Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer

M. Catherine Pietanza, Shirish M. Gadgeel, Afshin Dowlati, Thomas J. Lynch, Ravi Salgia, Kendrith M. Rowland, Michael S. Wertheim, Katharine A. Price, Gregory J. Riely, Christopher G. Azzoli, Vincent A. Miller, Lee M. Krug, Mark G. Kris, Jan H. Beumer, Margaret Tonda, Ben Mitchell, Naiyer A. Rizvi

Research output: Contribution to journalReview article

Abstract

XL647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (EGFR), vascular endothelial growth factor receptor 2, HER2 and Ephrin type-B receptor 4 (EphB4). We undertook an open-label, multi-institutional Phase II study to investigate the efficacy and safety of XL647 in treatment-naive non-small-cell lung cancer patients clinically enriched for the presence of EGFR mutations. Methods: Eligibility included patients with advanced-stage treatment-naive lung adenocarcinoma with a known sensitizing mutation of EGFR or patients with at least one of the following criteria: being Asian, female, or having minimal or no smoking history. Two dosing schedules were evaluated; in the "intermittent 5 & 9 dosing" cohort, XL647 350 mg for 5 days every 14 days was given; and in the "daily dosing" cohort, XL647 300 mg daily for 28 days was administered. Tumor EGFR mutation status was determined on available tissue. The primary end point was confirmed objective response rate. Results: Forty-one patients were treated on the intermittent 5 & 9 dosing- and 14 on the daily-dosing schedule. The majority of patients were eligible on the basis of smoking history. The response rate and progression-free survival for the two schedules combined were 20% and 5.3 months (90% confidence interval, 3.7-6.7), respectively. Thirty-eight patients (69%) had material available for mutation testing and 14 EGFR-sensitizing mutations were detected. The response rate and progression-free survival for EGFR-mutation-positive patients were 57% (8/14) and 9.3 months (90% confidence interval, 5.5-11.7). The toxicities were comparable between the two schedules; the most common adverse effects being diarrhea, nausea, and fatigue. Conclusions: XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations. The adverse-event profile was similar for the two dosing schedules.

Original languageEnglish (US)
Pages (from-to)856-865
Number of pages10
JournalJournal of Thoracic Oncology
Volume7
Issue number5
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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  • Cite this

    Pietanza, M. C., Gadgeel, S. M., Dowlati, A., Lynch, T. J., Salgia, R., Rowland, K. M., Wertheim, M. S., Price, K. A., Riely, G. J., Azzoli, C. G., Miller, V. A., Krug, L. M., Kris, M. G., Beumer, J. H., Tonda, M., Mitchell, B., & Rizvi, N. A. (2012). Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer. Journal of Thoracic Oncology, 7(5), 856-865. https://doi.org/10.1097/JTO.0b013e31824c943f