Originally published as JCO Early Release 10.1200/JCO.2007.14.8494 on May 5 2008

This Article Full Text Full Text (PDF) Publisher's Note Erratum (v26,p3472) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sequist, L. V. Articles by Lynch, T. J. Search for Related Content PubMed PubMed Citation Articles by Sequist, L. V. Articles by Lynch, T. J. Related Articles Related Editorial Social Bookmarking                            What's this?

First-Line Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer Harboring Somatic EGFR Mutations

Lecia V. Sequist, Renato G. Martins, David Spigel, Steven M. Grunberg, Alexander Spira, Pasi A. Jänne, Victoria A. Joshi, David McCollum, Tracey L. Evans, Alona Muzikansky, Georgiana L. Kuhlmann, Moon Han, Jonathan S. Goldberg, Jeffrey Settleman, A. John Iafrate, Jeffrey A. Engelman, Daniel A. Haber, Bruce E. Johnson, Thomas J. Lynch

From the Massachusetts General Hospital Cancer Center; Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital; Department of Pathology, Massachusetts General Hospital; Department of Biostatistics, Massachusetts General Hospital, Boston; Harvard Medical School/Partners Health Care Center for Genetics and Genomics, Cambridge, MA; University of Washington, Seattle, WA; Sarah Cannon Research Institute, Nashville, TN; Fletcher Allen Health Care, Burlington, VT; Fairfax-Northern Virginia Hematology-Oncology PC, Fairfax, VA; Texas Oncology/Sammons Cancer Center, Dallas, TX; University of Pennsylvania, Philadelphia, PA; and the Mt Kisco Medical Group, Mt Kisco, NY

Corresponding author: Lecia V. Sequist, MD, MPH, Massachusetts General Hospital Cancer Center, 32 Fruit St, Yawkey Suite 7B, Boston, MA 02114; e-mail: lvsequist{at}partners.org

Purpose Somatic mutations in the epidermal growth factor receptor (EGFR) correlate with increased response in patients with non–small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). The multicenter iTARGET trial prospectively examined first-line gefitinib in advanced NSCLC patients harboring EGFR mutations and explored the significance of EGFR mutation subtypes and TKI resistance mechanisms.

Patients and Methods Chemotherapy-naïve patients with advanced NSCLC with 1 clinical characteristic associated with EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate.

Results Ninety-eight patients underwent EGFR screening and mutations were detected in 34 (35%). EGFR mutations were primarily exon 19 deletions (53%) and L858R (26%) though 21% of mutation-positive cases had less common subtypes including exon 20 insertions, T790M/L858R, G719A, and L861Q. Thirty-one patients received gefitinib. The response rate was 55% (95% CI, 33 to 70) and median progression-free survival was 9.2 months (95% CI, 6.2 to 11.8). Therapy was well tolerated; 13% of patients had grade 3 toxicities including one grade 3 pneumonitis. Two patients with classic activating mutations exhibited de novo gefitinib resistance and had concurrent genetic anomalies usually associated with acquired TKI resistance, specifically the T790M EGFR mutation and MET amplification.

Conclusion First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.

published online ahead of print at www.jco.org on May 5, 2008.

Supported by a research grant from AstraZeneca, study IRUSIRES0483.

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Editorial

• Molecular Selection of Patients for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer With Epidermal Growth Factor Inhibitors: Not Quite Ready for Prime Time
  Frances A. Shepherd
  JCO 2008 26: 2426-2427 [Full Text]

This article has been cited by other articles:

				N. Peled, K. Yoshida, M. W. Wynes, and F. R. Hirsch Review: Predictive and prognostic markers for epidermal growth factor receptor inhibitor therapy in non-small cell lung cancer Therapeutic Advances in Medical Oncology, November 1, 2009; 1(3): 137 - 144. [Abstract] [PDF]

				A. T. Shaw, B. Y. Yeap, M. Mino-Kenudson, S. R. Digumarthy, D. B. Costa, R. S. Heist, B. Solomon, H. Stubbs, S. Admane, U. McDermott, et al. Clinical Features and Outcome of Patients With Non-Small-Cell Lung Cancer Who Harbor EML4-ALK J. Clin. Oncol., September 10, 2009; 27(26): 4247 - 4253. [Abstract] [Full Text] [PDF]

				T. S. Mok, Y.-L. Wu, S. Thongprasert, C.-H. Yang, D.-T. Chu, N. Saijo, P. Sunpaweravong, B. Han, B. Margono, Y. Ichinose, et al. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma N. Engl. J. Med., September 3, 2009; 361(10): 947 - 957. [Abstract] [Full Text] [PDF]

