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, 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
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 (R(2) = 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.
Trial registration: ClinicalTrials.gov NCT00779389 NCT01488318.
Conflict of interest statement
Authors declare no conflict of interest for the submitted work.
©2014 American Association for Cancer Research.
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Source: PubMed