Abstract 5587: 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: Dziadziuszko Rafal , Karlovich Chris , Wen Wei , Sun Jong-Mu , Chien Sean , Mann Elaina , O'Donnell Patrick , Angenendt Philipp , Wakelee Heather , Horn Leora , Spigel David , Sequist Lecia , Soria Jean-Charles , Solomon Benjamin , Camidge D. Ross , Goldman Jonathan , Gadgeel Shirish , Raponi Mitch , Allen Andrew , Wu Lin , Park Keunchil 
Published: May 2015

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 97 evaluable Stage IIIB/IV NSCLC patients, 40 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. In a subset of 30 patients, we compared the cobas plasma results to BEAMing, a highly quantitative and sensitive technology based on digital PCR. BEAMing was also used to serially monitor changes of the plasma EGFR mutation burden of several patients in response to CO-1686.

Results: Using tissue as the reference, the positive percent agreement between tissue and plasma was 73% (57/78) for activating mutations and 62% (21/34) 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 M0/M1a/M1b status was known for 73 EGFR mutation-positive patients. Of the 49 with extrathoracic metastatic disease (M1b), 43 were found to have an activating mutation in plasma (88%). Conversely, only 50% (12/24) of EGFR mutation-positive patients with intrathoracic metastatic disease (M0/M1a) had detectable activating mutations in plasma (p &lt;0.001). Similar results were observed for T790M. For the subset of 30 patients tested by BEAMing at baseline, the overall percent agreement between BEAMing and the cobas® EGFR blood test was 87% (26/30) for T790M and 90% (27/30) for activating mutations. Serial monitoring by BEAMing identified an initial decrease in plasma T790M levels in response to CO-1686 in 13 of 14 patients where clinical activity was observed.

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/M0 disease. Serial monitoring identified quantitative changes in EGFR mutation levels over time in patients treated with CO-1686. 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 Format: Rafal Dziadziuszko, Chris Karlovich, Wei Wen, Jong-Mu Sun, Sean Chien, Elaina Mann, Patrick O'Donnell, Philipp Angenendt, Heather Wakelee, Leora Horn, David Spigel, Lecia Sequist, Jean-Charles Soria, Benjamin Solomon, D. Ross Camidge, Jonathan Goldman, Shirish Gadgeel, Mitch Raponi, Andrew Allen, 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 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 5587. doi:10.1158/1538-7445.AM2014-5587