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

Clin Cancer Res. 2022 Dec 1;28(23):5040-5048. doi: 10.1158/1078-0432.CCR-21-4290.


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 = 24) or everolimus (n = 28). PFS favored everolimus, but was not significant [log-rank P = 0.093; HR = 0.44; 95% confidence interval (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 with 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 tumors (P = 0.79).

Conclusions: p16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus.

Trial registration: ClinicalTrials.gov NCT01111058.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinoma, Squamous Cell* / drug therapy
  • Carcinoma, Squamous Cell* / genetics
  • Epithelial Cells / pathology
  • Everolimus / adverse effects
  • Female
  • Head and Neck Neoplasms* / drug therapy
  • Head and Neck Neoplasms* / genetics
  • Humans
  • Male
  • Middle Aged
  • Prospective Studies
  • Squamous Cell Carcinoma of Head and Neck / drug therapy
  • Squamous Cell Carcinoma of Head and Neck / genetics


  • Everolimus

Associated data

  • ClinicalTrials.gov/NCT01111058