Abstract 2399: Circulating tumor DNA (ctDNA) analysis of PIK3CA and AKT1 mutations in patients enrolled onto the Phase 1b study of the PI3K inhibitor taselisib (GDC-0032) in solid malignancies
Authors: Wilson Timothy R. , Savage Heidi , Aimi Junko , Jin Jessica , Parmar Hema , Hsu Jerry , Krop Ian , Saura Cristina , Cervantes Andres , Sachdev Jasgit , Patel Manish , Cejalvo Juan , Oliveira Mafalda , Winer Eric , Von Hoff Daniel , Baselga Jose , Juric Dejan 
Published: August 2015

Abstract
The PI3K signaling pathway is one of the most frequently activated pathways in cancer, and controls critical proliferative and survival processes. Taselisib (GDC-0032) is a novel, oral, selective inhibitor of PI3K, sparing inhibition of PI3Kβ. (Ndubaku CO et al. J Med Chem 2013). Preclinically, taselisib demonstrates enhanced potency in PIK3CA mutant cells, with greater signaling and growth/survival effects in mutant cells vs. wild-type cells. In the phase Ia study with single agent taselisib, partial responses (PRs) were observed in 6/34 enrolled patients. All 6 responses were observed in patients with PIK3CA mutant tumors (Juric D. et al. AACR 2013), indicating the need to determine PIK3CA mutation status from patients treated with taselisib. Circulating tumor DNA (ctDNA) provides an up-to-date liquid biopsy that can be used to detect somatic mutation in oncogenes especially when tumor tissue is not available.
Analysis was undertaken on five cohorts of patients enrolled onto the taselisib Phase 1b study comprised of 106 patients. In total, 87 patients had tumor tissue available for PIK3CA mutation testing. Plasma was collected from 91 patients prior to treatment and 10 patients had matched plasma collected at the study discontinuation visit. Tissue samples were assessed using the Roche cobas PIK3CA mutation test that detects 17 PIK3CA hotspot mutations, of which 47 (54%) tissue samples were positive for PIK3CA mutations. Analysis of PIK3CA and AKT1 mutations from plasma was performed using an Inostics BEAMing digital PCR Oncobeam panel, which detects 8 PIK3CA hotspot mutations and 1 AKT1 mutation. ctDNA was detected in all 91 patients sampled, and ranged from 1.3ng to 1ug per milliliter of plasma. PIK3CA mutations were identified in the plasma of 51 patients (56%), and an AKT1 mutation was identified in one patient. For 80 patients that had both tissue and plasma available for PIK3CA mutation testing, a sensitivity of 81%, a specificity of 74% and an overall accuracy of 78% was observed. Allele frequency ranged from 0.02% to 75.58% with a median of 2.72%. In two cohorts that enrolled hormone receptor positive, HER2 negative breast cancer patients, a sensitivity of 84%, a specificity of 87% and an overall accuracy of 88% was observed between 42 matched tissue and plasma samples. In a patient who experienced a sustained clinical partial response to taselisib in combination with fulvestrant, a decrease in plasma PIK3CA allele frequency was observed from 3.05% in the pretreatment sample to 0.14% in the study discontinuation sample. In summary, analysis of PIK3CA mutations from plasma in patients enrolled onto trials testing the efficacy of taselisib may be a useful surrogate for patients when tissue is unavailable, an observation that is being assessed in ongoing trials.
Citation Format: Timothy R. Wilson, Heidi Savage, Junko Aimi, Jessica Jin, Hema Parmar, Jerry Hsu, Ian Krop, Cristina Saura, Andres Cervantes, Jasgit Sachdev, Manish Patel, Juan Cejalvo, Mafalda Oliveira, Eric Winer, Daniel Von Hoff, Jose Baselga, Dejan Juric. Circulating tumor DNA (ctDNA) analysis of PIK3CA and AKT1 mutations in patients enrolled onto the Phase 1b study of the PI3K inhibitor taselisib (GDC-0032) in solid malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2399. doi:10.1158/1538-7445.AM2015-2399