Non-invasive detection of EGFR T790M in gefitinib/erlotinib resistant NSCLC

Abstract

8075 Background: Fifty percent of NSCLC patients (pts) that develop a partial (PR) or complete (CR) response to gefitinib (G) or erlotinib (E) will develop a secondary EGFR T790M mutation as a mechanism of drug resistance. As most pts do not undergo repeated tumor biopsies, we evaluated the ability to detect EGFR T790M non-invasively from plasma DNA. Methods: NSCLC pts (n= 55) previously treated with G (n= 15) or E (n=36) or untreated (n=4) were included. Best response to prior treatment: CR/PR (n=28); SD (n=13); PD (n=10). EGFR mutant/wild type/unknown: 27/16/12. DxS real time PCR and WAVE technologies were used to screen for EGFR mutations in 72 plasma samples (median no. of samples per pt = 1; range = 1–5). Two methods of whole genome amplification (WGA) were explored to increase the yield of plasma DNA. Results: EGFR activating mutations were identified from plasma DNA in 32 (58%) pts. Concordance with primary EGFR tumor mutation was 70%. In 9 pts with a tumor EGFR mutation, we were unable to detect the mutation in plasma DNA. We detected EGFR T790M in 15/28 (53%) clinically resistant pts with prior CR/PR; 3/13 (23%) resistant pts with prior SD; and 0/10 (0%) resistant pts with prior PD. EGFR T790M was not detected in untreated pts. WGA was successful in 51/55 (93%) pts. There was no correlation between plasma DNA concentration and ability to detect EGFR activating or T790M mutation. Conclusions: We detected EGFR T790M from plasma DNA in 15 (53%) G or E resistant pts with prior CR/PR. This correlates closely with established estimates of EGFR T790M frequency (50%) from tumor biopsies in this pt population. Detection of EGFR T790M using non-invasive methods may aid in directing the course of subsequent therapy for G or E resistant pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Boehringer Ingelheim, Roche Pfizer Genzyme