A phase I/II study of erlotinib in combination with the anti-insulin-like growth factor-1 receptor monoclonal antibody IMC-A12 (cixutumumab) in patients with advanced non-small cell lung cancer

Andrew Weickhardt, Robert Doebele, Ana Oton, Janice Lettieri, Delee Maxson, Michele Reynolds, Amy Brown, Mary K. Jackson, Grace Dy, Araba Adjei, Gerald Fetterly, Xian Lu, Wilbur Franklin, Marileila Varella-Garcia, Fred R. Hirsch, Murry W. Wynes, Hagop Youssoufian, Alex Adjei, D. Ross Camidge

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44 Scopus citations

Abstract

Introduction: This phase I/II study evaluated the safety and antitumor effect of the combination of erlotinib with cixutumumab, a recombinant fully humanized anti-insulin-like growth factor-1 receptor IgG1 monoclonal antibody, in advanced non-small cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC were treated in an initial safety-lead and drop-down cohorts using erlotinib 150 mg/d with cixutumumab 6 or 5 mg/kg on days 1, 8, 15, and 22 in 28-day cycles (cohorts 1 and 2). Emerging pharmacokinetic data led to an additional cohort (3 + 3 design) with cixutumumab at 15 mg/kg on day 1 in 21-day cycles (cohort 3). Results: Eighteen patients entered the study (6 at 6 mg/kg, 8 at 5 mg/kg, and 4 at 15 mg/kg), with median age of 65 years. Four of six patients at 6 mg/kg experienced dose-limiting toxicities (DLTs), whereas at 5 mg/kg, one of eight patients experienced DLT but three of eight patients still required a dose delay during cycle 1. At 15 mg/kg every 21 days, two of four patients experienced DLTs. In all cohorts, DLTs were either G3 rash or fatigue. Five patients had stable disease as best response and 14 patients had progressive disease. The median progression-free survival was 39 days (range 21-432+ days). Biomarkers analyses showed a trend toward better progression-free survival seen with higher free baseline insulin-like growth factor-1 levels as seen with other insulin-like growth factor-1R inhibitors. Conclusions: The combinations of cixutumumab at 6 mg/kg every 7 days and 15 mg/kg every 21 days and full-dose erlotinib are not tolerable in unselected patients with NSCLC, as measured by DLT. Cixutumumab at 5 mg/kg every 7 days was tolerable per DLT, but dose delays were common. Efficacy in unselected patients with NSCLC seems to be low.

Original languageEnglish (US)
Pages (from-to)419-426
Number of pages8
JournalJournal of Thoracic Oncology
Volume7
Issue number2
DOIs
StatePublished - Feb 2012

Keywords

  • EGFR
  • IGF1R monoclonal antibody
  • Metastatic disease
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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    Weickhardt, A., Doebele, R., Oton, A., Lettieri, J., Maxson, D., Reynolds, M., Brown, A., Jackson, M. K., Dy, G., Adjei, A., Fetterly, G., Lu, X., Franklin, W., Varella-Garcia, M., Hirsch, F. R., Wynes, M. W., Youssoufian, H., Adjei, A., & Camidge, D. R. (2012). A phase I/II study of erlotinib in combination with the anti-insulin-like growth factor-1 receptor monoclonal antibody IMC-A12 (cixutumumab) in patients with advanced non-small cell lung cancer. Journal of Thoracic Oncology, 7(2), 419-426. https://doi.org/10.1097/JTO.0b013e31823c5b11