TY - JOUR
T1 - 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
AU - Leighl, Natasha B.
AU - Rizvi, Naiyer A.
AU - de Lima, Lopes Gilberto
AU - Arpornwirat, Wichit
AU - Rudin, Charles M.
AU - Chiappori, Alberto A.
AU - Ahn, Myung Ju
AU - Chow, Laura Q M
AU - Bazhenova, Lyudmila
AU - Dechaphunkul, Arunee
AU - Sunpaweravong, Patrapim
AU - Eaton, Keith
AU - Chen, Jihong
AU - Medley, Sonja
AU - Poondru, Srinivasu
AU - Singh, Margaret
AU - Steinberg, Joyce
AU - Juergens, Rosalyn A.
AU - Gadgeel, Shirish M.
PY - 2016/4/11
Y1 - 2016/4/11
N2 - 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.
AB - 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.
KW - Combination
KW - Epidermal growth factor receptor inhibitor
KW - First-line therapy
KW - Insulin-like growth factor-1 inhibitor
KW - Tyrosine kinase inhibitor
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U2 - 10.1016/j.cllc.2016.07.007
DO - 10.1016/j.cllc.2016.07.007
M3 - Article
C2 - 27686971
AN - SCOPUS:84996549428
SN - 1525-7304
JO - Clinical Lung Cancer
JF - Clinical Lung Cancer
ER -