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 patients with advanced-stage HNSCC 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 (10 mg, oral) for a maximum of 1 year. p16 IHC as a surrogate marker for human papillomavirus 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 ¼ 24) or everolimus (n ¼ 28). PFS favored everolimus, but was not significant [log-rank P ¼ 0.093; HR ¼ 0.44; 95% confidence interval (CI), 0.17–1.17]. There was no difference in OS (P ¼ 0.29; HR ¼ 0.57; 95% CI, 0.20–16.2). Everolimus resulted in significant improvement in PFS for p16-negative patients (n ¼ 31; P ¼ 0.031; HR ¼ 0.26; 95% CI, 0.07–0.97), although subgroup analysis showed no difference for p16-positive patients (n ¼ 21; P ¼ 0.93). Further, PFS was significantly higher in TP53-mutated (TP53mut) patients treated with everolimus compared with placebo (log-rank P ¼ 0.027; HR ¼ 0.24; 95% CI, 0.06–0.95). No treatment difference was seen in patients with TP53 wild-type tumors (P ¼ 0.79). Conclusions: p16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus.