Start Your Search
MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 2
MO21.07 - Monitoring of EGFR TKI sensitizing and resistance mutations in plasma DNA of advanced adenocarcinoma of NSCLC during erlotinib treatment. (ID 2168)
10:30 - 12:00 | Author(s): L. Wu
EGFR TKI sensitizing mutations in plasma DNA isolated prior to treatment were shown to be a potent predictor for survival outcome of advanced NSCLC (T. Mok, ASCO 2013). Levels of EGFR mutations (pEGFRmut) in plasma during treatment, including sensitizing and resistance mutations, may offer an opportunity to monitor patient’s response to therapy and disease progression. In this study, we measured the levels of pEGFRmut at every 4 weeks during erlotinib treatment and investigated the emergence of the T790M mutation in relationship to disease progression.
Retrospective EGFR mutation testing of plasma samples from an unselected cohort of 227 patients with adenocarcinoma with an allele-specific PCR assay, cobas® EGFR_blood test (in development at Roche Molecular Systems, Inc.). The test is designed to detect 42 mutations in exon 18-21 of the EGFR gene including TKI sensitizing mutations (Exon 19 deletions, L858R, G719X and L861Q), resistance mutation (T790M) and atypical mutations (S768I and Exon 20 Insertions). 2 ml plasma of each patient was used for EGFR_blood PCR test. The genomic equivalent copy number of plasma DNA was determined by comparing to a standard curve of genomic DNA.
25 (11%) of 227 unselected patients with adenocarcinoma had a sensitizing EGFR mutation in their plasma prior to the erlotinib treatment. Sequential plasma samples were retrieved for 23 of the 25 pEGFRmut+ patients. 22 (96%) of the 23 pEGFRmut+ patients had lower TKI sensitizing mutations after the first cycle (4 weeks) of erlotinib treatment. The mutated DNA was reduced below the limit of detection for 13 (57%) of the 23 pEGFRmut+ patients during the course of erlotinib treatment. At the time of progression, 6/23 had the same EGFR sensitizing mutations, 9/23 developed T790M mutation with the original mutation and 6/23 patients had no detectable mutation. T790M mutation was not detected in 227 plasma samples taken prior to erlotinib treatment. The figure shows the time course of two representative patients where a T790M resistance mutation emerges. In the 9 patients with T790M mutation, it can be detected in the blood between 15 and 344 days (mean of 98 days) before progression is clinically evident.Figure 1
The amounts of EGFR TKI sensitizing mutant DNA in plasma change during the erlotinib treatment. T790M mutation was not detected prior to erlotinib treatment and is detected between 15 and 344 days before disease progression is evident.
Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.
MO21.10 - Serial monitoring of plasma EGFR T790M levels and evaluation of EGFR mutational status in matched tissue and plasma from NSCLC patients treated with CO-1686 (ID 2498)
10:30 - 12:00 | Author(s): L. Wu
Background: We explored the minimally-invasive detection of EGFR mutations in circulating free DNA from plasma and studied 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 and the common initial activating mutations, 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 80 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. BEAMing was compared to cobas analysis at baseline, and also used to serially monitor plasma EGFR mutation levels in response to CO-1686.
Results: Using tissue as reference, the positive percent agreement between tissue and plasma was 76% (44/58) for activating mutations and 63% (17/27) 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 NSCLC patients.
EGFR mutation Evaluable patients Patients with tissue mutations* Patients with plasma mutations** Patients with same mutation detected in tissue and plasma Positive Percent Agreement*** L858R, del19, S768I, G719X, or ex20ins 80 58 44 44 76% T790M 80 27 19 17 63% * identified by the cobas® EGFR tissue test ** identified by the cobas® EGFR blood test ***agreement of blood and tissue mutation-positive results with tissue as reference; although tissue is reference, some mutations may be missed due to tumor heterogeneity