Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs

Mark G. Kris, Bruce E. Johnson, Lynne D. Berry, David J. Kwiatkowski, A. John Iafrate, Ignacio I. Wistuba, Marileila Varella-Garcia, Wilbur A. Franklin, Samuel L. Aronson, Pei Fang Su, Yu Shyr, D. Ross Camidge, Lecia V. Sequist, Bonnie S. Glisson, Fadlo R. Khuri, Edward B. Garon, William Pao, Charles Rudin, Joan Schiller, Eric B. Haura & 8 others Mark Socinski, Keisuke Shirai, Heidi Chen, Giuseppe Giaccone, Marc Ladanyi, Kelly Kugler, John D. Minna, Paul A. Bunn

Research output: Contribution to journalArticle

731 Citations (Scopus)

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

Original languageEnglish (US)
Pages (from-to)1998-2006
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume311
Issue number19
DOIs
StatePublished - 2014

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Lung Neoplasms
Pharmaceutical Preparations
Survival
Therapeutics
Neoplasms
Genotype
Genes
Propensity Score
Patient Care
Maintenance
Adenocarcinoma of lung
Clinical Trials
Physicians
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kris, M. G., Johnson, B. E., Berry, L. D., Kwiatkowski, D. J., Iafrate, A. J., Wistuba, I. I., ... Bunn, P. A. (2014). Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA - Journal of the American Medical Association, 311(19), 1998-2006. https://doi.org/10.1001/jama.2014.3741

Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. / Kris, Mark G.; Johnson, Bruce E.; Berry, Lynne D.; Kwiatkowski, David J.; Iafrate, A. John; Wistuba, Ignacio I.; Varella-Garcia, Marileila; Franklin, Wilbur A.; Aronson, Samuel L.; Su, Pei Fang; Shyr, Yu; Camidge, D. Ross; Sequist, Lecia V.; Glisson, Bonnie S.; Khuri, Fadlo R.; Garon, Edward B.; Pao, William; Rudin, Charles; Schiller, Joan; Haura, Eric B.; Socinski, Mark; Shirai, Keisuke; Chen, Heidi; Giaccone, Giuseppe; Ladanyi, Marc; Kugler, Kelly; Minna, John D.; Bunn, Paul A.

In: JAMA - Journal of the American Medical Association, Vol. 311, No. 19, 2014, p. 1998-2006.

Research output: Contribution to journalArticle

Kris, MG, Johnson, BE, Berry, LD, Kwiatkowski, DJ, Iafrate, AJ, Wistuba, II, Varella-Garcia, M, Franklin, WA, Aronson, SL, Su, PF, Shyr, Y, Camidge, DR, Sequist, LV, Glisson, BS, Khuri, FR, Garon, EB, Pao, W, Rudin, C, Schiller, J, Haura, EB, Socinski, M, Shirai, K, Chen, H, Giaccone, G, Ladanyi, M, Kugler, K, Minna, JD & Bunn, PA 2014, 'Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs', JAMA - Journal of the American Medical Association, vol. 311, no. 19, pp. 1998-2006. https://doi.org/10.1001/jama.2014.3741
Kris, Mark G. ; Johnson, Bruce E. ; Berry, Lynne D. ; Kwiatkowski, David J. ; Iafrate, A. John ; Wistuba, Ignacio I. ; Varella-Garcia, Marileila ; Franklin, Wilbur A. ; Aronson, Samuel L. ; Su, Pei Fang ; Shyr, Yu ; Camidge, D. Ross ; Sequist, Lecia V. ; Glisson, Bonnie S. ; Khuri, Fadlo R. ; Garon, Edward B. ; Pao, William ; Rudin, Charles ; Schiller, Joan ; Haura, Eric B. ; Socinski, Mark ; Shirai, Keisuke ; Chen, Heidi ; Giaccone, Giuseppe ; Ladanyi, Marc ; Kugler, Kelly ; Minna, John D. ; Bunn, Paul A. / Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. In: JAMA - Journal of the American Medical Association. 2014 ; Vol. 311, No. 19. pp. 1998-2006.
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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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T1 - Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs

AU - Kris, Mark G.

AU - Johnson, Bruce E.

AU - Berry, Lynne D.

AU - Kwiatkowski, David J.

AU - Iafrate, A. John

AU - Wistuba, Ignacio I.

AU - Varella-Garcia, Marileila

AU - Franklin, Wilbur A.

AU - Aronson, Samuel L.

AU - Su, Pei Fang

AU - Shyr, Yu

AU - Camidge, D. Ross

AU - Sequist, Lecia V.

AU - Glisson, Bonnie S.

AU - Khuri, Fadlo R.

AU - Garon, Edward B.

AU - Pao, William

AU - Rudin, Charles

AU - Schiller, Joan

AU - Haura, Eric B.

AU - Socinski, Mark

AU - Shirai, Keisuke

AU - Chen, Heidi

AU - Giaccone, Giuseppe

AU - Ladanyi, Marc

AU - Kugler, Kelly

AU - Minna, John D.

AU - Bunn, Paul A.

PY - 2014

Y1 - 2014

N2 - 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

AB - 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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