A randomized phase II/III study of dalotuzumab in combination with cetuximab and irinotecan in chemorefractory, KRAS wild-type, metastatic colorectal cancer

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, David J. Watkins

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    Background: Insulin-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. Methods: Eligible patients were randomly assigned to dalotuzumab 10 mg/kg weekly (arm A), dalotuzumab 7.5 mg/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. Results: The 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). Conclusions: Adding 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.

    Original languageEnglish (US)
    Article numberdjv258
    JournalJournal of the National Cancer Institute
    Issue number12
    StatePublished - Dec 2015


    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Sclafani, F., Kim, T. Y., Cunningham, D., Kim, T. W., Tabernero, J., Schmoll, H. J., Roh, J. K., Kim, S. Y., Park, Y. S., Guren, T. K., Hawkes, E., Clarke, S. J., Ferry, D., Frödin, J. E., Ayers, M., Nebozhyn, M., Peckitt, C., Loboda, A., Mauro, D. J., & Watkins, D. J. (2015). A randomized phase II/III study of dalotuzumab in combination with cetuximab and irinotecan in chemorefractory, KRAS wild-type, metastatic colorectal cancer. Journal of the National Cancer Institute, 107(12), [djv258]. https://doi.org/10.1093/jnci/djv258