Everolimus, a safe, cheap and well-tolerated drug, prolonged progression-free survival (PFS) compared with placebo during the year patients with advanced head and neck squamous cell carcinoma (HNSCC) were on it,indicates.
However, once discontinued, the PFS advantage in favor of active therapy was no longer significant at 2 years, the same study suggests.
“The 5-year survival rate for advanced head and neck HPV [human papillomavirus]-negative smokers is dismal; hence the need for adjuvant therapy after a complete response to definitive therapy,” Cherie-Ann Nathan, MD, of Louisiana State University Health in Shreveport, Louisiana, said at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.
“[Since] their survival rates have not changed in decades despite advances in surgery, radiation therapy, and chemotherapy, these findings 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,” she added in a statement.
The investigator-initiated trial randomly assigned 28 patients with advanced HNSCC to everolimus 10 mg orally once daily or placebo for a maximum of 1 year or until disease progression, whichever came first.
Patients had stage IV HNSCC but had to be disease-free clinically and radiologically following definitive treatment with chemoradiation or surgery followed by chemoradiation. There was no difference in the type of definitive treatment received prior to the intervention between the two groups.
Adjuvant therapy was initiated between 8 and 16 weeks after completing definitive therapy.
If patients had HPV-positive oropharyngeal cancer, they had to have a minimum of 10 pack-years of smoking history.
“The primary endpoint was PFS at 2 years; the secondary endpoint was toxicity,” Nathan observed.
Oral mucositis and leukopenia were common but only 7% of patients developed grade 3 mucositis or leukopenia.
Other grade 3 or greater toxicities were reported in 16 patients and were similar to the adverse events (AEs) noted in other trials with everolimus. Only two patients developed serious AEs possibly related to the drug.
At 1 year, 81% of patients on everolimus were disease-free compared with 57% of patients on placebo (P = .04), Nathan reported.
However, at 2 years, PFS – although continuing to favor those treated with adjuvant therapy – was no longer significant even though it was clear that during the year patients were receiving treatment, “there was a consistent, protective effect of everolimus,” Nathan suggested.
Special effect among TP53-mutated patients?
Targeted exon sequencing was also carried out, the results from which showed that TP53 was the most commonly mutated gene.
“As expected, HPV-negative tumors were more likely to be mutated for TP53,” Nathan observed. Approximately 80% of HPV-negative smoking-related HNSCC tumors carry the TP53 mutation.
Interestingly, survival rates were significantly higher in TP53-mutated patients treated with everolimus: 70% of the patients were still alive at 2 years compared with only 22% of placebo controls (P = .026), she said.
This is a surprising finding, Nathan suggested, as patients with TP53 mutations traditionally have worse survival than those without, suggesting that these patients in particular appear to benefit from adjuvant everolimus.
“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,” Nathan speculated.
However, additional trials are needed to confirm the link between the TP53 mutation and survival and to assess the safety of keeping patients with HNSCC on an mTOR inhibitor for longer than 1 year.
The study was funded by Novartis. Nathan has disclosed no relevant financial relationships.
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