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

• Published in: Clinical cancer research Vol. 23; no. 9; pp. 2186 - 2194
• Main Authors: Uppaluri, Ravindra, Winkler, Ashley E., Lin, Tianxiang, Law, Jonathan H., Haughey, Bruce H., Nussenbaum, Brian, Paniello, Randal C., Rich, Jason T., Diaz, Jason A., Michel, Loren P., Wildes, Tanya, Dunn, Gavin P., Zolkind, Paul, Kallogjeri, Dorina, Piccirillo, Jay F., Dehdashti, Farrokh, Siegel, Barry A., Chernock, Rebecca D., Lewis, James S., Adkins, Douglas R.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.05.2017
• Subjects: Activation; Adult; Aged; Biomarkers; Biomarkers, Tumor - genetics; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - surgery; CD44 antigen; Clinical trials; Complications; Computed tomography; Constipation; Drug-Related Side Effects and Adverse Reactions - pathology; Exanthema; Experimental design; Female; Fluorine; Gene Expression Regulation, Neoplastic - drug effects; Humans; Hyaluronan Receptors - genetics; Male; MAP Kinase Signaling System - drug effects; Metabolic pathways; Metabolic response; Metabolism; Middle Aged; Mouth - drug effects; Mouth - pathology; Mouth Neoplasms - drug therapy; Mouth Neoplasms - genetics; Mouth Neoplasms - pathology; Mouth Neoplasms - surgery; Nausea; Neoadjuvant Therapy; Neoplasm Staging; Oral cavity; Patients; Perforation; Positron emission; Positron emission tomography; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Pyridones - administration & dosage; Pyridones - adverse effects; Pyrimidinones - administration & dosage; Pyrimidinones - adverse effects; Radioisotopes; Reduction; Squamous cell carcinoma; Surgery; Wounds
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-1469

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.