XL647-A multitargeted tyrosine kinase inhibitor: Results of a phase II study in subjects with non-small cell lung cancer who have progressed after responding to treatment with either gefitinib or erlotinib

M. Catherine Pietanza, Thomas James Lynch, Primo N Lara, John Cho, Ronald H. Yanagihara, Nandagopal Vrindavanam, Naveed Mahfooz Chowhan, Shirish M. Gadgeel, Nathan A. Pennell, Roel Funke, Ben Mitchell, Heather A. Wakelee, Vincent A. Miller

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Introduction: Although patients with non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) activating mutations commonly experience significant regressions when treated with erlotinib or gefitinib, they uniformly develop resistance to these agents. The secondary EGFR T790M mutation is found in 50% of patients with acquired resistance. Herein, we studied XL647, an oral small molecule inhibitor of multiple receptor tyrosine kinases, including EGFR, VEGFR2, HER2, and EphB4, in NSCLC patients known or suspected of having tumors harboring T790M. Methods: Eligible patients included those with relapsed or recurrent advanced NSCLC who progressed after ≥12 weeks of stable disease or response to erlotinib or gefitinib and/or those patients with a documented EGFR T790M. XL647 300 mg was administered once daily. The primary end point was objective response rate. Pretreatment plasma samples were collected for mutation testing of circulating tumor DNA. Results: Forty-one patients were enrolled; 33 were evaluable for efficacy. One partial response was observed (response rate 3% and 90% confidence interval, 0% to 14%). Of patients whose tumors harbored T790M, 67% (8/12) had progression of disease as best response compared with 14% (3/21) of those without this mutation. Plasma samples from 40 patients were available for mutation testing, 14 (35%) of which were found to have EGFR mutations. Conclusions: The 3% response rate observed did not meet the prespecified threshold to recommend further study of XL647 in patients who develop acquired resistance to erlotinib or gefitinib. Patients with T790M had a significantly worse progression-free survival.

Original languageEnglish (US)
Pages (from-to)219-226
Number of pages8
JournalJournal of Thoracic Oncology
Volume7
Issue number1
DOIs
StatePublished - Jan 2012

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Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Epidermal Growth Factor Receptor
Mutation
Therapeutics
Neoplasms
Erlotinib Hydrochloride
gefitinib
XL647
Disease-Free Survival
Disease Progression
Confidence Intervals
DNA

Keywords

  • Acquired resistance
  • EGFR-resistance mutation
  • EGFR-sensitizing mutation
  • Molecular analysis
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

XL647-A multitargeted tyrosine kinase inhibitor : Results of a phase II study in subjects with non-small cell lung cancer who have progressed after responding to treatment with either gefitinib or erlotinib. / Pietanza, M. Catherine; Lynch, Thomas James; Lara, Primo N; Cho, John; Yanagihara, Ronald H.; Vrindavanam, Nandagopal; Chowhan, Naveed Mahfooz; Gadgeel, Shirish M.; Pennell, Nathan A.; Funke, Roel; Mitchell, Ben; Wakelee, Heather A.; Miller, Vincent A.

In: Journal of Thoracic Oncology, Vol. 7, No. 1, 01.2012, p. 219-226.

