Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
Background: NSCLC patients with activating mutations of the EGFR initially
respond well to TKIs, but about half such patients develop TKI resistance
through acquisition of a secondary T790M mutation. Whereas next-generation
EGFR-TKIs have been developed to overcome T790M-mediated resistance,
performance of a second tumor biopsy to assess T790M mutation status can
be problematic. Methods: We developed and evaluated liquid biopsy assays for
detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital
PCR (ddPCR) in EGFR mutation–positive patients with acquired EGFR-TKI
resistance. Results: A total of 260 patients was enrolled between November
2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG
8014LTR) study. Plasma specimens from all subjects as well as tumor tissue
or malignant pleural effusion or ascites from 41 patients were collected after
the development of EGFR-TKI resistance. All plasma samples were genotyped
successfully and the results were reported to physicians within 14 days. TKIsensitizing
and T790M mutations were detected in plasma of 120 (46.2%) and
75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients
with plasma positive for TKI-sensitizing mutations. For the 41 patients
with paired samples obtained after acquisition of EGFR-TKI resistance, the
concordance for mutation detection by ddPCR in plasma compared with tumor
tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations
and 65.9% for T790M. Conclusion: Noninvasive genotyping by ddPCR with
cell-free DNA extracted from plasma is a promising approach to the detection
of gene mutations during targeted treatment.
Keywords: T790M mutation, Acquired resistance, liquid biopsy, digital PCR
MA08: TREATMENT MONITORING IN ADVANCED NSCLC
TUESDAY, DECEMBER 6, 2016 - 11:00-12:30
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
Brian Woodward 1 , Parissa Keshavarzian 1 , Ragi Phillips 1 , Sandeep Pingle 2 ,
Vlada Melnikova 2 , Mark Erlander 2 , Hatim Husain 1
1 Ucsd Moores Cancer Center, La Jolla/CA/United States of America, 2 Trovagene Inc,
San Diego/CA/United States of America
Background: 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. Methods: 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. Results: 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/10 5 genome equivalents (GEq) of urine T790M had response to third
generation TKIs. In patients who had urine EGFR T790M from 10-30 copies/10 5
GEq, three serial measurements in the 10-30 range predicted response. EGFR
T790M copies of less than 10 copies/10 5 GEq did not predict response to third
generation inhibitors. Conclusion: 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/10 5 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