Abstract A03: Comprehensive predictive biomarker evaluation in two phase II clinical trials of the PI3K/mTOR inhibitor GDC-0980 in metastatic renal cell carcinoma and advanced endometrial cancer
Authors: Spoerke Jill M. , Makker Vicky , Aghajanian Carol , Thomas Powles , Motzer Robert J. , Lauchle Jennifer O. , Parmar Hema , Gilbert Houston , Lin Wei , O'Keeffe Bridget , Byrtek Michelle , Koeppen Hartmut , Wang Yulei , Lu Shan , Huw Ling-Yuh , Hampton Garret M. , Lackner Mark R. 
Published: October 2015

Abstract
Background: The PI3K/mTOR pathway is frequently activated in cancer by multiple mechanisms. GDC-0980 is a dual pan-PI3K and mTOR (TORC1/2) inhibitor that has been evaluated in two Phase II studies (J Clin Oncol 32:5s, 2014 [suppl; abstr 4525 and 5513]). The randomized ROVER study showed that the PI3K/mTOR inhibitor GDC-0980 did not improve efficacy over the TORC1 inhibitor everolimus in metastatic renal cell carcinoma (mRCC). The single arm MAGGIE study evaluated the activity of GDC-0080 in patients with advanced endometrial cancer (EC). Although some single agent anti-tumor activity was observed, overall evaluation of anti-tumor activity of GDC-0980 was limited by tolerability, especially in diabetic patients. Comprehensive biomarker analysis, including targeted next generation sequencing (NGS) and a panel of biomarkers tailored to each tumor type, was conducted in both Phase II studies to determine the prevalence of PI3K/mTOR pathway alterations, and to assess the association between anti-tumor activity and candidate predictive biomarkers.
Methods: The primary and secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). Archival tissue samples were collected for biomarker analysis, and correlations with efficacy were retrospectively explored. Samples were subjected to targeted NGS (Illumina) covering 88 oncogenes and tumor suppressors, copy number analysis using quantitative-PCR, PTEN immunohistochemistry (IHC), HIF1A IHC (ROVER), and gene expression analysis (NanoString nCounter® System, ROVER).
Results: In ROVER, the median PFS was significantly shorter for GDC-0980 than everolimus. Retrospective biomarker analyses revealed a relationship between VHL mutation status (by NGS) and improved PFS with everolimus but not GDC-0980. High HIF1A protein expression was associated with longer PFS in both arms, whereas low expression of STK11/LKB1 mRNA was associated with benefit with everolimus only. Additional gene expression analysis of PI3K pathway, apoptosis/cell cycle, and tumor immunity related genes will be presented. In MAGGIE, PFS at 6 months was estimated to be 20%, and the ORR was 9% (unconfirmed). Evaluable archival tumor samples were obtained from 88% of the patients and 52% of patients had at least one alteration in PIK3CA, PTEN or AKT1. PTEN loss by IHC was generally well correlated with mutation status determined by NGS. All 5 patients with either a confirmed or investigator assessed partial response had at least one PI3K pathway alteration.
Conclusions: Clinical data to date have suggested that identification of predictive biomarkers for agents targeting PI3K/mTOR signaling is challenging and will require tailoring to specific tumor types. Here we provide comprehensive assessment from two phase II clinical studies of GDC-0980. Our data, although retrospective in nature and requiring confirmation, suggest that pathway activation along the VHL-HIF1A axis may be predictive of anti-tumor activity for mTOR-targeting agents in mRCC. Our results in EC suggest that at least in this study population, frequency of pathway alterations was somewhat lower than observed in prior published data, but the presence of PIK3CA or AKT1 mutations or PTEN loss enriched for anti-tumor activity. Clinical trial information: NCT01442090 (mRCC), NCT01455493 (EC).
Citation Format: Jill M. Spoerke, Vicky Makker, Carol Aghajanian, Powles Thomas, Robert J. Motzer, Jennifer O. Lauchle, Hema Parmar, Houston Gilbert, Wei Lin, Bridget O'Keeffe, Michelle Byrtek, Hartmut Koeppen, Yulei Wang, Shan Lu, Ling-Yuh Huw, Garret M. Hampton, Mark R. Lackner. Comprehensive predictive biomarker evaluation in two phase II clinical trials of the PI3K/mTOR inhibitor GDC-0980 in metastatic renal cell carcinoma and advanced endometrial cancer. [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 A03.