Pembrolizumab and Cabozantinib in Recurrent Metastatic Head and Neck Squamous Cell Carcinoma (RMHNSCC): 2-Year Long Term Survival Update with Biomarker Analysis

Purpose/Objective(s)Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors have immunomodulatory properties and may improve clinical outcomes in combination with anti-PD-1 therapy. Pembrolizumab and cabozantinib were well tolerated and showed promising clinical activity in patients with RMHNSCC in our reported phase 2 trial. Baseline CD8+ T cell infiltration correlated with overall response rate (ORR) (p=0.0512). We report 2-year follow-up results focusing on long-term efficacy and safety of this combination as well as further biomarker analyses.Materials/MethodsThis open label, single arm, multicenter, phase 2 study screened 50 patients with RMHNSCC, of whom 36 received pembrolizumab and cabozantinib. The primary endpoint was (ORR) as well as safety and tolerability. Secondary endpoints included PFS, OS, and correlative studies of tissue and blood. We report the 2-yr long term efficacy and safety of this regimen. Multiplex immunohistochemistry staining for CD3, CD8, CD20, and CD103+ cells, as well as hypoxia gene expression signature were evaluated and correlated with ORR, PFS and OS.ResultsWith a median follow-up of 22.4 months (95%CI 19.2-31.8), 14 pts (38.9%) remain alive with 7 pts (19.4%) having no disease progression and 1 pt (2.8%) with no evidence of disease. One pt continues on treatment. Median PFS was 12.8 mos., with 1-yr PFS of 53.2% (95% CI 38.8-72.9%) and 2-yr PFS of 32.6 % (95% CI 18.8-56.3%). Median OS was 27.7 mos, with 1-yr OS of 73.8% (95% CI 60.4-90.1%) and 2-yr OS of 54.7% (95% CI 38.9-76.8%). Median duration of response is 12.6 mos, with 2-yr rate of 38.5% (95% CI 30.8-81.8%). Most common grade 3-4 treatment-related adverse events (TRAEs) included AST increase and oral mucositis (5.6%); ALT, bilirubin, GGT, and lipase increase (2.8% each); and hyponatremia (2.8%). TRAEs persisting beyond 12 months from enrollment include hypothyroidism (5.6%) and increased AST and ALT (5.6%). The higher median number of tumor-infiltrating CD103+ cells correlated with improved OS (HR=0.15, p=0.007).ConclusionLong-term results of our phase II pembrolizumab and cabozantinib study in RMHNSCC demonstrate encouraging 2-yr PFS and OS and maintaining manageable safety profiles. Our findings support further investigation of this combinatorial regimen in a confirmatory randomized trial. Evaluation of CD103 + cells as a predictive biomarker deserves further validation.