Research output: Contribution to journalArticle

Pietanza, MC, Lynch, TJ, Lara, PN, Cho, J, Yanagihara, RH, Vrindavanam, N, Chowhan, NM, Gadgeel, SM, Pennell, NA, Funke, R, Mitchell, B, Wakelee, HA & Miller, VA 2012, 'XL647-A multitargeted tyrosine kinase inhibitor: Results of a phase II study in subjects with non-small cell lung cancer who have progressed after responding to treatment with either gefitinib or erlotinib', Journal of Thoracic Oncology, vol. 7, no. 1, pp. 219-226. https://doi.org/10.1097/JTO.0b013e31822eebf9
Pietanza, M. Catherine ; Lynch, Thomas James ; Lara, Primo N ; Cho, John ; Yanagihara, Ronald H. ; Vrindavanam, Nandagopal ; Chowhan, Naveed Mahfooz ; Gadgeel, Shirish M. ; Pennell, Nathan A. ; Funke, Roel ; Mitchell, Ben ; Wakelee, Heather A. ; Miller, Vincent A. / XL647-A multitargeted tyrosine kinase inhibitor : Results of a phase II study in subjects with non-small cell lung cancer who have progressed after responding to treatment with either gefitinib or erlotinib. In: Journal of Thoracic Oncology. 2012 ; Vol. 7, No. 1. pp. 219-226.
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abstract = "Introduction: Although patients with non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) activating mutations commonly experience significant regressions when treated with erlotinib or gefitinib, they uniformly develop resistance to these agents. The secondary EGFR T790M mutation is found in 50{\%} of patients with acquired resistance. Herein, we studied XL647, an oral small molecule inhibitor of multiple receptor tyrosine kinases, including EGFR, VEGFR2, HER2, and EphB4, in NSCLC patients known or suspected of having tumors harboring T790M. Methods: Eligible patients included those with relapsed or recurrent advanced NSCLC who progressed after ≥12 weeks of stable disease or response to erlotinib or gefitinib and/or those patients with a documented EGFR T790M. XL647 300 mg was administered once daily. The primary end point was objective response rate. Pretreatment plasma samples were collected for mutation testing of circulating tumor DNA. Results: Forty-one patients were enrolled; 33 were evaluable for efficacy. One partial response was observed (response rate 3{\%} and 90{\%} confidence interval, 0{\%} to 14{\%}). Of patients whose tumors harbored T790M, 67{\%} (8/12) had progression of disease as best response compared with 14{\%} (3/21) of those without this mutation. Plasma samples from 40 patients were available for mutation testing, 14 (35{\%}) of which were found to have EGFR mutations. Conclusions: The 3{\%} response rate observed did not meet the prespecified threshold to recommend further study of XL647 in patients who develop acquired resistance to erlotinib or gefitinib. Patients with T790M had a significantly worse progression-free survival.",
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AU - Lynch, Thomas James

AU - Lara, Primo N

AU - Cho, John

AU - Yanagihara, Ronald H.

AU - Vrindavanam, Nandagopal

AU - Chowhan, Naveed Mahfooz

AU - Gadgeel, Shirish M.

AU - Pennell, Nathan A.

AU - Funke, Roel

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N2 - Introduction: Although patients with non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) activating mutations commonly experience significant regressions when treated with erlotinib or gefitinib, they uniformly develop resistance to these agents. The secondary EGFR T790M mutation is found in 50% of patients with acquired resistance. Herein, we studied XL647, an oral small molecule inhibitor of multiple receptor tyrosine kinases, including EGFR, VEGFR2, HER2, and EphB4, in NSCLC patients known or suspected of having tumors harboring T790M. Methods: Eligible patients included those with relapsed or recurrent advanced NSCLC who progressed after ≥12 weeks of stable disease or response to erlotinib or gefitinib and/or those patients with a documented EGFR T790M. XL647 300 mg was administered once daily. The primary end point was objective response rate. Pretreatment plasma samples were collected for mutation testing of circulating tumor DNA. Results: Forty-one patients were enrolled; 33 were evaluable for efficacy. One partial response was observed (response rate 3% and 90% confidence interval, 0% to 14%). Of patients whose tumors harbored T790M, 67% (8/12) had progression of disease as best response compared with 14% (3/21) of those without this mutation. Plasma samples from 40 patients were available for mutation testing, 14 (35%) of which were found to have EGFR mutations. Conclusions: The 3% response rate observed did not meet the prespecified threshold to recommend further study of XL647 in patients who develop acquired resistance to erlotinib or gefitinib. Patients with T790M had a significantly worse progression-free survival.

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