Abstract B25: Serial monitoring of EGFR mutations in plasma and evaluation of EGFR mutation status in matched tissue and plasma from NSCLC patients treated with CO-1686.
Authors: Sun Jong-Mu , Karlovich Chris , Wen Wei , Wakelee Heather , Chien Sean , Mann Elaina , O'Donnell Patrick , Angenendt Philipp , Dziadziuszko Rafal , Horn Leora , Spigel David R. , Sequist Lecia , Soria Jean-Charles , Solomon Benjamin , Camidge D. Ross , Goldman Jonathan , Gadgeel Shirish M. , Raponi Mitch , Wu Lin , Park Keunchil 
Published: August 2014

Abstract
Background: We examined the detection of EGFR mutations in circulating free DNA from plasma and the concordance of EGFR mutation status between matched plasma and tumor tissue in a cohort of newly diagnosed or relapsed patients with advanced NSCLC. CO-1686 is an oral, potent, small-molecule irreversible tyrosine kinase inhibitor that selectively targets mutant forms of EGFR, including T790M, L858R and Del(19), while sparing wild-type EGFR. Promising clinical activity has recently been reported from an on-going Phase I/II trial.
Methods: Matched tumor tissue and blood from 84 Stage IIIB/IV NSCLC patients, 41 treated with CO-1686, were tested using two allele-specific PCR assays, the cobas® EGFR FFPET and cobas® EGFR blood tests. Each test detects 41 mutations in EGFR, including the T790M resistance mutation, exon 19 deletions and L858R. We also used BEAMing, a highly quantitative and sensitive technology based on digital PCR, to assess a subset of 18 patients treated with CO-1686 both at baseline and on-study drug.
Results: Using tissue as reference, the positive percent agreement between tissue and plasma was 77% (47/61) for activating mutations and 62% (18/29) for T790M. The cobas® EGFR blood test identified two patients with T790M mutations in plasma that were not detected in the corresponding tumor biopsy_likely because of tumor heterogeneity. The M1a/M1b status was known for 63 EGFR mutation-positive patients. Of the 44 with extrathoracic metastatic disease (M1b), 38 were found to have an activating mutation in plasma (86%). Conversely, only 53% (10/19) of EGFR mutation-positive patients with intrathoracic metastatic disease (M1a) had detectable activating mutations in plasma (p = 0.0081). For the 18 patients profiled by BEAMing, the overall percent agreement between BEAMing and the cobas® EGFR blood test was 94% (17/18) for T790M and 83% (15/18) for activating mutations. Nine of the 18 patients had detectable baseline plasma T790M levels, and several patients treated with CO-1686 had an initial decrease in plasma T790M by BEAMing.
Conclusions: Using the cobas® EGFR blood test, a high proportion of EGFR mutations identified in tissue were also detected in plasma. Mutations were more readily detectable in the plasma of patients with M1b rather than M1a disease. These findings suggest that the cobas® EGFR blood test and BEAMing can be useful tools for the non-invasive assessment and monitoring of EGFR mutations in the plasma of NSCLC patients.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B25.
Citation Format: Jong-Mu Sun, Chris Karlovich, Wei Wen, Heather Wakelee, Sean Chien, Elaina Mann, Patrick O'Donnell, Philipp Angenendt, Rafal Dziadziuszko, Leora Horn, David R. Spigel, Lecia Sequist, Jean-Charles Soria, Benjamin Solomon, D. Ross Camidge, Jonathan Goldman, Shirish M. Gadgeel, Mitch Raponi, Lin Wu, Keunchil Park. Serial monitoring of EGFR mutations in plasma and evaluation of EGFR mutation status in matched tissue and plasma from NSCLC patients treated with CO-1686. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B25.