activated in cancer by multiple mechanisms including PI3K activating mutations, PTEN loss, RTK activation, and other means. GDC-0941 and GDC-0980 are selective PI3K and dual PI3K/mTOR inhibitors, respectively, which are currently in phase II clinical development. Assays for candidate predictive and pharmacodynamic biomarkers were conducted on patient samples collected from phase I studies of GDC-0941 and GDC-0980. The purpose was to confirm pathway inhibition at tolerable doses, as well as look for association between anti-tumor activity and candidate predictive biomarkers.
Methods: Archival tumor tissue samples were analyzed using a 6 gene qPCR mutation assay (PIK3CA, EGFR, KRAS, BRAF, NRAS, AKT1), an immunohistochemistry assay for PTEN, and a fluorescence in situ hybridization (FISH) assay for PIK3CA. Select samples were analyzed for an expanded qPCR mutation panel and subjected to targeted next-generation sequencing (Illumina). For pharmacodynamic biomarker assays, pre- and post-treatment biopsies were collected from a subset of patients. In addition to previously described pS6 analysis, samples were analyzed for phospho-AKT, phospho-PRAS40, and CyclinD1 by immunohistochemistry.
Results: Predictive biomarker assays were conducted on over 200 samples from the phase I studies. Overall we found a prevalence of 7% PIK3CA mutations and 12% loss of PTEN in these samples. PIK3CA amplification was observed in several samples from ovarian cancer patients. Based on several means of evaluating tumor response (FDG-PET, RECIST, time on study), activity was seen at or below clinically relevant doses in several different tumor types, including breast, ovarian, and mesothelioma. We report here the predictive biomarker status in all patients from whom tissue was available, and analysis of the extent to which these alterations are associated clinical outcome, to the extent such associations can be determined from a phase I dose escalation study designed to look a safety and tolerability.
Conclusions: Pharmacodynamic assays confirmed effective pathway knockdown at safe and tolerated clinical doses of GDC-0941 and GDC-0980. Anti-tumor activity was observed in patients with PIK3CA mutations, as well as some patients whose tumors did not harbor pathway alterations. These data support patient stratification in phase II clinical studies to determine whether predictive biomarkers will be useful in identifying responsive patients.
Citation Format: Jill Spoerke, Rupal Desai, Rajesh Patel, Jill Fredrickson, Yulei Wang, Gallia Levy, Steve Gendreau, Jennifer Lauchle, Mika Derynck, Rajiv Raja, Hartmut Koeppen, Garret Hampton, Yibing Yan, Mark R. Lackner. Biomarker evaluation in phase I clinical trials of selective PI3K and PI3K/mTOR inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4567. doi:10.1158/1538-7445.AM2013-4567