Natasha B Leighl1, Naiyer A Rizvi2, Lopes Gilberto de Lima3, Wichit Arpornwirat4, Charles M Rudin5, Alberto A Chiappori6, Myung-Ju Ahn7, Laura Q M Chow8, Lyudmila Bazhenova9, Arunee Dechaphunkul10, Patrapim Sunpaweravong11, Keith Eaton12, Jihong Chen13, Sonja Medley13, Srinivasu Poondru13, Margaret Singh13, Joyce Steinberg13, Rosalyn A Juergens14, Shirish M Gadgeel15. 1. Cancer Clinical Research Unit, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. 2. Department of Hematology and Oncology, Columbia University Medical Center, New York, NY. 3. Oncoclinicas Group, Hcor Onco, Sao Paulo, SP, Brazil; Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD. 4. National Cancer Research, Bangkok, Thailand. 5. Memorial Sloan Kettering Cancer Center, New York, NY. 6. Moffitt Cancer Center, Tampa, FL. 7. Department of Hematology and Oncology, Sungkyunkwan University, Seoul, South Korea. 8. University of Washington, Seattle, WA. 9. Department of Clinical Oncology, School of Medicine, UC San Diego Moores Cancer Center, San Diego, CA. 10. Departments of Pathology, Hematology, and Surgery, Prince of Songkla University, Songkhla, Thailand. 11. Department of Internal Medicine, Prince of Songkla University, Songkhla, Thailand. 12. Prince of Songkla University, Songkhla, Thailand; Medical Oncology at University of Washington School of Medicine, Seattle Cancer Care Alliance, Seattle, WA. 13. Astellas, Northbrook, IL. 14. Juravinski Cancer Centre, Department of Oncology, McMaster University, Hamilton, ON, Canada. Electronic address: juergensr@hhsc.ca. 15. Karmanos Cancer Institute, Wayne State University, Detroit, MI; Hematology-Oncology, Wayne State University, Detroit, MI.
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.
RCT Entities:
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.
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