Clinical application of the MEK inhibitor trametinib in dogs with oral squamous cell carcinoma

Background: Oral squamous cell carcinoma (OSCC) is a common and deadly disease in dogs. The current standard of care involves wide-margin surgical excision of tumor tissue, which is frequently disfiguring and can be debilitating, leading to a reduced quality of life. Recent studies have demonstrated that OSCC in dogs typically shows highly elevated RAS signaling compared to healthy gingival tissue. Here, we demonstrate that the FDA-approved drug trametinib, which is prescribed in humans for BRAF -mutant melanomas, is effective in treating OSCC in dogs. Methods: Domestic companion dogs (N = 20) with spontaneously occurring OSCC tumors were recruited over a two-year period for an interventional study without concurrent controls. Dogs were prescribed 0.015 to 0.035 mg/kg trametinib daily to be given orally, and owners monitored their dog’s health at home. Treatment was continued for 8 weeks, with examinations every 2 weeks. Tumor volume was assessed by caliper measurement and by computed tomography (CT) imaging. Results: Five dogs achieved a partial response (PR), and one dog had a complete response (CR) based on CT imaging at the end of 8 weeks of treatment, however cancer cells were detected by histological examination. Four dogs had stable disease (SD), and ten dogs were removed from the trial after demonstrating progressive disease (PD). Response categorization was based on R.E.C.I.S.T. criteria, and PD was typically detected by caliper measurements within 2-4 weeks of beginning treatment. The overall response rate was 50% (30% CR/PR, 20% SD). Adverse events were rare, low grade, and resolved with outpatient supportive care. Conclusions: Trametinib effectively blocks the growth of canine OSCC in ~50% of dogs and is well tolerated with minimal side effects. Approximately one-third of the dogs treated showed at least partial tumor volume decrease. Considering all of our findings together, we determine that trametinib is a plausible neoadjuvant step for OSCC which shows clinical benefit for approximately half of dogs prior to surgical intervention. Overall, this work presents an effective, safe, and available targeted therapeutic approach for the treatment of OSCC tumors in dogs.