MA08.11 Monitoring the Emergence of EGFR T790M ctDNA in Urine from EGFR Mutated NSCLC Patients to Predict Response to 3rd Generation Anti-EGFR TKIs

Abstract

EGFR T790M mutation occurs in about half of EGFR mutated NSCLC patients with acquired EGFR-TKI resistance. It is currently unknown if switching therapy to a third generation anti-EGFR TKI based on circulating tumor DNA at first detection with urine is superior to switching therapy based on radiographic progression. Herein we demonstrate the identification of T790M in urine months before radiographic progression, patient responses when treated with an anti-EGFR third generation TKIs, clinical cutoffs that may be predictive of benefit, and a novel clinical trial to consider for treatment selection. From 2014 to 2016 a total of 42 patients with EGFR activating mutations were followed at UCSD Moores Cancer Center through multiple lines of therapy. 34 patients had serial urine collection every 4-6wks from time of first visit. Clinical progression was assessed with CT imaging performed every two months. Among the 42 patients, 35 patients had metastatic disease (6 with intrathoracic M1a disease and 29 with distant metastasis M1b). Urine volume ranged from 30-100ml. Average time from first line TKI start to urine T790M was 15.7mos (CI 9.6-25.6), time from TKI start to radiographic progression was 21.9mos (CI 10.7-27.0), and time from urine T790M to radiographic progression was 3.6mos (CI 0.9-6.8). All patients with >30 copies/105 genome equivalents (GEq) of urine T790M had response to third generation TKIs. In patients who had urine EGFR T790M from 10-30 copies/105 GEq, three serial measurements in the 10-30 range predicted response. EGFR T790M copies of less than 10 copies/105 GEq did not predict response to third generation inhibitors. EGFR T790M can be identified in urine before radiographic progression and quantitative cut-offs can be predictive of response. We are testing this prospectively in a clinical trial with serial ctDNA analyses obtained for resistance monitoring for up to 24 months on first line TKI therapy. Patients who have urine detection of T790M (>30 copies or three serial collections with 10-30 copies/105 GEq) at 12 months and before progression are randomized to second line third generation TKI therapy or continuation of the first line therapy until progression. Patients with undetectable urinary T790M or <10 copies/105 GEq will continue on the first line therapy past 12 months until progression. Overall survival, progression free survival, and time to progression will be compared between cohorts to validate the early detection of T790M by urine ctDNA and understand the impact of an early switch in therapy based on ctDNA analyses.