Phase II efficacy and pharmacogenomic study of selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements

D. Neil Hayes, Amy S. Lucas, Tawee Tanvetyanon, Monika K. Krzyzanowska, Christine H. Chung, Barbara A. Murphy, Jill Gilbert, Ranee Mehra, Dominic T. Moore, Arif Sheikh, Janelle Hoskins, Michele C. Hayward, Ni Zhao, Wendi O'Connor, Karen E. Weck, Roger B. Cohen, Ezra E.W. Cohen

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Abstract

Purpose: A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC). Experimental Design: Patients with advanced IRPTC with or without follicular elements and documented disease progression within the preceding 12 months were eligible to receive selumetinib at a dose of 100 mg twice daily. The primary endpoint was objective response rate using Response Evaluation Criteria in Solid Tumors. Secondary endpoints were safety, overall survival, and progression-free survival (PFS). Tumor genotype including mutations in BRAF, NRAS, and HRAS was assessed. Results: Best responses in 32 evaluable patients out of 39 enrolled were 1 partial response (3%), 21 stable disease (54%), and 11 progressive disease (28%). Disease stability maintenance occurred for 16 weeks in 49%, 24 weeks in 36%. Median PFS was 32 weeks. BRAF V600E mutants (12 of 26 evaluated, 46%) had a longer median PFS compared with patients with BRAF wild-type (WT) tumors (33 versus 11 weeks, respectively, HR = 0.6, not significant, P = 0.3). The mostcommonadverse events and grades 3 to 4 toxicities included rash, fatigue, diarrhea, and peripheral edema. Two pulmonary deaths occurred in the study and were judged unlikely to be related to the study drug. Conclusions: Selumetinib was well tolerated but the study was negative with regard to the primary outcome. Secondary analyses suggest that future studies of selumetinib and other mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) inhibitors in IRPTC should consider BRAF V600E mutation status in the trial design based on differential trends in outcome.

Original languageEnglish (US)
Pages (from-to)2056-2065
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number7
DOIs
StatePublished - Apr 1 2012

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hayes, D. N., Lucas, A. S., Tanvetyanon, T., Krzyzanowska, M. K., Chung, C. H., Murphy, B. A., Gilbert, J., Mehra, R., Moore, D. T., Sheikh, A., Hoskins, J., Hayward, M. C., Zhao, N., O'Connor, W., Weck, K. E., Cohen, R. B., & Cohen, E. E. W. (2012). Phase II efficacy and pharmacogenomic study of selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clinical Cancer Research, 18(7), 2056-2065. https://doi.org/10.1158/1078-0432.CCR-11-0563