HPV circulating tumor DNA as a marker to monitor response to pembrolizumab and vorinostat combination in patients with advanced HPV-related squamous cell carcinoma

Purpose: Limited data are available on the role of circulating tumor DNA of Human Papillomavirus (HPV-ctDNA) as a pharmacodynamic marker to monitor response to treatment in the recurrent/metastatic (R/M) setting. Our study aimed to investigate the sensitivity and pharmacodynamic value of HPV-ctDNA levels during treatment in patients with R/M HPV-related squamous cell carcinoma (SCC) treated with pembrolizumab in combination with vorinostat. Experimental Design: Plasma samples were prospectively collected from HPV-related SCC patients before treatment initiation and every six weeks until disease progression. HPV-ctDNA was quantified using droplet digital PCR (ddPCR). The levels before treatment were analyzed according to patients and tumor characteristics. Landmark analyses were performed to study the association between HPV-ctDNA level variation and both progression-free survival and overall survival. Results: HPV-ctDNA was detected before treatment in all 57 patients with an HPV-related SCC. HPV-ctDNA levels correlated with the number of HPV copy in tumor tissues (p<0.001). Higher levels of HPV-ctDNA in plasma samples were observed in anal cancer in comparison with other tumor types (p<0.0001), and in patients with distant metastases with or without locoregional recurrence as compared with patients with locoregional recurrence alone (p=0.02). The increase of HPV-ctDNA levels during treatment was associated with a lower overall response rate (p=0.01), as well as shorter progression-free survival and overall survival (both, p=0.01). Conclusions: Dynamic HPV-ctDNA variation levels during treatment have a pharmacodynamic value and may help monitoring treatment response in patients with advanced HPV-related SCC of different locations.