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Original Investigation
May 21, 2014

Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs

Author Affiliations
  • 1Memorial Sloan Kettering Cancer Center, New York, New York
  • 2Dana-Farber Cancer Institute, Boston, Massachusetts
  • 3Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
  • 4Brigham and Women’s Hospital, Boston, Massachusetts
  • 5Massachusetts General Hospital, Boston
  • 6The University of Texas MD Anderson Cancer Center, Houston
  • 7University of Colorado Cancer Center Denver, Aurora
  • 8The Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts
  • 9Winship Cancer Institute of Emory University, Atlanta, Georgia
  • 10David Geffen School of Medicine, University of California, Los Angeles
  • 11The John Hopkins University, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
  • 12University of Texas Southwestern, Medical Center, Dallas
  • 13H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
  • 14University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
  • 15Medical University of South Carolina, Charleston
  • 16National Cancer Institute, Bethesda, Maryland
  • 17Georgetown University School of Medicine, Washington, DC
JAMA. 2014;311(19):1998-2006. doi:10.1001/jama.2014.3741
Abstract

Importance  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.

Objectives  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.

Design, Setting, and Participants  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.

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

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT01014286.

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