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

详细信息    查看全文

• 作者：Natasha B. Leighl¹ ; Naiyer A. Rizvi² ; Lopes Gilberto de Lima Jr.³ ; ⁴ ; Wichit Arpornwirat⁵ ; Charles M. Rudin⁶ ; Alberto A. Chiappori⁷ ; Myung-Ju Ahn⁸ ; Laura Q.M. Chow⁹ ; Lyudmila Bazhenova¹⁰ ; Arunee Dechaphunkul¹¹ ; Patrapim Sunpaweravong¹² ; Keith Eaton¹³ ; ¹⁴ ; Jihong Chen¹⁵ ; Sonja Medley¹⁵ ; Srinivasu Poondru¹⁵ ; Margaret Singh¹⁵ ; Joyce Steinberg¹⁵ ; Rosalyn A. Juergens¹⁶ ; ^{juergensr@hhsc.ca} ; Shirish M. Gadgeel¹⁷ ; ¹⁸
• 关键词：Combination ; Epidermal growth factor receptor inhibitor ; First-line therapy ; Insulin-like growth factor-1 inhibitor ; Tyrosine kinase inhibitor
• 刊名：Clinical Lung Cancer
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：18
• 期：1
• 页码：34-42.e2
• 全文大小：448 K
• 卷排序：18

文摘

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 MethodsWe 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.ResultsAfter 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.ConclusionAdding 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.