Antitumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR exon 20 insertions

Nicolas Floc'h, Matthew J. Martin, Jonathan Riess, Jonathan P. Orme, Anna D. Staniszewska, Ludovic Menard, Maria Emanuela Cuomo, Daniel J. O'Neill, Richard A. Ward, Raymond M.V. Finlay, Darren McKerrecher, Mingshan Cheng, Daniel P. Vang, Rebekah A. Burich, James G. Keck, David R Gandara, Philip Mack, Darren A.E. Cross

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non–small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterized osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signaling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo. The antitumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient-derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC.

Original languageEnglish (US)
Pages (from-to)885-896
Number of pages12
JournalMolecular Cancer Therapeutics
Volume17
Issue number5
DOIs
StatePublished - May 1 2018

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Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Exons
Heterografts
Insertional Mutagenesis
osimertinib
Clustered Regularly Interspaced Short Palindromic Repeats
Cell Line
Neoplasms
Standard of Care
Growth
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Antitumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR exon 20 insertions. / Floc'h, Nicolas; Martin, Matthew J.; Riess, Jonathan; Orme, Jonathan P.; Staniszewska, Anna D.; Menard, Ludovic; Cuomo, Maria Emanuela; O'Neill, Daniel J.; Ward, Richard A.; Finlay, Raymond M.V.; McKerrecher, Darren; Cheng, Mingshan; Vang, Daniel P.; Burich, Rebekah A.; Keck, James G.; Gandara, David R; Mack, Philip; Cross, Darren A.E.

In: Molecular Cancer Therapeutics, Vol. 17, No. 5, 01.05.2018, p. 885-896.

Research output: Contribution to journalArticle

Floc'h, N, Martin, MJ, Riess, J, Orme, JP, Staniszewska, AD, Menard, L, Cuomo, ME, O'Neill, DJ, Ward, RA, Finlay, RMV, McKerrecher, D, Cheng, M, Vang, DP, Burich, RA, Keck, JG, Gandara, DR, Mack, P & Cross, DAE 2018, 'Antitumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR exon 20 insertions', Molecular Cancer Therapeutics, vol. 17, no. 5, pp. 885-896. https://doi.org/10.1158/1535-7163.MCT-17-0758
Floc'h, Nicolas ; Martin, Matthew J. ; Riess, Jonathan ; Orme, Jonathan P. ; Staniszewska, Anna D. ; Menard, Ludovic ; Cuomo, Maria Emanuela ; O'Neill, Daniel J. ; Ward, Richard A. ; Finlay, Raymond M.V. ; McKerrecher, Darren ; Cheng, Mingshan ; Vang, Daniel P. ; Burich, Rebekah A. ; Keck, James G. ; Gandara, David R ; Mack, Philip ; Cross, Darren A.E. / Antitumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR exon 20 insertions. In: Molecular Cancer Therapeutics. 2018 ; Vol. 17, No. 5. pp. 885-896.
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AU - Martin, Matthew J.

AU - Riess, Jonathan

AU - Orme, Jonathan P.

AU - Staniszewska, Anna D.

AU - Menard, Ludovic

AU - Cuomo, Maria Emanuela

AU - O'Neill, Daniel J.

AU - Ward, Richard A.

AU - Finlay, Raymond M.V.

AU - McKerrecher, Darren

AU - Cheng, Mingshan

AU - Vang, Daniel P.

AU - Burich, Rebekah A.

AU - Keck, James G.

AU - Gandara, David R

AU - Mack, Philip

AU - Cross, Darren A.E.

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N2 - EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non–small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterized osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signaling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo. The antitumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient-derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC.

AB - EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non–small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterized osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signaling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo. The antitumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient-derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC.

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