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

By M. Kris, B. Johnson, L. Berry, D. Kwiatkowski, A. Iafrate, I. Wistuba, M. Varella-Garcia, W. Franklin, S. L. Aronson, P. Su and 18 more. Journal of the American Medical Association (JAMA), 2014

1,641 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/07fff1c9d77fb2b8731d7d86b38c7ac05df654c7

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Citations in the corpus

EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer (NSCLC): A Retrospective Analysis (2016, background): “Moreover, KRAS mutations are the most frequent oncogenic driver in NSCLC (4).”
Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. (2015, background): “0 DTD JMDI392_proof therapeutic approaches.(8) Massively parallel next-generation sequencing (NGS) technology fulfills this need because it enables the unbiased identification of mutations across the genome or across more targeted regions with high sensitivity and specificity.”
Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. (2018, background): “mon oncogenic driver mutations found in NSCLC and their association with clinical benefit from ICI treatment.(24) Mutations in KRAS were common (n = 83), and the”
Understanding and targeting resistance mechanisms in NSCLC (2017, background): “Discovery of (10R)-7-amino-12fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure”
Current Challenges in Cancer Treatment. (2016, background): “] 2016 longer survival compared with those with driver alterations but not receiving targeted therapies or those without oncogenic aberrations susceptible of specific treatment.(14) Finally, integrative and comprehensive molecular characterizations of both adenocarcinomas and squamous cell carcinoma”
Feasibility of Large-Scale Genomic Testing to Facilitate Enrollment Onto Genomically Matched Clinical Trials. (2015, background): “In the Lung Cancer Mutation Consortium, an oncogenic driver was found in 64% of patients who underwent genomic testing; however, only 28% of patients were enrolled onto a marker-selected trial.(7) In the SAFIR01 breast cancer trial, a targetable alteration was identified in 46% of patients and thera”
Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations (2015, neutral): “The most common disease types were colorectal cancer (37 patients), non–small-cell lung cancer (20), Erdheim–Chester disease or Langerhans’-cell histiocytosis (18), primary brain tumors (13), cholangiocarcinoma (8), anaplastic thyroid cancer (7), and multiple myeloma (5).”
Analytical and Clinical Validation of a Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA (2015, background): “academic centers, one oncogenic driver mutation could be tested in 91% of tissue specimens but the ten desired target gene alterations could only be measured in 66% of them, a shortfall of 25% [8].”
Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer (2018, positive): “It is important that lung cancer patients are tested for oncogenic drivers of cancer and receive matched targeted therapy [4].”