Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.

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In multiple cancer types, high tumor mutational burden (TMB) is associated with longer survival after treatment with immune checkpoint inhibitors (ICI). The association of TMB with survival outside of the immunotherapy context is poorly understood. We analyzed 10,233 patients (80% non-ICI-treated, 20% ICI-treated) with 17 cancer types, before/without ICI treatment, or after ICI treatment. In non-ICI-treated patients, higher TMB (higher percentile within cancer type) was not associated with better prognosis; in fact, in many cancer types, higher TMB was associated with poorer survival, in contrast to ICI-treated patients, in whom higher TMB was associated with longer survival.

the US Food and Drug Administration approved the anti-programmed cell death 1 drug pembrolizumab for patients with malignant solid tumors of any histologic type with high tumor mutational burden (TMB; Ն10 mutations per megabase). The predictive value of this universal cutoff for high TMB is not well understood.OBJECTIVE To examine the performance of a universal definition of high TMB in an independent cohort of patients with solid tumors treated with immune checkpoint inhibitors. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study included 1678 patients at a single cancer referral center treated with immune checkpoint inhibitors from January 1, 2015, to December 31, 2018. Patients had 16 different cancer types and were treated with anti-programmed cell death 1 or programmed cell death ligand-1 immunotherapy. Tumors underwent next-generation sequencing.EXPOSURES At least 1 dose of immune checkpoint inhibitors. MAIN OUTCOMES AND MEASURESBest overall response to immune checkpoint inhibitor therapy. The hypothesis tested was formulated after data collection and prior to analysis. RESULTSOf 1678 patients, 924 (55%) were male, and the median age was 64 years (interquartile range, 55-71 years). Using the universal cutoff of 10 mutations per megabase, 416 tumors (25%) were categorized as having high TMB. Across cancer types, the proportion of TMB-high tumors ranged from 0% of kidney cancers to 53% of melanomas (113 of 214). Tumors categorized as TMB-high had higher response rates compared with TMB-low tumors in only 11 of 16 cancer types. In the entire cohort, response rates increased with higher cutoffs for TMB-high categorization, reaching 41% (169 of 416) for TMB more than 10 and 56% (90 of 161) for TMB more than 18, the highest TMB decile. Response rates also increased with TMB percentile within cancer type. Using cancer-specific cutoffs, 457 tumors (27%) were categorized as TMB-high. Response rates within cancer type ranged from 4% for pancreatic cancer (1 of 26) to 70% for melanoma (46 of 66). Cancer-specific cutoffs were associated with numerically higher response rates for TMB-high compared with TMB-low tumors in 14 of 16 cancer types. CONCLUSIONS AND RELEVANCEThe data from this cohort study validate the finding of generally higher response rates following immune checkpoint inhibitor therapy for tumors with TMB of 10 or more mutations per megabase, across multiple cancer types. However, the predictive value of a universal numerical threshold for TMB-high was limited, owing to variability across cancer types and unclear associations with survival outcomes. Further investigation will help define cancer type-specific TMB cutoffs to guide decision-making.

High pretreatment count of peripheral neutrophils and/or monocytes was independently related with worse prognosis in patients with HNSCC. Classification based on pretreatment neutrophil and monocyte counts enabled the identification of different prognostic profiles. © 2016 Wiley Periodicals, Inc. Head Neck 39: 219-226, 2017.