Erlotinib, erlotinib-sulindac versus placebo: A randomized, double-blind, placebo-controlled window trial in operable head and neck cancer

Neil D. Gross, Julie E. Bauman, William E. Gooding, William Denq, Sufi M. Thomas, Lin Wang, Simion Chiosea, Brian L. Hood, Melanie S. Flint, Mai Sun, Thomas P. Conrads, Robert L. Ferris, Jonas T. Johnson, Seungwon Kim, Athanassios Argiris, Lori Wirth, Marina N. Nikiforova, Jill M. Siegfried, Jennifer R. Grandis

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30 Scopus citations

Abstract

Purpose: The EGF receptor (EGFR) and COX2 pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic antitumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a nonselective COX inhibitor; versus placebo. Experimental Design: Patients with untreated, operable stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after seven to 14 days of treatment. The primary endpoint was change in Ki67 proliferation index. We hypothesized an ordering effect in Ki67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX2 signaling intermediates. Results: From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, P = 0.04). Wilcoxon pairwise contrasts confirmed greater Ki67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo, P = 0.043; erlotinib vs. placebo, P = 0.027). There was a significant trend in ordering of Ki67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, P = 0.0185). Low baseline pSrc correlated with greater Ki67 reduction (R2 = 0.312, P = 0.024). Conclusions: Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target.

Original languageEnglish (US)
Pages (from-to)3289-3298
Number of pages10
JournalClinical Cancer Research
Volume20
Issue number12
DOIs
StatePublished - Jun 15 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Gross, N. D., Bauman, J. E., Gooding, W. E., Denq, W., Thomas, S. M., Wang, L., Chiosea, S., Hood, B. L., Flint, M. S., Sun, M., Conrads, T. P., Ferris, R. L., Johnson, J. T., Kim, S., Argiris, A., Wirth, L., Nikiforova, M. N., Siegfried, J. M., & Grandis, J. R. (2014). Erlotinib, erlotinib-sulindac versus placebo: A randomized, double-blind, placebo-controlled window trial in operable head and neck cancer. Clinical Cancer Research, 20(12), 3289-3298. https://doi.org/10.1158/1078-0432.CCR-13-3360