Ebiomarker And Clinical Response Of Oral Cavity Squamous Cell Carcinoma To The Mek 1/2 Inhibitor Trametinib: A Phase Ii Neoadjuvant Window Of Opportunity Clinical Trial

Purpose: Ras/MEK/ERK pathway activation is common in oral cavity squamous cell carcinoma (OCSCC). To determine biomarker and clinical tumor response of MEK inhibition in patients with OCSCC, we performed a neoadjuvant window of opportunity trial in which the MEK inhibitor trametinib was administered before surgery (NCT01553851). Patients and Methods: Patients with untreated Stage II-IV OCSCC were scheduled to receive trametinib 2 mg/day orally for 7-14 days prior to surgery (last dose 24 hours before surgery). Tumor specimens from the primary site obtained before and after trametinib underwent immunohistochemistry staining for p-ERK1/2 (a marker of Ras/MEK/ERK activation) and CD44 (a protein upregulated by ERK activation), which represented the primary endpoint. Secondary endpoints included comparison of changes in pre- and post-trametinib tumor measurement by clinical examination and in metabolic activity (SUVmax) by FDG-PET/CT (partial response: u003e25% reduction). Adverse events (AE) and surgical/wound complications were evaluated. Results: Of the 20 enrolled patients, 17 (85%) completed the study as planned. Three patients withdrew from the study due to AE, two (nausea; duodenal perforation) related to trametinib and one (constipation) related to narcotics. The most common drug-related AE was mild rash (9/20 patients, 45%). Nineteen patients (95%) underwent surgery and neck dissection with no unexpected surgical/wound complications. Fifteen patients (75%) were evaluable for the primary biomarker endpoint. 5 (25%) patients either had insufficient pre- or post-treatment biopsies or did not complete the trial. Reduction in p-ERK1/2 expression occurred in 7/15 evaluable patients (47%), whereas a reduction in CD44 occurred in 3/15 (20%). Reduction in tumor size (median 40%, range -74 to +17%) assessed by clinical examination was observed in 12/17 (71%) evaluable patients, and partial metabolic tumor response assessed by FDG-PET/CT was observed in 5/13 (38%) patients. Conclusions: Trametinib was safe to administer as a neoadjuvant treatment in patients with OCSCC and several patients displayed significant reduction in Ras/MEK/ERK pathway activation, and in clinical and metabolic tumor responses. Further exploration of trametinib response in OCSCC patients is warranted. Citation Format: Ravindra Uppaluri, Ashley Winkler, Tianxiang Lin, Jonathan Law, Bruce Haughey, Brian Nussenbaum, Randal Paniello, Jason Rich, Jason Diaz, Loren Michel, Tanya Wildes, Gavin Dunn, Dorina Kallogjeri, Paul Zolkind, Farrokh Dehdashti, Barry Siegel, Rebecca Chernock, James S. Lewis, Jay Piccirillo, Douglas Adkins. Biomarker and clinical response of oral cavity squamous cell carcinoma to the MEK 1/2 inhibitor trametinib: A phase II neoadjuvant window of opportunity clinical trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT070.