				R. Rosell, T. Moran, C. Queralt, R. Porta, F. Cardenal, C. Camps, M. Majem, G. Lopez-Vivanco, D. Isla, M. Provencio, et al. Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer N. Engl. J. Med., September 3, 2009; 361(10): 958 - 967. [Abstract] [Full Text] [PDF]

				D. M. Jackman, V. A. Miller, L.-A. Cioffredi, B. Y. Yeap, P. A. Janne, G. J. Riely, M. G. Ruiz, G. Giaccone, L. V. Sequist, and B. E. Johnson Impact of Epidermal Growth Factor Receptor and KRAS Mutations on Clinical Outcomes in Previously Untreated Non-Small Cell Lung Cancer Patients: Results of an Online Tumor Registry of Clinical Trials Clin. Cancer Res., August 15, 2009; 15(16): 5267 - 5273. [Abstract] [Full Text] [PDF]

				S. Ocak, M. L. Sos, R. K. Thomas, and P. P. Massion High-throughput molecular analysis in lung cancer: insights into biology and potential clinical applications Eur. Respir. J., August 1, 2009; 34(2): 489 - 506. [Abstract] [Full Text] [PDF]

				S. Morita, I. Okamoto, K. Kobayashi, K. Yamazaki, H. Asahina, A. Inoue, K. Hagiwara, N. Sunaga, N. Yanagitani, T. Hida, et al. Combined Survival Analysis of Prospective Clinical Trials of Gefitinib for Non-Small Cell Lung Cancer with EGFR Mutations Clin. Cancer Res., July 1, 2009; 15(13): 4493 - 4498. [Abstract] [Full Text] [PDF]

				L. V. Sequist, J. A. Engelman, and T. J. Lynch Toward Noninvasive Genomic Screening of Lung Cancer Patients J. Clin. Oncol., June 1, 2009; 27(16): 2589 - 2591. [Full Text] [PDF]

				U. McDermott, R. Y. Ames, A. J. Iafrate, S. Maheswaran, H. Stubbs, P. Greninger, K. McCutcheon, R. Milano, A. Tam, D. Y. Lee, et al. Ligand-Dependent Platelet-Derived Growth Factor Receptor (PDGFR)-{alpha} Activation Sensitizes Rare Lung Cancer and Sarcoma Cells to PDGFR Kinase Inhibitors Cancer Res., May 1, 2009; 69(9): 3937 - 3946. [Abstract] [Full Text] [PDF]

				J. Yu, S. Kane, J. Wu, E. Benedettini, D. Li, C. Reeves, G. Innocenti, R. Wetzel, K. Crosby, A. Becker, et al. Mutation-Specific Antibodies for the Detection of EGFR Mutations in Non-Small-Cell Lung Cancer Clin. Cancer Res., May 1, 2009; 15(9): 3023 - 3028. [Abstract] [Full Text] [PDF]

				Y. Kuang, A. Rogers, B. Y. Yeap, L. Wang, M. Makrigiorgos, K. Vetrand, S. Thiede, R. J. Distel, and P. A. Janne Noninvasive Detection of EGFR T790M in Gefitinib or Erlotinib Resistant Non-Small Cell Lung Cancer Clin. Cancer Res., April 15, 2009; 15(8): 2630 - 2636. [Abstract] [Full Text] [PDF]

				G. Sartori, A. Cavazza, A. Sgambato, A. Marchioni, F. Barbieri, L. Longo, M. Bavieri, B. Murer, E. Meschiari, S. Tamberi, et al. EGFR and K-ras Mutations Along the Spectrum of Pulmonary Epithelial Tumors of the Lung and Elaboration of a Combined Clinicopathologic and Molecular Scoring System to Predict Clinical Responsiveness to EGFR Inhibitors Am J Clin Pathol, April 1, 2009; 131(4): 478 - 489. [Abstract] [Full Text] [PDF]

				C. J. Langer The "Lazarus Response" in Treatment-Naive, Poor Performance Status Patients With Non-Small-Cell Lung Cancer and Epidermal Growth Factor Receptor Mutation J. Clin. Oncol., March 20, 2009; 27(9): 1350 - 1354. [Full Text] [PDF]

