Prognostic and predictive impact of neutrophil‐to‐lymphocyte ratio and HLA‐I genotyping in advanced esophageal squamous cell carcinoma patients receiving immune checkpoint inhibitor monotherapy

Abstract

Background: Immune checkpoint inhibitors (ICIs) have become standard-of-care in patients with pretreated advanced esophageal squamous cell carcinoma (ESCC). However, reliable biomarkers for clinical outcomes are lacking for ICIs. The exploration of effective biomarkers is therefore needed to optimize patient benefit in the treatment of ESCC. Methods: Sixty-nine patients with advanced ESCC enrolled at one center from two prospective trials were consecutively analyzed. NLR was dynamically collected and high-resolution HLA-I genotyping were performed on genomic DNA. Overall response rate (ORR), median progression-free survival (mPFS) and median overall survival (mOS) were investigated. Results: Thirty-three (47.8%) of 69 patients with baseline NLR ≥4 demonstrated significantly worse clinical outcomes (ORR 9.1% vs. 36.1%, p = 0.018; mPFS 1.8 vs. 3.2 months, hazard ratio [HR] 1.79, p = 0.026; mOS 7.4 vs. 11.0 months, HR 2.28, p = 0.008). An NLR decrease ≥20% at the first radiological evaluation was associated with longer OS (median, 14.0 vs. 7.9 months, p = 0.038). Eleven (15.9%) patients with HLA-I homozygosity presented poorer clinical outcomes (ORR 0 vs. 27.6%, p = 0.056; mPFS 1.8 vs. 2.4 months, HR 3.37, p = 0.010; mOS 5.6 vs. 10.5 months, HR 3.97, p = 0.004). Patients with baseline NLR ≥4 and HLA-I homozygosity had the worst outcome (ORR 0; mPFS 1.4 months; mOS 1.8 months) among all. The association between NLR, HLA-I genotyping and clinical outcomes was independent of programmed death receptor ligand-1 expression. Conclusions: NLR and HLA-I genotyping could have predictive and prognostic value in patients with advanced ESCC receiving camrelizumab, and the combination of biomarkers may help to identify more patient benefit from immunotherapy.K E Y W O R D S camrelizumab, esophageal squamous cell carcinoma (ESCC), human leukocyte antigen (HLA)-I genotyping, neutrophil-to-lymphocyte ratio (NLR)

Focus on the Dynamics of Neutrophil-to-Lymphocyte Ratio in Cancer Patients Treated with Immune Checkpoint Inhibitors: A Meta-Analysis and Systematic Review

“…In total, 38 studies involving 4154 patients were included in this meta-analysis and systematic review [ 8 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Thirty-seven studies had a retrospective study design, and only one study was prospective [ 24 ].…”

“…The proportion of patients with increased NLR ranged from 24.6% to 60.8% in 12 studies, and the pooled percentage of patients with increased NLR was 49.7% (95CI%: 43.7–55.8%) ( Figure S1 ). Although ICI treatment did not influence the trend in NLR overall, six studies [ 27 , 32 , 37 , 42 , 45 , 53 ] reported that the NLR level in patients without response to immunotherapy tended to significantly increase after ICI treatment, and in contrast, patients who responded to ICI treatment have similar or lower NLR level before and after immunotherapy ( Table S1 ). Notably, a retrospective study with data from a multicenter prospective trial using a mixed effects regression analysis with per-patient random intercept reported that patients with CR/PR/SD had a lower log-transformed NLR at study entry ( p = 0.03) and the NLR level was stable during follow-up overall [ 37 ], which corresponded to our results.…”

“…Eighteen studies (Sekine et al reported two independent cohorts) [ 8 , 21 , 22 , 23 , 26 , 29 , 30 , 33 , 34 , 40 , 44 , 45 , 47 , 48 , 50 , 51 , 52 , 54 ] including 2324 patients looked at the association between OS and the different trends in NLR after ICI treatment. Fifteen studies [ 8 , 21 , 23 , 26 , 29 , 30 , 33 , 34 , 40 , 44 , 47 , 48 , 50 , 51 , 54 ] reported the relationship between the upward trend in NLR and OS, and the subsequent time points for rechecking NLR included 4–8 weeks, a treatment cycle after ICI treatment, or before the second infusion.…”

“…Results indicated the pooled HR was 2.05 (95%CI: 1.79–2.35, p < 0.001), suggesting the negative prognostic role of the upward trend in NLR in patients who received immunotherapy ( Figure 2 A). Twelve studies (13 cohorts) [ 21 , 22 , 29 , 30 , 40 , 44 , 45 , 47 , 48 , 51 , 52 , 54 ] investigated the association between the downward trend in NLR and OS. The time points for rechecking included 4–8 weeks, after the first treatment cycle, before the second infusion, or after two doses.…”

“…In fact, recently published studies about immunotherapy and the dynamics of NLR suggested the special role of early change in NLR in predicting the efficacy of immunotherapy and final survival outcomes [ 8 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Specifically, they observed the following three points: (1) The trend in NLR (upward or downward) may be associated with the outcome of tumor response after ICI treatment.…”