Pembrolizumab and Cabozantinib in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Long-term Survival Update with a Biomarker Analysis

Abstract

Purpose: Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) have immunomodulatory properties and improve clinical outcomes in combination with anti-PD-1 therapy in different malignancies. We report the long-term efficacy and safety of pembrolizumab and cabozantinib in patients with RMHNSCC and include a correlative biomarker analysis.

Patients and methods: This open-label, single-arm, multicenter, phase 2 study screened 50 patients with RMHNSCC, of whom 36 received pembrolizumab and cabozantinib. The primary endpoint was overall response rate (ORR), safety, and tolerability. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and correlative studies of tissue and blood. We report the long-term PFS, OS, and safety of treated patients and describe correlative biomarkers evaluating p-MET expression and tumor immune microenvironment (TIME) using multiplex immunohistochemistry.

Results: With median follow-up of 22.4 months, the median PFS was 12.8 months with a 2-year PFS of 32.6% (95% CI, 18.8%-56.3%) and the median OS was 27.7 months with a 2-year OS of 54.7% [95% confidence interval (CI), 38.9%-76.8%]. The median duration of response was 12.6 months with a 2-year rate of 38.5% (95% CI, 30.8%-81.8%). Long-term treatment-related adverse events included manageable hypothyroidism (5.5%) and grade 1 elevated aspartate aminotransferase and alanine aminotransferase (2.8%). Baseline tumor p-MET expression correlated with ORR (P = 0.0055). Higher density of CD8+, CD103+, and CSF1-R+ cells at baseline correlated with improved OS [hazard ratio (HR) = 5.27, P = 0.030; HR = 8.79, P = 0.017; HR = 6.87, P = 0.040, respectively].

Conclusions: Pembrolizumab and cabozantinib provided prolonged encouraging long-term disease control and survival with a maintained favorable safety profile. The prognostic significance of higher density of CD8+, CD103+, and CSF1-R+ cells in TIME deserve further evaluation in similar clinical settings.

Figure 1.. Clinical efficacy of pembrolizumab/cabozantinib in RMHNSCC.

Progression-free survival (A) and overall survival (B) were assessed with median follow up of 22.4 months among 36 patients. Median PFS and OS and their 95% CI were estimated by Kaplan-Meier analysis.

Figure 2.. Duration of response in responding patients receiving pembrolizumab/cabozantinib combination therapy.

Arrows represent continued responders from time of enrollment to last follow up. Black circles represent death events. Blue arrows represent patients with HPV negative or unknown disease, Red arrows represent patients with HPV positive disease. Median duration of response among responders is 12.6 months. A durable responder is a subject who has confirmed response for at least 6 months.

Figure 3.. Correlation between p-MET and overall response rate.

Baseline tumor p-MET was analyzed by immunohistochemistry in 25 patients and its expression was correlated with ORR.

Figure 4.. Overall survival by median CD8 (A), CD103 (B), tumor lymphoid values and by CSF1R (C) tumor myeloid values.

Baseline tumor CD8, CD103, and CSF1R levels were analyzed by multiplexed immunohistochemistry. Tumors were categorized as having high vs. low expression based on the median number of marker positive cells. Blue curve represent outcome of patients with above median values, red curves represent outcome of patients below median values.