A Randomized Multi-Institutional Phase II Trial of Everolimus as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck

Abstract Purpose: Investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced stage head and neck squamous cell carcinoma (HNSCC) and provide outcomes related to correlative biological factors associated with disease control. Patients and Methods: This was a prospective, randomized, double-blind phase II trial of advanced stage HNSCC patients from 13 institutions who were confirmed disease-free post-definitive therapy and enrolled between December 2010 and March 2015. Patients received adjuvant everolimus or placebo daily (10mg, oral) for a maximum of 1 year. p16 IHC as a surrogate marker for HPV infection and whole exome sequencing were performed. Cox proportional hazard models estimated hazard rates. Log-rank tests evaluated differences in survival. The primary endpoint was PFS. Secondary endpoints and objectives included overall survival (OS) and toxicity assessment. Results: 52 patients (median [range] age, 58, [37-76] years; 43 men [83%], 9 women [17%]) were randomized to placebo (n=24) or everolimus (n=28). PFS favored everolimus, but was not significant (log-rank P=0.093; HR=0.44, 95% CI: 0.17-1.17). There was no difference in OS (P=0.29; HR=0.57, 95% CI: 0.20-16.2). Everolimus resulted in significant improvement in PFS for p16-negative patients (n=31) (P=0.031; HR=0.26, 95% CI: 0.07-0.97), although subgroup analysis showed no difference for p16-positive patients (n=21) (P=0.93). Further, PFS was significantly higher in TP53 mutated (TP53mut) patients treated with everolimus compared to placebo (Log-Rank P=0.027; HR=0.24, 95% CI: 0.06-0.95). No treatment difference was seen in patients with TP53 wild-type (TP53wt) tumors (p=0.79). Conclusions: p16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus.