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Clin Cancer Res. 2017 May 1;23(9):2186-2194. doi: 10.1158/1078-0432.CCR-16-1469. Epub 2016 Nov 9.

Biomarker and Tumor Responses of Oral Cavity Squamous Cell Carcinoma to Trametinib: A Phase II Neoadjuvant Window-of-Opportunity Clinical Trial.

Author information

1
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri. Ravindra_Uppaluri@DFCI.Harvard.edu.
2
Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
3
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.
4
Division of Medical Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri.
5
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.
6
Division of Nuclear Medicine, Mallinckrodt Institute of Radiology, St. Louis, Missouri.
7
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
8
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.

Abstract

Purpose: Ras/MEK/ERK pathway activation is common in oral cavity squamous cell carcinoma (OCSCC). We performed a neoadjuvant (preoperative) trial to determine the biomarker and tumor response of OCSCC to MEK inhibition with trametinib.Experimental Design: Patients with stage II-IV OCSCC received trametinib (2 mg/day, minimum 7 days) prior to surgery. Primary tumor specimens were obtained before and after trametinib to evaluate immunohistochemical staining for p-ERK1/2 and CD44, the primary endpoint. Secondary endpoints included changes in clinical tumor measurements and metabolic activity [maximum standardized uptake values (SUVmax) by F-18 fluorodeoxyglucose positron emission tomography/CT), and in tumor downstaging. Drug-related adverse events (AE) and surgical/wound complications were evaluated.Results: Of 20 enrolled patients, 17 (85%) completed the study. Three patients withdrew because of either trametinib-related (n = 2: nausea, duodenal perforation) or unrelated (n = 1: constipation) AEs. The most common AE was rash (9/20 patients, 45%). Seventeen patients underwent surgery. No unexpected surgical/wound complications occurred. Evaluable matched pre- and posttrametinib specimens were available in 15 (88%) of these patients. Reduction in p-ERK1/2 and CD44 expression occurred in 5 (33%) and 2 (13%) patients, respectively. Clinical tumor response by modified World Health Organization criteria was observed in 11 of 17 (65%) evaluable patients (median 46% decrease, range 14%-74%). Partial metabolic response (≥25% reduction in SUVmax) was observed in 6 of 13 (46%) evaluable patients (median 25% decrease, range 6%-52%). Clinical-to-pathologic tumor downstaging occurred in 9 of 17 (53%) evaluable patients.Conclusions: Trametinib resulted in significant reduction in Ras/MEK/ERK pathway activation and in clinical and metabolic tumor responses in patients with OCSCC. Clin Cancer Res; 23(9); 2186-94. ©2016 AACR.

PMID:
28151720
PMCID:
PMC5509449
DOI:
10.1158/1078-0432.CCR-16-1469
[Indexed for MEDLINE]
Free PMC Article

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