Biomarker and tumor responses of oral cavity squamous cell carcinoma to trametinib: A phase II neoadjuvant window-of-opportunity clinical trial

Ravindra Uppaluri, Ashley E. Winkler, Tianxiang Lin, Jonathan H. Law, Bruce H. Haughey, Brian Nussenbaum, Randal C. Paniello, Jason T. Rich, Jason A. Diaz, Loren P. Michel, Tanya Wildes, Gavin P. Dunn, Paul Zolkind, Dorina Kallogjeri, Jay F. Piccirillo, Farrokh Dehdashti, Barry A. Siegel, Rebecca D. Chernock, James S. Lewis, Douglas R. Adkins

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 trametinibrelated (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.

Original languageEnglish
Pages (from-to)2186-2194
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number9
DOIs
StatePublished - May 1 2017

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