Assessment of EGFR Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686)

Abstract

Purpose: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors.Experimental Design: Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing.Results: The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P < 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 -74%] for cobas tumor T790M-positive and 44% (95% CI, 25 -63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to 10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response.Conclusions: These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386-95. Ó2016 AACR.

Liquid biopsy based biomarkers in non-small cell lung cancer for diagnosis and treatment monitoring

“…For the T790M detection, the sensitivity and specificity were 73% and 67% for the first technology and 81% and 58%, respectively, with a concordance between the platforms >90%. Another recent publication comparing BEAMing and cobas test showed a higher concordance between BEAMing plasma and tumor EGFR results than between cobas EGFR plasma and tumor (82% for activating mutations and 73% for T790M using BEAMing vs. 73% and 64%, respectively, using cobas plasma test) (54). NGS: the emerging of new drugs that target other genomic alterations than EGFR mutations have significantly increased the complexity of biomarker testing.…”

Exosome-Based Detection of EGFR T790M in Plasma from Non–Small Cell Lung Cancer Patients

“…Mutations such as T790M can be found in both cfDNA and exosomal RNA/DNA, so combining these sources of nucleic acids increases sensitivity (27)(28)(29). This improves detection in patients with limited copies of circulating T790M in the cfDNA fraction, such as those with early stage disease or intrathoracic (M0/M1a) lung cancer patients (~25-30% of all newly diagnosed cases) (19). In addition to the increased sensitivity of mutation detection, it has been shown that mutations on exoNA correlate better to overall survival compared to cfDNA mutation analysis (27).…”

Clinical and Investigational Applications of Liquid Biopsy in Non-Small Cell Lung Cancer

“…For the T790M mutation, the digital platforms outperformed the nondigital platforms. Recent publication comparing also BEAMing and cobas test, showed a higher positive percent agreement between BEAMing plasma and tumor results than cobas EGFR plasma and tumor results (82% for activating mutations and 73% for T790M using BEAMing vs 73% and 64%, respectively, using cobas plasma test) [45] . The emerge of new drugs that target other genomic alterations rather than EGFR mutations have significantly increase the complexity of biomarker testing.…”