The phosphoinositol-3-kinase (PI3K) signaling pathway is one of the most frequently activated pathways in oncogenesis, and controls critical cellular processes such as proliferation, transcription and survival. GDC 0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30 fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. The gene that encodes the p110 alpha isoform of PI3K, PIK3CA, is frequently mutated in breast, colorectal and endometrial cancers. Preclinical data indicate that GDC-0032 has increased activity against PIK3CA mutant cancer cell lines.
As presented by Juric et al., 34 patients were enrolled in this study and dose escalation has been completed (Juric D. et al. AACR 2013, Abstract LB-64). Metabolic partial responses via FDG-PET were observed in 6 out of 13 patients assessed, and clinical partial responses (PRs) were observed in 6 patients, with 5 of these patients having PIK3CA mutant cancers. Tumor tissue was obtained from 30 out of 34 patients enrolled onto the study. The most frequently recruited cancer type was breast cancer (41%) followed by colorectal (15%) and lung cancer (15%). Fourteen patients enrolled onto the study had PIK3CA mutant tumors (41%) as determined using a TaqMan-based PCR assay. Three patients had total loss of PTEN expression, as assessed by immunohistochemical staining, and a further 3 patients had reduced PTEN expression based on a H-score assessment. Out of the 6 patients that had reduced PTEN expression, 2 patients had coexisting mutations with PIK3CA. Where known, 4 out of 5 patients that had a PR showed intact PTEN expression, with the fifth patient having reduced PTEN expression. Samples were further analyzed using an in-house developed PCR-based multiplexed assay that detects activating mutations within an additional ten oncogenes. PIK3CA mutations were largely mutually exclusive with mutations in the Ras pathway, however 3 out of the 14 PIK3CA mutant patients had a coexisting mutation within KRas. A further 2 patients had KRas mutations, 1 patient had a NRas mutation and 2 patients had EGFR mutations. Preliminary analysis suggests lack of benefit in patients with KRas mutations treated with GDC-0032 single agent. Optional on-study biopsies were collected from 2 patients and demonstrated pharmacodynamic inhibition of the PI3K pathway as assessed by reverse phase protein array for approximately 45 endpoints, including 1 patient at the lowest dose. In conclusion, our preliminary data indicates that GDC-0032 demonstrates single agent activity in patients with PIK3CA mutations tumors with unaltered PTEN or MAP-kinase pathways.
Citation Format: Timothy R. Wilson, Heidi Savage, Carol O'Brien, Sandra Sanabria, Ray S. Lin, Marie-Claire Wagle, Yibing Yan, Mark R. Lackner, Hema Parmar, Jerry Y. Hsu, Dejan Juric, Ian E. Krop, Ramesh K. Ramanathan, Daniel D. Von Hoff, Jose Baselga. Expanded biomarker results from a phase I dose escalation study of GDC-0032, a beta isoform-sparing PI3K inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 915. doi:10.1158/1538-7445.AM2014-915