• Francesco Sclafani, Tae Y Kim, David Cunningham, Tae W Kim, Josep Tabernero, Hans J Schmoll, Jae K Roh, Sun Y Kim, Young S Park, Tormod K Guren, Eliza Hawkes, Steven J Clarke, David Ferry, Jan-Erik Frödin, Mark Ayers, Michael Nebozhyn, Clare Peckitt, Andrey Loboda, David J Mauro, and David J Watkins.
• The Royal Marsden NHS Foundation Trust, London and Surrey, UK (FS, DC, EH, CP, DJW); Seoul National University College of Medicine, Seoul, Korea (TYK); Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (TWK); Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain (JT); University Clinic Halle (Saale), Martin Luther University Halle-Wittenberg, Halle, Germany (HJS); Yonsey Cancer Center, Yonsey University, College of Medicine, Seoul, Korea (JKR); Center for Colorectal Cancer, National Cancer Center, Seoul, Korea (SYK); Samsung Medical Center, Seoul, Korea (YSP); Oslo University Hospital, Oslo, Norway (TKG); Concord Repatriation General Hospital, Concord, Sydney, Australia (SJC); New Cross Hospital, Wolverhamptom, UK (DF); Karolinska University Hospital, Stockholm, Sweden (JEF); Merck & Co., Inc., Whitehouse Station, NJ (MA, MN, AL, DJM).
• J. Natl. Cancer Inst. 2015 Dec 1; 107 (12): djv258.

BackgroundInsulin-like growth factor type 1 receptor (IGF-1R) mediates resistance to epidermal growth factor receptor (EGFR) inhibition and may represent a therapeutic target. We conducted a multicenter, randomized, double blind, phase II/III trial of dalotuzumab, an anti-IGF-1R monoclonal antibody, with standard therapy in chemo-refractory, KRAS wild-type metastatic colorectal cancer.MethodsEligible patients were randomly assigned to dalotuzumab 10mg/kg weekly (arm A), dalotuzumab 7.5mg/kg every alternate week (arm B), or placebo (arm C) in combination with cetuximab and irinotecan. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included exploratory biomarker analyses. All statistical tests were two-sided.ResultsThe trial was prematurely discontinued for futility after 344 eligible KRAS wild-type patients were included in the primary efficacy population (arm A = 116, arm B = 117, arm C = 111). Median PFS was 3.9 months in arm A (hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 0.98 to 1.83, P = .07) and 5.4 months in arm B (HR = 1.13, 95% CI = 0.83 to 1.55, P = .44) compared with 5.6 months in arm C. Median OS was 10.8 months in arm A (HR = 1.41, 95% CI = 0.99 to 2.00, P = .06) and 11.6 months in arm B (HR = 1.26, 95% CI = 0.89 to 1.79, P = .18) compared with 14.0 months in arm C. Grade 3 or higher asthenia and hyperglycaemia occurred more frequently with dalotuzumab compared with placebo. In exploratory biomarker analyses, patients with high IGF-1 mRNA tumors in arm A had numerically better PFS (5.6 vs 3.6 months, HR = 0.59, 95% CI = 0.28 to 1.23, P = .16) and OS (17.9 vs 9.4 months, HR = 0.67, 95% CI = 0.31 to 1.45, P = .31) compared with those with high IGF-1 mRNA tumors in arm C. In contrast, in arm C high IGF-1 mRNA expression predicted lower response rate (17.6% vs 37.3%, P = .04), shorter PFS (3.6 vs 6.6 months, HR = 2.15, 95% CI = 1.15 to 4.02, P = .02), and shorter OS (9.4 vs 15.5 months, HR = 2.42, 95% CI = 1.21 to 4.82, P = .01).ConclusionsAdding dalotuzumab to irinotecan and cetuximab was feasible but did not improve survival outcome. IGF-1R ligands are promising biomarkers for differential response to anti-EGFR and anti-IGF-1R therapies.© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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