Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.
OBJECTIVE
Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials.


OBJECTIVE
To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival.


METHODS
From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival.


METHODS
Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies.


METHODS
Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival.


RESULTS
From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score-adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006).


CONCLUSIONS
Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival.


BACKGROUND
clinicaltrials.gov Identifier: NCT01014286.
Memorial Sloan Kettering Cancer Center, New York, New York.
Mark G
MG
Kris
Dana-Farber Cancer Institute, Boston, Massachusetts.
Bruce E
BE
Johnson
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
Lynne D
LD
Berry
Brigham and Women's Hospital, Boston, Massachusetts.
David J
DJ
Kwiatkowski
Massachusetts General Hospital, Boston.
A John
AJ
Iafrate
The University of Texas MD Anderson Cancer Center, Houston.
Ignacio I
II
Wistuba
University of Colorado Cancer Center Denver, Aurora.
Marileila
M
Varella-Garcia
University of Colorado Cancer Center Denver, Aurora.
Wilbur A
WA
Franklin
The Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts.
Samuel L
SL
Aronson
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
Pei-Fang
PF
Su
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
Yu
Y
Shyr
University of Colorado Cancer Center Denver, Aurora.
D Ross
DR
Camidge
Massachusetts General Hospital, Boston.
Lecia V
LV
Sequist
The University of Texas MD Anderson Cancer Center, Houston.
Bonnie S
BS
Glisson
Winship Cancer Institute of Emory University, Atlanta, Georgia.
Fadlo R
FR
Khuri
David Geffen School of Medicine, University of California, Los Angeles.
Edward B
EB
Garon
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
William
W
Pao
The John Hopkins University, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
Charles
C
Rudin
University of Texas Southwestern, Medical Center, Dallas.
Joan
J
Schiller
H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Eric B
EB
Haura
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Mark
M
Socinski
Medical University of South Carolina, Charleston.
Keisuke
K
Shirai
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
Heidi
H
Chen
National Cancer Institute, Bethesda, Maryland17Georgetown University School of Medicine, Washington, DC.
Giuseppe
G
Giaccone
Memorial Sloan Kettering Cancer Center, New York, New York.
Marc
M
Ladanyi
University of Colorado Cancer Center Denver, Aurora.
Kelly
K
Kugler
University of Texas Southwestern, Medical Center, Dallas.
John D
JD
Minna
University of Colorado Cancer Center Denver, Aurora.
Paul A
PA
Bunn
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060885:Multiplex Polymerase Chain Reaction; D011519:Proto-Oncogenes; D017422:Sequence Analysis, DNA / Q000379:methods; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016019:Survival Analysis