Phase 2 Study of Erlotinib in Combination With Linsitinib (OSI-906) or Placebo in Chemotherapy-Naive Patients With Non-Small-Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations

Natasha B. Leighl, Naiyer A. Rizvi, Lopes Gilberto de Lima, Wichit Arpornwirat, Charles M. Rudin, Alberto A. Chiappori, Myung Ju Ahn, Laura Q M Chow, Lyudmila Bazhenova, Arunee Dechaphunkul, Patrapim Sunpaweravong, Keith Eaton, Jihong Chen, Sonja Medley, Srinivasu Poondru, Margaret Singh, Joyce Steinberg, Rosalyn A. Juergens, Shirish M. Gadgeel

Research output: Contribution to journalArticle

Abstract

Introduction: First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non-small-cell lung cancer with . EGFR-activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes. Patients and Methods: We performed a randomized, double-blind, placebo-controlled phase II study of linsitinib, a dual IGF-1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with . EGFR-mutation positive, advanced non-small-cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival. Results: After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression-free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; . P = .29). Overall response rate (47.7% vs. 75.0%; . P = .02) and disease control rate (77.3% vs. 95.5%; . P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results. Conclusion: Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer.

Original languageEnglish (US)
JournalClinical Lung Cancer
DOIs
StateAccepted/In press - Apr 11 2016
Externally publishedYes

Keywords

  • Combination
  • Epidermal growth factor receptor inhibitor
  • First-line therapy
  • Insulin-like growth factor-1 inhibitor
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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    Leighl, N. B., Rizvi, N. A., de Lima, L. G., Arpornwirat, W., Rudin, C. M., Chiappori, A. A., Ahn, M. J., Chow, L. Q. M., Bazhenova, L., Dechaphunkul, A., Sunpaweravong, P., Eaton, K., Chen, J., Medley, S., Poondru, S., Singh, M., Steinberg, J., Juergens, R. A., & Gadgeel, S. M. (Accepted/In press). Phase 2 Study of Erlotinib in Combination With Linsitinib (OSI-906) or Placebo in Chemotherapy-Naive Patients With Non-Small-Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations. Clinical Lung Cancer. https://doi.org/10.1016/j.cllc.2016.07.007