Adjuvant Everolimus Improves Survival in Locally Advanced HNSCC

In an interview with Oncology Learning Network, Cherie-Ann O. Nathan, MD, Jack W. Pou Endowed Professor and Chair of Otolaryngology/Head and Neck Surgery at Louisiana State University Health Sciences Center, Shreveport, discussed the findings and clinical significance of a phase 2 study comparing everolimus with placebo as adjuvant therapy for the treatment of patients with locally advanced head and neck squamous cell cancer (HNSCC; Int J Radiat Oncol Biol Phys. 2020;106[5]:1116).

Dr Nathan is also the Director of Head and Neck Surgery at Feist-Weiller Cancer Center; current President of the American Head and Neck Society; and was Chair Elect for the Multidisciplinary Head and Neck Meeting in Scottsdale, Arizona.

Why did you and your co-investigators conduct this research?

The dismal 5-year survival rate for advanced stage smoking related HNSCC of <30% has not changed in the past 30 years, hence the need for adjuvant therapy. The AKT/mTOR pathway is activated in most HNSCCs and pathway activation in surrounding normal mucosa is associated with recurrences.

Oral mTOR inhibitors appear well tolerated and effective in window of opportunity HNSCC trials. We hope that head and neck cancer can be treated as a chronic disease, similar to some breast cancers.

Please briefly describe your study and its findings.

The purpose of this trial (NCT01111058) was to determine whether adjuvant everolimus improves 2-year progression-free survival (PFS) in patients with advanced HNSCC and investigate correlative biological factors associated with response.

After confirming patients were disease free with definitive curative-intent therapy, patients received either everolimus (10-mg orally) or placebo for a maximum of 1 year. p16 IHC and whole exome sequencing were performed on tumors. Cox proportional hazard models estimated 1- and 2-year survival. Log rank tests evaluated differences in survival. Randomization was stratified for stage, initial therapy (IVa surgical vs IVa nonsurgical vs IVb), and treating institution. Although the 2-year PFS was not significant (P = .36), at 1 year (duration on everolimus) 81.16% of patients given everolimus were disease-free compared to 56.88% given placebo (P = .039).

A National Cancer institute granted to my lab investigated correlative biological factors associated with response to therapy. Remarkably, subset analysis of TP53 mutational status determined significantly higher survival rates in TP53 mutated patients treated with everolimus (70.0% at 2 years) compared to TP53-mutated patients treated with placebo (22.5% at 2 years; Log-Rank P = .036). This difference between placebo and everolimus was not seen in the TP53 wild-type group (P = .56).

What are the possible real-world applications of these findings in clinical practice?

TP53-mutated patients have the worst outcomes amongst HNSCC patients and could benefit from adjuvant therapy. Although this was a small sample size and a post hoc analysis, patients with p53 mutations could benefit from a drug that is proven safe and well-tolerated for prolonged periods.

Do you and your co-investigators intend to expand upon this research?

Ezra Cohen, MD, FRCPSC, FASCO, Professor of Hematology/Oncology at University of California, San Diego, initiated the trial with me when he was at University of Chicago, the sponsor for the current trial, and Novartis funded the trial. We want to engage in larger, randomized trials to demonstrate whether mTOR inhibition will improve survival in HNSCC, especially focusing in the highest risk patients (ie, p53-mutated, HPV-negative tumors).

Is there anything else you would like to add?

The sample size was small but the effect of the drug was clearly seen while patients were on treatment. Everolimus is used for patients with breast cancer or renal-cell cancer for extended periods without major side effects, and there is potential for patients with TP53-mutated head and neck disease to see a survival benefit, as well.

Given the healthcare costs are astronomical it is exciting to see a drug that is well-tolerated and affordable show promise for patients who would benefit from adjuvant therapy.