Targeting the Tumor Microenvironment through mTOR Inhibition and Chemotherapy as Induction Therapy for Locally Advanced Head and Neck Squamous Cell Carcinoma: The CAPRA Study.

Abstract

Simple SummaryThe PI3K-AKT-mTOR pathway is dysregulated in 70% of head and neck squamous cell carcinoma (HNSCC) and linked to the tumor microenvironment. This weekly induction treatment combined the mTOR inhibitor everolimus with carboplatin-paclitaxel chemotherapy for locally advanced T3-4/N0-3 HNSCC. In 41 patients, safety profile was favorable and overall response rate was 75.6%. Translational data demonstrated specific target engagement with p-S6K decrease in tumor tissue and pro-immunogenic cytokine release in peripheral blood. Induction treatment with chemotherapy and mTOR inhibitors may provide new therapeutic options and rationale for combinations with immune oncology agents for locally advanced HNSCC.Mammalian target of rapamycin (mTOR) regulates cellular functions by integrating intracellular signals and signals from the tumor microenvironment (TME). The PI3K-AKT-mTOR pathway is activated in 70% of head and neck squamous cell carcinoma (HNSCC) and associated with poor prognosis. This phase I-II study investigated the effect of mTOR inhibition using weekly everolimus (30 mg for dose level 1, 50 mg for dose level 2) combined with weekly induction chemotherapy (AUC2 carboplatin and 60 mg/m2 paclitaxel) in treatment-naïve patients with locally advanced T3-4/N0-3 HNSCC. Patients received 9 weekly cycles before chemoradiotherapy. Objectives were safety and antitumor activity along with tissue and blood molecular biomarkers. A total of 50 patients were enrolled. Among 41 evaluable patients treated at the recommended dose of 50 mg everolimus weekly, tolerance was good and overall response rate was 75.6%, including 20 major responses (≥50% reduction in tumor size). A significant decrease in expression of p-S6K (p-value: 0.007) and Ki67 (p-value: 0.01) was observed in post-treatment tumor tissue. Pro-immunogenic cytokine release (Th1 cytokines IFN-γ, IL-2, and TNF-β) was observed in the peripheral blood. The combination of everolimus and chemotherapy in HNSCC was safe and achieved major tumor responses. This strategy favorably impacts the TME and might be combined with immunotherapeutic agents.