The mTOR inhibitor everolimus, used to treat breast and kidney cancers, may benefit patients with advanced squamous cell carcinoma of the head and neck, according to data presented at the 2020 Multidisciplinary Head and Neck Cancers Symposium.¹

The results of an investigator-initiated, phase II trial showed significant improvement in 1-year progression-free survival in patients with advanced-stage cancer who were randomly assigned to everolimus vs placebo (81.16% vs 56.88%; P = .039). Notably, in a non-preplanned subgroup analysis, patients with TP53 mutations had significantly higher survival rates with everolimus at 2 years (70.0%) than did patients with TP53 mutations treated with placebo (22.5%).

“There is a real need for adjuvant therapy in advanced head and neck squamous cell carcinoma,” said Cherie-Ann Olympia Nathan, MD, Chairman and Professor of Otolaryngology/Head & Neck Surgery at Louisiana State University Health Shreveport. “This study provides suggestive evidence that patients could potentially benefit from everolimus and that further studies, particularly in patients with TP53 mutations, are warranted.”

“This study provides suggestive evidence that patients could potentially benefit from everolimus and that further studies … are warranted.”

— Cherie-Ann Olympia Nathan, MD

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As Dr. Nathan explained, the 5-year survival rate for patients with advanced-stage, smoking-related head and neck squamous cell carcinoma is less than 30% and has not improved in the past 30 years. Preclinical data have shown that the AKT/mTOR pathway is activated in most squamous cell head and neck cancers and that pathway activation in surrounding normal mucosa is associated with recurrences. Moreover, in window-of-opportunity trials for squamous cell head and neck cancer, oral mTOR inhibitors appear to be well tolerated and effective. Further validation in larger studies is warranted.

Study Methods

For this study, Dr. Nathan and colleagues sought to determine whether adjuvant everolimus improves 2-year progression-free survival in patients with advanced squamous cell head and neck cancer and to investigate correlative biologic factors associated with response. Investigators stratified randomization for disease stage, type of initial therapy, and treating institution.

After confirming complete response, patients received either everolimus (10 mg orally) or placebo for a maximum of 1 year or until disease progression. Patients who were treated for stage IV disease had to be disease-free, clinically and radiologically, and had to initiate adjuvant therapy between 8 and 16 weeks after completing therapy. Patients with human papillomavirus–positive oral pharyngeal cancer had to have a minimum of 10 pack-years smoking history.

Everolimus: Well Tolerated and Effective

As Dr. Nathan reported, the study closed prematurely, but 52 patients enrolled at 13 sites, with 24 patients receiving placebo and 28 patients receiving everolimus. After randomization, there were no significant differences in demographic or tumor characteristics, noted Dr. Nathan, and the primary site of the tumor was the oral pharynx. There was also no difference in the type of treatment received within everolimus or placebo groups.

Safety data showed that the treatment was well tolerated. Oral mucositis and leukopenia were common, low-grade adverse events possibly related to treatment. Grade 3 or higher toxicity was reported in 16 patients treated with everolimus and 7 patients who received placebo; serious adverse events were seen in 3 and 5 patients, respectively. These adverse events were similar to those in other trials of everolimus, Dr. Nathan said.

Findings suggest that everolimus was not only safe but effective as well. Progression-free survival was significantly better while patients were on everolimus during the first year as compared with the placebo group. At 1 year while on treatment, 82% of patients receiving everolimus were disease-free vs 57% receiving placebo (P = .04). Although it continued to favor everolimus, however, the primary endpoint of 2-year progression-free survival was no longer significant, said Dr. Nathan.

In addition, post hoc analysis showed a slight improvement in overall survival at 1 year for patients receiving everolimus, but there was no significant difference at 2 years.

TP53 Mutations

Targeted exome sequencing identified TP53 as the most commonly mutated gene and the only one with sufficient power for analysis. Surprisingly, said Dr. Nathan, results of the study showed that patients with TP53 mutations benefited significantly from everolimus. At 2 years, 70% of patients with TP53 mutations treated with everolimus were alive compared with 22% of patients treated with placebo (P = .026). This difference was not seen in the wild-type group.

Future studies may show that extended use of mTOR inhibitors in patients with TP53 mutations, who are known to have the worst outcomes, may improve survival in this group at high risk of tumor relapse, authors of the study concluded.

“Targeted therapies in breast cancer have allowed it to become a chronic disease,” said Dr. Nathan. “I think everolimus should be [further] investigated in patients with advanced head and neck cancer.” 

DISCLOSURE: This was an investigator-initiated trial sponsored by the University of Chicago and funded by Novartis. Correlative studies were supported by an RO1 grant from the National Cancer Institute. Dr. Nathan has received institutional research funding from Novartis and holds a patent for a curcumin chewing gum.

REFERENCE

1. Nathan CAO, Hayes DN, Harismendy O, et al: Multi-institutional randomized double-blind phase II trial of everolimus vs placebo as adjuvant therapy in patients with locally advanced squamous cell cancer of the head and neck. 2020 Multidisciplinary Head and Neck Cancers Symposium. Abstract 5. Presented February 27, 2020.