The mTOR inhibitor everolimus may extend progression-free survival for patients with advanced head and neck cancer who are at high risk for recurrence after standard treatment. Patients enrolled in a randomized phase II trial who received the agent were more likely to be cancer-free 1 year after therapy than those treated with placebo, and the benefit persisted for those with TP53 genetic mutations. The findings were presented by Nathan et al at the 2020 Multidisciplinary Head and Neck Cancers Symposium (Abstract 5).

Cherie-Ann O. Nathan, MD

“While cure rates tend to be upward of 85% for patients with head and neck cancers associated with human papillomavirus (HPV), they tend to be less than 40% for patients with disease related to smoking,” said lead author Cherie-Ann O. Nathan, MD, Professor and Chair of Otolaryngology/Head and Neck Surgery at Louisiana State University Health Shreveport and Director of Head and Neck Surgery at Feist-Weiller Cancer Center. “These patients are [having disease recurrence] most often, and their survival rates have not changed in decades, despite advances in surgery, radiation therapy, and chemotherapy.”

Study Methodology

To address this disparity, the researchers focused on patients with advanced HPV-negative head and neck squamous cell carcinoma or HPV-positive disease and smoking history of more than 10 pack-years. They enrolled 52 patients to receive up to 1 year of either everolimus or placebo. Eligible patients had to be free of disease after either definitive treatment with chemoradiation therapy or surgery followed by chemoradiation.

Results

After 1 year, 81% of patients on everolimus remained progression-free, compared to 57% of those in the placebo group (P = .039). Dr. Nathan clarified that this timepoint was not stipulated a priori and is a post hoc analysis.

Two-year progression-free survival, which was the primary endpoint, continued to favor everolimus, but was no longer significant. Subset analysis determined that for patients with TP53 mutations, the survival difference remained significant for an additional year after they stopped immunotherapy (2-year progression-free survival of 70% vs 22.5%, P = .036). The difference was not significant at 2 years for patients without the mutation.

Although TP53 mutations occur in almost 80% of HPV-negative, smoking-related cases of head and neck squamous cell carcinoma, the potential link between TP53, the mTOR pathway, and survival was a surprise to the researchers.

“There's really no drug that targets TP53, and so we've never had a targeted therapy for it or considered it an actionable mutation,” explained Dr. Nathan.

Sixteen of the 28 patients on everolimus and 7 of the 24 patients on the placebo drug experienced grade 3 or higher toxicities, including three and five serious adverse events, respectively. Dr. Nathan said everolimus’s tolerability indicates that it may have potential as longer-term maintenance therapy to delay recurrence for high-risk patients.

“Although the sample size is small, as it closed due to lack of accrual, these findings indicate that patients [with head and neck squamous cell carcinoma] at high risk for tumor relapse could be given mTOR inhibitors to stall progression and keep any residual cancer cells from growing. Our hope is that head and neck cancer can be treated as chronic disease, similar to some breast cancers,” she explained.

Additional trials are needed to confirm the link between TP53 and survival, as well as to determine the safety of keeping patients with head and neck cancer on treatment with everolimus for multiple years.

Disclosure: For full disclosures of the study authors, visit astro.confex.com.