AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer

Pasi A. Jänne, James Chih-Hsin Yang, Dong Wan Kim, David Planchard, Yuichiro Ohe, Suresh S. Ramalingam, Myung Ju Ahn, Sang We Kim, Wu Chou Su, Leora Horn, Daniel Haggstrom, Enriqueta Felip, Joo Hang Kim, Paul Frewer, Mireille Cantarini, Kathryn H. Brown, Paul A. Dickinson, Serban Ghiorghiu, Malcolm Ranson

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Abstract

Background: The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. Methods: We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included doseescalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy. Results: A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients. Conclusions: AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors.

Original languageEnglish
Pages (from-to)1689-1699
Number of pages11
JournalNew England Journal of Medicine
Volume372
Issue number18
DOIs
StatePublished - 30 Apr 2015

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Confidence Intervals
Lung Neoplasms
Mutation
AZD9291
Disease Progression
Poisons
Appetite
Exanthema
Drug Resistance
Nausea
Disease-Free Survival
Diarrhea
Neoplasms
Pharmacokinetics

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Jänne, P. A., Chih-Hsin Yang, J., Kim, D. W., Planchard, D., Ohe, Y., Ramalingam, S. S., ... Ranson, M. (2015). AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. New England Journal of Medicine, 372(18), 1689-1699. https://doi.org/10.1056/NEJMoa1411817
Jänne, Pasi A. ; Chih-Hsin Yang, James ; Kim, Dong Wan ; Planchard, David ; Ohe, Yuichiro ; Ramalingam, Suresh S. ; Ahn, Myung Ju ; Kim, Sang We ; Su, Wu Chou ; Horn, Leora ; Haggstrom, Daniel ; Felip, Enriqueta ; Kim, Joo Hang ; Frewer, Paul ; Cantarini, Mireille ; Brown, Kathryn H. ; Dickinson, Paul A. ; Ghiorghiu, Serban ; Ranson, Malcolm. / AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. In: New England Journal of Medicine. 2015 ; Vol. 372, No. 18. pp. 1689-1699.
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abstract = "Background: The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. Methods: We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included doseescalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy. Results: A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51{\%} (95{\%} confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61{\%} (95{\%} CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21{\%} (95{\%} CI, 12 to 34). The median progression-free survival was 9.6 months (95{\%} CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95{\%} CI, 2.1 to 4.3) in EGFR T790M-negative patients. Conclusions: AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors.",
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Jänne, PA, Chih-Hsin Yang, J, Kim, DW, Planchard, D, Ohe, Y, Ramalingam, SS, Ahn, MJ, Kim, SW, Su, WC, Horn, L, Haggstrom, D, Felip, E, Kim, JH, Frewer, P, Cantarini, M, Brown, KH, Dickinson, PA, Ghiorghiu, S & Ranson, M 2015, 'AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer', New England Journal of Medicine, vol. 372, no. 18, pp. 1689-1699. https://doi.org/10.1056/NEJMoa1411817

AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. / Jänne, Pasi A.; Chih-Hsin Yang, James; Kim, Dong Wan; Planchard, David; Ohe, Yuichiro; Ramalingam, Suresh S.; Ahn, Myung Ju; Kim, Sang We; Su, Wu Chou; Horn, Leora; Haggstrom, Daniel; Felip, Enriqueta; Kim, Joo Hang; Frewer, Paul; Cantarini, Mireille; Brown, Kathryn H.; Dickinson, Paul A.; Ghiorghiu, Serban; Ranson, Malcolm.

In: New England Journal of Medicine, Vol. 372, No. 18, 30.04.2015, p. 1689-1699.

Research output: Contribution to journalArticle

TY - JOUR

T1 - AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer

AU - Jänne, Pasi A.

AU - Chih-Hsin Yang, James

AU - Kim, Dong Wan

AU - Planchard, David

AU - Ohe, Yuichiro

AU - Ramalingam, Suresh S.

AU - Ahn, Myung Ju

AU - Kim, Sang We

AU - Su, Wu Chou

AU - Horn, Leora

AU - Haggstrom, Daniel

AU - Felip, Enriqueta

AU - Kim, Joo Hang

AU - Frewer, Paul

AU - Cantarini, Mireille

AU - Brown, Kathryn H.

AU - Dickinson, Paul A.

AU - Ghiorghiu, Serban

AU - Ranson, Malcolm

PY - 2015/4/30

Y1 - 2015/4/30

N2 - Background: The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. Methods: We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included doseescalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy. Results: A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients. Conclusions: AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors.

AB - Background: The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. Methods: We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included doseescalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy. Results: A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients. Conclusions: AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors.

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DO - 10.1056/NEJMoa1411817

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AN - SCOPUS:84928739294

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Jänne PA, Chih-Hsin Yang J, Kim DW, Planchard D, Ohe Y, Ramalingam SS et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. New England Journal of Medicine. 2015 Apr 30;372(18):1689-1699. https://doi.org/10.1056/NEJMoa1411817