Abstract 966: Predictive biomarkers of the AKT inhibitor, GDC-0068, in single agent and combination studies
Authors: Savage Heidi M. , Nannini-Pepe Michelle , Lin Kui , Atwal Siminder K. , Lackner Mark R. , Punnoose Elizabeth A. 
Published: August 2012

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-0068 is a potent, highly selective, ATP-competitive pan-AKT inhibitor that is currently in Phase 1a and Phase 1b clinical development. Here, we describe the cell line screening efforts and xenograft studies that provide rationale for a predictive biomarker strategy both for single agent studies and combinations with chemotherapeutic agents. Methods: Cell line screening using GDC-0068 as a single agent and in combination with other agents provided a means of identifying predictive markers across various indications and drug combinations. Single agent screens were performed with GDC-0068 in 9 prostate, 54 breast, and 18 ovarian cell lines. We evaluated combination activity of GDC-0068 with docetaxel, doxorubicin, rapamycin and MEK inhibitor in a panel of 24 cell lines and combination activity of GDC-0068 with 5FU/Cisplatin (Folfox) in a panel of 11 gastric and 15 head and neck cancer cell lines. We also evaluated both single agent activity and combination activity in select xenograft models. Results: Single agent screens identified PTEN loss, PIK3CA activating mutations, and RTK activation (HER2 in breast) as key predictive markers in breast, ovarian and prostate cell lines. Similarly, in prostate cancer xenograft models, the highest tumor growth inhibition was seen in models with PI3K pathway activation, e.g. via PTEN loss. In the GDC-0068 combination studies, MEK inhibitors provided the most significant synergy across different targeted and chemotherapy agents tested (rapamycin, docetaxel, doxurubicin). In combination with 5FU/Cisplatin, we observed additive effects in gastric and head and neck cell lines and this response was best observed in cell lines with pathway activation: PTEN loss, PI3K mutations or amplifications, and/or high pAKT. The in vitro results were recapitulated in vivo with the combination of GDC-0068 with either docetaxel or carboplatin enhancing the antitumor efficacy compared to either single agent alone in multiple tumor xenograft models. All combinations were well tolerated as assessed by animal body weights and mortalities. Conclusions: Across various indications, PTEN loss or PI3K pathway activation via PIK3CA activating mutations are strong predictive biomarkers of GDC-0068 activity either as a single agent or in combination studies and provide a strong diagnostic hypothesis for evaluation in the clinic. Based on these results and others, GDC-0068 is currently being tested for single agent activity in a diagnostically selected Phase 1a expansion cohort in breast and prostate cancer, and in multiple combination Phase Ib trials.
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 966. doi:1538-7445.AM2012-966