Abstract Introduction First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of advanced non–small-cell lung cancer (NSCLC) 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 2 study of linsitinib, a dual IGF-1R and insulin receptor TKI, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR -mutation positive, advanced NSCLC. 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 (PFS). Results After randomization of 88 patients (44 each arm), the trial was unblinded early due to inferiority in the linsitinib arm. Median PFS for linsitinib versus placebo group was 8.4 versus 12.4 months (HR 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. While most adverse events (AEs) were ≤ grade 2, linsitinib plus erlotinib was associated with increased AEs 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.