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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2442-2449
Number of pages8
JournalJournal of Clinical Oncology
Volume26
Issue number15
DOIs
StatePublished - Sep 15 2008
Externally publishedYes

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Mutation
Protein-Tyrosine Kinases
Exons
gefitinib
Standard of Care
Combination Drug Therapy
DNA Sequence Analysis
Multicenter Studies
Disease-Free Survival
Pneumonia
Genotype
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sequist, L. V., Martins, R. G., Spigel, D., Grunberg, S. M., Spira, A., Jänne, P. A., ... Lynch, T. J. (2008). First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. Journal of Clinical Oncology, 26(15), 2442-2449. https://doi.org/10.1200/JCO.2007.14.8494

First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. / Sequist, Lecia V.; Martins, Renato G.; Spigel, David; Grunberg, Steven M.; Spira, Alexander; Jänne, Pasi A.; Joshi, Victoria A.; McCollum, David; Evans, Tracey L.; Muzikansky, Alona; Kuhlmann, Georgiana L.; Han, Moon; Goldberg, Jonathan S.; Settleman, Jeffrey; Iafrate, A. John; Engelman, Jeffrey A.; Haber, Daniel A.; Johnson, Bruce E.; Lynch, Thomas J.

In: Journal of Clinical Oncology, Vol. 26, No. 15, 15.09.2008, p. 2442-2449.

Research output: Contribution to journalArticle

Sequist, LV, Martins, RG, Spigel, D, Grunberg, SM, Spira, A, Jänne, PA, Joshi, VA, McCollum, D, Evans, TL, Muzikansky, A, Kuhlmann, GL, Han, M, Goldberg, JS, Settleman, J, Iafrate, AJ, Engelman, JA, Haber, DA, Johnson, BE & Lynch, TJ 2008, 'First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations', Journal of Clinical Oncology, vol. 26, no. 15, pp. 2442-2449. https://doi.org/10.1200/JCO.2007.14.8494
Sequist, Lecia V. ; Martins, Renato G. ; Spigel, David ; Grunberg, Steven M. ; Spira, Alexander ; Jänne, Pasi A. ; Joshi, Victoria A. ; McCollum, David ; Evans, Tracey L. ; Muzikansky, Alona ; Kuhlmann, Georgiana L. ; Han, Moon ; Goldberg, Jonathan S. ; Settleman, Jeffrey ; Iafrate, A. John ; Engelman, Jeffrey A. ; Haber, Daniel A. ; Johnson, Bruce E. ; Lynch, Thomas J. / First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. In: Journal of Clinical Oncology. 2008 ; Vol. 26, No. 15. pp. 2442-2449.
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abstract = "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-na{\"i}ve 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.",
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AU - Martins, Renato G.

AU - Spigel, David

AU - Grunberg, Steven M.

AU - Spira, Alexander

AU - Jänne, Pasi A.

AU - Joshi, Victoria A.

AU - McCollum, David

AU - Evans, Tracey L.

AU - Muzikansky, Alona

AU - Kuhlmann, Georgiana L.

AU - Han, Moon

AU - Goldberg, Jonathan S.

AU - Settleman, Jeffrey

AU - Iafrate, A. John

AU - Engelman, Jeffrey A.

AU - Haber, Daniel A.

AU - Johnson, Bruce E.

AU - Lynch, Thomas J.

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N2 - 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.

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