Abstract
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 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 mutation panel and genome-wide copy number alterations using the Oncoscan platform (Affymetrix). For pharmacodynamic biomarker assays, analyses were initially limited to pre and post treatment phospho-AKT levels in platelet rich plasma. Once substantial downmodulation of pAKT in surrogate tissue was observed, pre- and post treatment biopsies were collected from a subset of patients and analyzed for phospho-S6 levels by immunohistochemistry. Results: Predictive biomarker assays were conducted on over 150 samples from the phase I study. Overall we found a prevalence of 7% PIK3CA mutations and 15% loss of PTEN in these samples. PIK3CA amplification was observed in several samples from ovarian cancer patients. Overall there were five confirmed partial responses in the studies, and two of these occurred in patients with activating mutations in PIK3CA. Robust PD knockdown of pAKT in surrogate tissue was observed in the early stage of dose-escalation. Moreover, substantial knockdown of pS6 was seen in tumor tissues in patients treated at or below the recommended phase II dose. 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 a predictive biomarker will be useful in identifying responsive patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4821. doi:1538-7445.AM2012-4821
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
