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

Abstract

Purpose Ras/MEK/ERK pathway activation is common in oral cavity squamous cell carcinoma (OCSCC). We performed a neoadjuvant (pre-operative) trial to determine biomarker and tumor response of OCSCC to MEK inhibition with trametinib. Patients and Methods 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 immunohistochemistry 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/computed tomography), and in tumor downstaging. Drug-related adverse events (AEs) 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 post-trametinib 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 to 74%). Partial metabolic response (≥25% reduction in SUVmax) was observed in 6 of 13 (46%) evaluable patients (median 25% decrease, range 6 to 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 OCSCC patients.

Oral Cavity Squamous Cell Carcinoma Xenografts Retain Complex Genotypes and Intertumor Molecular Heterogeneity

“…In 2013, we initiated a PDX study for OCSCC across 114 patients from three cohorts: treatment-naive primary OCSCC patients undergoing standard-of-care primary resection (n = 84), patients enrolled in a neoadjuvant trametinib clinical trial ( ClinicalTrials.gov : NCT01553851; n = 20) ( Uppaluri et al, 2017 ), and patients enrolled in a neoadjuvant pembrolizumab clinical trial ( ClinicalTrials.gov : NCT02296684; n = 10, data not published). PDXs were attempted from treatment-naive tumor samples from all patients (n = 114), post-treatment surgical resections from patients enrolled in the trametinib clinical trial (n = 20) or the pembrolizumab clinical trial (n = 10), and patients with relapsed disease (n = 3).…”

Tumor-intrinsic signaling pathways: key roles in the regulation of the immunosuppressive tumor microenvironment

“…Moreover, Uppaluri et al [103] performed a clinical trial to determine the tumor response of oral cavity squamous cell carcinoma to treatment with the MEK inhibitor trametinib and found that trametinib caused a significant reduction of RAS/MEK/ERK signaling pathway activation and clinical tumor response.…”

Genomics and advances towards precision medicine for head and neck squamous cell carcinoma

“…However, convergence of these signals and activation of the MEK and ERK effectors of the MAPK pathway is prevalent and has been targeted in preclinical and early clinical studies. Biomarker and clinical responses to MEK inhibitor Trametinib were recently reported in HNSCC in a window of opportunity trial . MEK inhibitor PD‐0325901 has shown single‐agent activity and ability to overcome resistance and enhance antitumor effects in vivo with the dual PI3K/mTOR inhibitor PF‐384 .…”