Circulating tumour DNA kinetics in recurrent/metastatic head & neck squamous cell sarcinoma (R/M HNSCC) patients

Immune checkpoint blockade (ICB) has become a standard-of-care in the treatment of recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC). However, only a subset of patients benefit from treatment and as such there is an urgent need to identify prognostic and predictive biomarkers of response to aid clinical decision-making. This work aims to evaluate clinicopathological features of R/M HNSCC, including markers of systemic inflammation and circulating tumour (ctDNA) kinetics under treatment selection pressure. Patients and methods R/M HNSCC patients treated with systemic therapy, platinum-based chemotherapy or ICB, underwent longitudinal blood sampling. Biomarkers tested included ctDNA, measured by CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) and markers of host inflammation, measured by neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Results Among 53 eligible patients, 16 (30%) received chemotherapy, 30 (57%) ICB [anti-PD1/L1] monotherapy and 7 (13%) combination immunotherapy. Median progression-free (PFS) and overall survival (OS) were 2.8 months (95% CI 1.3-4.3) and 8.2 months (95% CI 5.6-10.8), respectively. Seven (13%) patients experienced a partial response and 21 (40%) derived clinical benefit. At baseline, median ctDNA variant allele frequency (VAF) was 4.3%. Baseline ctDNA abundance was not associated with OS (p=0.56) nor PFS (p=0.54). However, a change in ctDNA VAF after one cycle of treatment (ΔVAF (T1-2)) was predictive of both PFS (p<0.01) and OS (p<0.01). Additionally, decrease in ΔVAF identified patients with longer OS despite early radiological progression, 8.2 vs 4.6 months, HR 0.44 (95% CI 0.19–0.87) p=0.03. At baseline, pre-treatment peripheral blood NLR and PLR are prognostic of PFS and OS. After incorporating NLR and PLR into multivariable Cox models, ctDNA ΔVAF retained an association with OS. Conclusions Early dynamic changes in ctDNA abundance, after one cycle of treatment, compared to baseline predicted both OS and PFS in R/M HNSCC patients on systemic therapy. A decrease in ΔVAF identified patients with longer OS despite early radiological progression. Further prospective studies are needed to validate these findings.