Tumor-informed ctDNA assay to predict outcome in recurrent and/or metastatic squamous cell carcinoma of the head and neck treated with PD-1 inhibitor.

While immunotherapy improves overall survival (OS) of patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN), only 15-20% of patients derive a long-term benefit. We hypothesized that circulating tumor DNA (ctDNA) kinetics during immunotherapy with or without chemotherapy could predict the treatment efficacy in patients with R/M SCCHN. Using a personalized, tumor-informed ctDNA assay, we evaluated ctDNA kinetics from pre-treatment to on-treatment (6 to 10 weeks after treatment initiation) time points. The primary endpoint was the concordance between ctDNA kinetics and best overall response (BOR). Secondary endpoints were the association of ctDNA clearance and kinetics with OS and progression-free survival (PFS). Of the 41 patients, ctDNA assays were successfully designed for 29, and ctDNA was detected pre-treatment in 25 patients. ctDNA kinetics was significantly correlated with BOR (P = 0.00032). Patients with unfavorable ctDNA kinetics had significantly worse PFS when compared to those with favorable ctDNA kinetics (HR = 16.98, 95%Cl 3.35-86.1; P = 0.0006). Six patients had ctDNA clearance, all of whom presented complete or partial response as BOR. PFS and OS were significantly improved in patients with ctDNA clearance compared to those without clearance (PFS: P = 0.0006, OS: P = 0.027). ctDNA kinetics, assessed with a tumor-informed assay, can predict anti-PD1 therapy efficacy in R/M SCCHN. Early ctDNA clearance during the initial weeks of immunotherapy appears to be a strong predictive marker for favorable response, as well as improved PFS and OS.