				H. Jiang Overview of Gefitinib in Non-small Cell Lung Cancer: An Asian Perspective Jpn. J. Clin. Oncol., March 1, 2009; 39(3): 137 - 150. [Abstract] [Full Text] [PDF]

				P. Laurent-Puig, A. Lievre, and H. Blons Mutations and Response to Epidermal Growth Factor Receptor Inhibitors Clin. Cancer Res., February 15, 2009; 15(4): 1133 - 1139. [Abstract] [Full Text] [PDF]

				F. Cappuzzo, P. A. Janne, M. Skokan, G. Finocchiaro, E. Rossi, C. Ligorio, P. A. Zucali, L. Terracciano, L. Toschi, M. Roncalli, et al. MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients Ann. Onc., February 1, 2009; 20(2): 298 - 304. [Abstract] [Full Text] [PDF]

				M. A. Pantaleo, M. Nannini, A. Maleddu, S. Fanti, C. Nanni, S. Boschi, F. Lodi, G. Nicoletti, L. Landuzzi, P. L. Lollini, et al. Experimental results and related clinical implications of PET detection of epidermal growth factor receptor (EGFr) in cancer Ann. Onc., February 1, 2009; 20(2): 213 - 226. [Abstract] [Full Text] [PDF]

				M. A. Socinski What Guides Decisions about the Use of Epidermal Growth Factor Receptor Antibody or Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Advanced Non-small Cell Lung Cancer? ASCO Educational Book, January 1, 2009; 2009(1): 436 - 443. [Abstract] [Full Text] [PDF]

				T. M. Chin, M. P. Quinlan, A. Singh, L. V. Sequist, T. J. Lynch, D. A. Haber, S. V. Sharma, and J. Settleman Reduced Erlotinib Sensitivity of Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer following Cisplatin Exposure: A Cell Culture Model of Second-line Erlotinib Treatment Clin. Cancer Res., November 1, 2008; 14(21): 6867 - 6876. [Abstract] [Full Text] [PDF]

				D. B. Costa, K.-S. H. Nguyen, B. C. Cho, L. V. Sequist, D. M. Jackman, G. J. Riely, B. Y. Yeap, B. Halmos, J. H. Kim, P. A. Janne, et al. Effects of Erlotinib in EGFR Mutated Non-Small Cell Lung Cancers with Resistance to Gefitinib Clin. Cancer Res., November 1, 2008; 14(21): 7060 - 7067. [Abstract] [Full Text] [PDF]

				P. A. Janne Gefitinib First or Gefitinib Second: Is Timing Everything in the Treatment of EGFR Mutant Non-Small Cell Lung Cancer? Am. J. Respir. Crit. Care Med., October 15, 2008; 178(8): 783 - 785. [Full Text] [PDF]

				M. Bhutani, A. K. Pathak, and L. Mao SWOG S0023: What Meets the Eye May Be Only Half the Truth J. Clin. Oncol., October 10, 2008; 26(29): 4848 - 4849. [Full Text] [PDF]

				C. H. Chau, O. Rixe, H. McLeod, and W. D. Figg Validation of Analytic Methods for Biomarkers Used in Drug Development Clin. Cancer Res., October 1, 2008; 14(19): 5967 - 5976. [Abstract] [Full Text] [PDF]

				G. J. Riely, M. G. Kris, D. Rosenbaum, J. Marks, A. Li, D. A. Chitale, K. Nafa, E. R. Riedel, M. Hsu, W. Pao, et al. Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma Clin. Cancer Res., September 15, 2008; 14(18): 5731 - 5734. [Abstract] [Full Text] [PDF]

				L. V. Sequist, J. E. Settleman, J. B. Ackman, and A. J. Iafrate Case 23-2008 -- A 26-Year-Old Man with Back Pain and a Mass in the Lung N. Engl. J. Med., July 24, 2008; 359(4): 405 - 414. [Full Text] [PDF]

				S. Maheswaran, L. V. Sequist, S. Nagrath, L. Ulkus, B. Brannigan, C. V. Collura, E. Inserra, S. Diederichs, A. J. Iafrate, D. W. Bell, et al. Detection of Mutations in EGFR in Circulating Lung-Cancer Cells N. Engl. J. Med., July 24, 2008; 359(4): 366 - 377. [Abstract] [Full Text] [PDF]

				F. A. Shepherd Molecular Selection of Patients for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer With Epidermal Growth Factor Inhibitors: Not Quite Ready for Prime Time J. Clin. Oncol., May 20, 2008; 26(15): 2426 - 2427. [Full Text] [PDF]