Inhibition of mTOR Signaling and Clinical Activity of Rapamycin in Head and Neck Cancer in a Window of Opportunity Trial

Purpose: We studied the impact of mTOR signaling inhibition with rapamycin in head and neck squamous cell carcinoma (HNSCC) in the neoadjuvant setting. The goals were to evaluate the mTOR pathway as a therapeutic target for advanced HNSCC patients, and the clinical safety, anti-tumor, and molecular activity of rapamycin administration on HNSCC. Experimental Design: Patients with untreated stage II-IVA HNSCC received rapamycin for 21 days (day 1, 15mg; days 2-12, 5mg) prior to definitive treatment with surgery or chemoradiation. Treatment responses were assessed clinically and radiographically with CT and FDG-PET. Pre- and post-treatment biopsies and blood were obtained for toxicity, immune monitoring and immunohistochemical assessment of mTOR signaling, as well as exome sequencing. Results: Sixteen patients (8 oral cavity, 8 oropharyngeal) completed rapamycin and definitive treatment. Half of patients were p16 positive. One patient had a pathological complete response and 4 (25%) patients met RECIST criteria for response (1 CR, 3 PR, 12 SD). Treatment was well tolerated with no grade 4 or unexpected toxicities. No significant immune suppression was observed. Downstream mTOR signaling was downregulated in tumor tissues as measured by phosphorylation of S6 (p<0.0001), AKT (p<0.0001), and 4EBP (p=0.0361), with a significant compensatory increase in phosphorylated ERK in most patients (p<0.001). Ki67 was reduced in tumor biopsies in all patients (p=0.013). Conclusions: Rapamycin treatment was well tolerated, reduced mTOR signaling and tumor growth, and resulted in significant clinical responses despite the brief treatment duration, thus supporting the potential role of mTOR inhibitors in treatment regimens for HNSCC.

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