Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation.
OBJECTIVE
Patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI) after a median of 10 to 16 months. In half of these cases, a second EGFR mutation, T790M, underlies acquired resistance. We undertook this study to examine the clinical course of patients harboring the T790M mutation following progression on TKI.


METHODS
EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs were identified as part of a prospective rebiopsy protocol in which postprogression tumor specimens were collected for molecular analysis. Postprogression survival and characteristics of disease progression were compared in patients with and without T790M.


RESULTS
We identified T790M in the initial rebiopsy specimens from 58 of 93 patients (62%, 95% CI: 52-72). T790M was more common in biopsies of lung/pleura tissue and lymph nodes than in more distant sites (P = 0.014). Median postprogression survival was 16 months (interquartile range = 9-29 months); patients with T790M had a significantly longer postprogression survival (P = 0.036). Patients without T790M more often progressed in a previously uninvolved organ system (P = 0.014) and exhibited a poorer performance status at time of progression (P = 0.007).


CONCLUSIONS
Among patients with acquired resistance to EGFR TKIs, the presence of T790M defines a clinical subset with a relatively favorable prognosis and more indolent progression. Knowledge of T790M status is therefore important both for the clinical care of these patients and for the optimal design and interpretation of clinical trials in this setting.
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York 10065, USA.
Geoffrey R
GR
Oxnard
Maria E
ME
Arcila
Camelia S
CS
Sima
Gregory J
GJ
Riely
Juliann
J
Chmielecki
Mark G
MG
Kris
William
W
Pao
Marc
M
Ladanyi
Vincent A
VA
Miller
D000230:Adenocarcinoma / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001706:Biopsy; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D009154:Mutation; D011379:Prognosis; D011446:Prospective Studies; D013997:Time Factors
D000970:Antineoplastic Agents; D066246:ErbB Receptors