Neutrophil-to-Lymphocyte Ratio Kinetics and Survival with Neoadjuvant Immuno-chemotherapy and Response-Stratified Chemoradiation in Locoregionally Advanced Head and Neck Cancer

Purpose/Objective(s)Efficacy of immune checkpoint inhibitors (ICI) in curative head and neck squamous cell carcinoma (HNSCC) may be hampered by therapeutic ablation of tumor-draining lymphatics with standard chemoradiation (CRT). Recent emergence of neoadjuvant immunotherapy in HNSCC highlights the need for biomarkers to optimize anti-tumor immunity while eliminating locoregional microscopic disease. An elevated neutrophil-to-lymphocyte ratio (NLR) may reflect an unfavorable balance between pro-tumor inflammation and anti-tumor immunity and is associated with poor immunotherapy outcomes, yet its role as a biomarker of neoadjuvant HNSCC immunotherapy is unknown. We studied the association between NLR dynamics and prognosis in HNSCC patients treated with neoadjuvant immuno-chemotherapy followed by dose and volume response-stratified CRT.Materials/Methods106 (71 HPV positive and 35 HPV negative) locoregionally advanced HNSCC patients prospectively enrolled in two clinical trials (NCT03107182; NCT039449150) were treated with neoadjuvant nivolumab and chemotherapy followed by dose and volume response-stratified treatment with reduced or standard CRT (including elimination of elective nodal radiation). NLRs for each patient were calculated at baseline, after neoadjuvant therapy, and 1, 3, 6, 9, and 12 months after treatment completion. NLRs at baseline and after neoadjuvant therapy were divided into quartiles, with high NLRs being the highest quartile (>3.66 and >5.63, respectively). NLR differences between reduced and standard CRT groups were analyzed by Wilcoxon ranked sum test. Overall survival (OS) and progression free survival (PFS) were analyzed by Kaplan-Meier and Cox regression methods.ResultsAmong HPV positive patients, 37% were Stage II/III; among HPV negative patients, 97% were Stage IV (AJCC 8th ed.). 77% of all patients received reduced CRT. Median follow-up was 26.7 months. High NLRs after neoadjuvant nivolumab/chemotherapy were associated with worse OS and PFS (p=0.006 and p=0.03, respectively), while baseline high NLRs demonstrated a non-significant trend toward worse OS and PFS (p=0.16 and p=0.10, respectively). In multivariate analysis controlling for tobacco use, ECOG, stage/HPV status, treatment stratification, and PD-L1 CPS, high NLRs after neoadjuvant nivolumab/chemotherapy remained independently associated with worse OS (HR: 5.58, 95% CI: 1.51-20.56, p=0.01) and PFS (HR: 3.09, 95% CI: 1.10-8.67, p=0.03). During follow-up, NLRs were significantly lower in patients receiving reduced CRT compared to those receiving standard CRT at all time points after treatment (p<0.05).ConclusionHigh NLRs after neoadjuvant immuno-chemotherapy associated with worse survival in locoregionally advanced HNSCC patients. Reduced CRT led to more favorable NLRs which may enhance anti-tumor immunity after neoadjuvant immunotherapy. Further work characterizing dynamic changes in immune phenotype with neoadjuvant HNSCC immunotherapy is warranted.