Biomarker and Tumor Responses of Oral Cavity Squamous Cell Carcinoma to 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). 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.
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri. Ravindra_Uppaluri@DFCI.Harvard.edu.|Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
Ravindra
R
Uppaluri
Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
Ashley E
AE
Winkler
Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
Tianxiang
T
Lin
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
Jonathan H
JH
Law
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
Bruce H
BH
Haughey
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
Brian
B
Nussenbaum
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
Randal C
RC
Paniello
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
Jason T
JT
Rich
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
Jason A
JA
Diaz
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Division of Medical Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri.
Loren P
LP
Michel
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Division of Medical Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri.
Tanya
T
Wildes
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.
Gavin P
GP
Dunn
Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
Paul
P
Zolkind
Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
Dorina
D
Kallogjeri
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri.
Jay F
JF
Piccirillo
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Division of Nuclear Medicine, Mallinckrodt Institute of Radiology, St. Louis, Missouri.
Farrokh
F
Dehdashti
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Division of Nuclear Medicine, Mallinckrodt Institute of Radiology, St. Louis, Missouri.
Barry A
BA
Siegel
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
Rebecca D
RD
Chernock
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
James S
JS
Lewis
Alvin J. Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.|Division of Medical Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri.
Douglas R
DR
Adkins
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009055:Mouth / Q000187:drug effects / Q000473:pathology; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000009:adverse effects
D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib