SCOTTSDALE, AZ-The targeted therapy mTOR inhibitor everolimus may extend progression-free survival (PFS) for patients with advanced head and neck cancer who are at high risk for recurrence after standard treatment. Most patients enrolled in a randomized phase II trial who received the drug were cancer-free a year after therapy, as compared to those who took a placebo. The benefit persisted for those with mutations in their TP53 gene.
The 5-year survival rate for advanced stage smoking-related squamous cell carcinoma of the head and neck is less than 30 percent and this dismal rate has not changed in the past 30 years, noted 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. She presented the results of the study at the 2020 Multidisciplinary Head and Neck Cancers Symposium.
"Akt/mTOR is activated in most patients with squamous cell carcinoma of the head and neck and pathway activation in surrounding normal mucosa is associated with recurrences. Oral mTOR inhibitors appear well-tolerated and effective in window of opportunity squamous cell carcinoma of the head and neck trials," said Nathan.
"While cure rates tend to be upwards of 85 percent for patients with head and neck cancers associated with HPV, they tend to be less than 40 percent for patients with disease related to smoking. These patients are recurring most often, and their survival rates have not changed in decades, despite advances in surgery, radiation therapy, and chemotherapy."
Study Details
Nathan and colleagues conducted a multi-institutional, randomized, double-blind trial of everolimus versus placebo as adjuvant therapy in 52 patients with locally advanced squamous cell carcinoma of the head and neck (Abstract 5). They 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. The patients from 13 institutions received up to 1 year of either everolimus (28 patients) or a placebo (24 patients). There were no significant differences in demographic characteristics.
Eligible patients had to be free of disease after either definitive treatment with chemoradiation therapy or surgery followed by chemoradiation. The researchers then tracked how long they remained cancer-free with additional therapy.
After 1 year, 81 percent of patients on everolimus remained progression-free, compared to 57 percent of those in the placebo group. Nathan clarified that this time point was not stipulated a priori and is a post-hoc analysis. Two-year PFS, which was the primary endpoint, continued to favor everolimus, but was no longer significant. There were no significant differences in overall survival (OS) at 1 or 2 years.
"Remarkably, subset analysis of TP53 mutational status determined significantly higher survival rates in TP53-mutated patients treated with everolimus (70% at 2 years) compared to TP53-mutated patients treated with placebo (22.5% at 2 years)," said Nathan. The difference was not significant at 2 years for patients without this mutation, she noted.
TP53 mutations occur in almost 80 percent of HPV-negative, smoking-related cases of squamous cell carcinoma of the head and neck. Even so, the potential link between TP53, the mTOR pathway, and survival surprised the researchers. "There is really no drug that targets TP53, and so we have never had a targeted therapy for it or considered it an actionable mutation," said Nathan.
Sixteen of the 28 patients on everolimus and seven of the 24 patients on placebo experienced Grade 3 or higher toxicities, including three and five serious adverse events, respectively. The drug's tolerability indicates that it may have potential as longer-term maintenance therapy to delay recurrence for high-risk patients, she said.
"Although the sample size is small, as it closed due to lack of accrual, these finding indicate that patients 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," said Nathan. "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."
In conclusion, Nathan said: "There is need for adjuvant therapy in advanced squamous cell carcinoma of the head and neck. Our study showed that patients with TP53 mutations benefited significantly from everolimus. In addition, irrespective of p53 status, PFS, and OS were significantly better while patients were on everolimus during the first year, when compared to the placebo group."
Future studies with extended use of mTOR inhibitors in TP53-mutated patients that are known to have the worst outcomes may improve survival in this group at high risk of tumor relapse. Additional trials are needed to confirm the link between TP53 and survival, as well as to determine the safety of keeping patients with squamous cell carcinoma of the head and neck on the drug for multiple years.
Mark L. Fuerst is a contributing writer.