In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 6051-6051
Abstract:
6051 Background: The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways are upregulated in HNSCC. Crosstalk potentiates growth, proliferation and invasion. Preclinical models show synergistic anti-tumor effects from dual blockade. We evaluated biomarker modulation in paired tumor specimens from a 3-arm phase 0 trial of erlotinib, a small molecule EGFR inhibitor; erlotinib + sulindac, a non-selective COX inhibitor; vs. placebo. Methods: Patients (pts) with untreated stage II-IVb HNSCC were randomized 5:5:3 to neoadjuvant erlotinib 150 mg daily (Arm 1, n = 19), erlotinib + sulindac 150 mg twice daily (Arm 2, n = 16), or placebo (n = 12). Pts were treated for 7-14 days. Tumor specimens were collected pre- and post-treatment. The primary endpoint was change in Ki-67 proliferative index. We hypothesized an ordering in Ki-67 down-modulation, with Arm 2 〉 Arm 1 〉 placebo. A Jonckheere-Terpstra test evaluated trend; a Wilcoxon test was applied to pairwise contrasts. We prepared tissue microarrays for IHC, to explore pharmacodynamic modulation of 21 EGFR and COX-2 pathway constituents including EGFR, Src, STAT3, Akt, EP2 and EP4. Results: From Dec 2005 – Dec 2008, 48 pts enrolled; 28 tumor pairs were evaluable for biomarker modulation. Class toxicities of EGFR inhibition, including acneiform rash and diarrhea, were observed on Arms 1 and 2. Compared to placebo, Ki-67 was reduced by erlotinib (p = 0.0005) or by erlotinib-sulindac (p = 0.0001). There was a trend in ordering of Ki-67 down-modulation, with greater effect from the addition of sulindac (exact Jonckeheere-Terpstra, Arm 1 vs. 2, p = 0.003). Among 21 protein candidates tested for association with Ki-67, only low baseline p-Src correlated with greater Ki-67 reduction in both erlotinib groups (R 2 = 0.312, p = 0.024). Conclusions: Relative to placebo, brief neoadjuvant treatment with erlotinib or erlotinib-sulindac significantly decreased the proliferative index in operable HNSCC. Sulindac enhanced Ki-67 down-modulation. Efficacy studies of dual EGFR-COX inhibition are justified. Baseline p-Src warrants further study as a resistance biomarker for anti-EGFR therapy. Clinical trial information: NCT01515137.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2013.31.15_suppl.6051
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2013
detail.hit.zdb_id:
2005181-5
Permalink