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

Abstract

This was a phase II study of linsitinib plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with epidermal growth factor receptor-mutation positive, advanced, non—small-cell lung cancer. Linsitinib plus erlotinib resulted in inferior outcomes compared with erlotinib alone. Linsitinib combination was associated with increased adverse events that led to decreased erlotinib exposure. Results highlight the complexity of targeting insulin-like growth factor-1 receptor signaling. 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.

Phase 2 study evaluating intermittent and continuous linsitinib and weekly paclitaxel in patients with recurrent platinum resistant ovarian epithelial cancer

“…In a phase 3 study, linsitinib, administered as a single agent, did not improve progression-free or overall survival compared with placebo in patients with locally advanced or metastatic adrenocortical carcinoma [22]. Linsitinib, however, has demonstrated antitumor activity in combination with erlotinib in solid tumors [23], including nonsmall cell lung cancer [24].…”

Measurement and models accounting for cell death capture hidden variation in compound response

“…IGF-1R inhibitors have been validated for their efficacy in various cancer types as mono-and combined therapies in preclinical studies [28][29][30] . Despite promising preclinical evidence, only limited responses were observed in clinical trials [31][32][33][34] . From our drug combination experiments with the IGF-1R inhibitor OSI-906, we discovered that the analysis by cell viability alone found a strong synergistic interaction, while our analysis accounting cell growth and death identified an additive response.…”

Erlotinib-based doublet targeted therapy versus erlotinib alone in previously treated advanced non-small-cell lung cancer: a meta-analysis from 24 randomized controlled trials

“…Another investigating erlotinib plus Linsitinib (an IGF-1R inhibitor) or placebo in chemotherapy-naive patients. [ 41 ] Considering the limited number of relevant studies in first-line setting, our meta-analysis which seems lagging in the contemporary management of NSCLC is actually of great referential value in assessing efficacy of erlotinib versus doublets in first-line therapy. Future clinical studies should be designed based on the actual data in our meta-analysis.…”