Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer.

Efficient use of nivolumab in non-small-cell lung cancer (NSCLC) has been limited by the lack of a definitive predictive biomarker. In patients with metastatic melanoma treated with ipilimumab, a pretreatment neutrophil-to-lymphocyte ratio (NLR)<5 has been associated with improved survival. This retrospective cohort study aimed to determine whether the pretreatment NLR was associated with outcomes in NSCLC patients treated with nivolumab. We reviewed the medical records of all patients with previously treated advanced NSCLC who received nivolumab between March 2015 and March 2016 outside of a clinical trial at the University of Pennsylvania. Patients were dichotomized according to pretreatment NLR<5 vs. ≥5. Multivariable logistic regression and Cox proportional hazards models were used to assess the impact of pretreatment NLR on overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). 175 patients were treated. Median age was 68 (range, 33-88); 54% were female. Twenty-five percent of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2; 46% had received ≥2 prior systemic therapies. In multivariate analyses, pretreatment neutrophil-to-lymphocyte ratio (NLR) ≥5 was independently associated with inferior OS (median 5.5 vs. 8.4 months; HR 2.07, 95% CI 1.3-3.3; p=0.002) and inferior PFS (median 1.9 vs. 2.8 months; HR 1.43, 95% CI 1.02-2.0; p=0.04). In a cohort of patients with NSCLC treated with nivolumab in routine practice, pretreatment NLR≥5 was associated with inferior outcomes. It is unclear whether this marker is predictive or prognostic. Prospective studies are warranted to determine the utility of NLR in the context of other biomarkers of programmed death-1 (PD-1) therapy.

Bagley SJ ，Kothari S ，Aggarwal C ，Bauml JM ，Alley EW ，Evans TL ，Kosteva JA ，Ciunci CA ，Gabriel PE ，Thompson JC ，Stonehouse-Lee S ，Sherry VE ，Gilbert E ，Eaby-Sandy B ，Mutale F ，DiLullo G ，Cohen RB ，Vachani A ，Langer CJ ... -  《-》

Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab.

Immunotherapy with the programmed death receptor-1 (PD-1) antibody nivolumab has changed the field of metastatic non-small cell lung cancer (NSCLC) treatment. Nivolumab shows better outcome compared to standard second line chemotherapy, but reliable prognostic markers are lacking. High neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers of host inflammation and associated with worse overall survival (OS) in several tumor types, but have not been analysed extensively in lung cancer in the era of immunotherapy. Patients with metastatic NSCLC treated with nivolumab were enrolled. Pre-treatment NLR and PLR were calculated by division of neutrophils and platelets by lymphocytes measured in peripheral blood. Cox regression analyses were conducted to study the prognostic role of NLR and PLR on OS and progression free survival (PFS). Logistic regression was used to study the association of NLR and PLR. The combined impact of NLR and other known prognostic factors was explored with multivariable regression. Fifty-two patients were included. Elevated NLR was associated with worse OS (HR for log(NLR)=3.64, 95% CI 1.78-7.46, p<0.001) and lower response rates (OR for log(NLR)=0.17, 95% CI 0.04-0.68, p=0.013). There was no significant association with PFS (HR for log(NLR)=1.46, 95% CI=0.91-2.34, p=0.114). The AUC for the prediction of 10-month survival using log(NLR) was 0.738, the AUC for the prediction of response to nivolumab was 0.776. Relationships with PLR were similar. NLR and PLR didn't correlate with other known prognostic factors (i.e histology, tobacco use, ECOG performance status,) in our cohort. Inclusion of NLR in multivariable models with these other factors significantly improved the prediction of OS. Elevated pre-treatment NLR and PLR are associated with shorter OS and PFS and with lower response rates in patients with metastatic NSCLC treated with nivolumab independently of other prognostic factors.

Diem S ，Schmid S ，Krapf M ，Flatz L ，Born D ，Jochum W ，Templeton AJ ，Früh M ... -  《-》

Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab.

Nakaya A ，Kurata T ，Yoshioka H ，Takeyasu Y ，Niki M ，Kibata K ，Satsutani N ，Ogata M ，Miyara T ，Nomura S ... -  《-》

Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio can predict clinical outcomes in patients with metastatic non-small-cell lung cancer treated with nivolumab.

Explore markers to predict the clinical outcomes of checkpoint inhibitors have high unmet needs. The following study investigates whether hematologic parameter such as systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) is associated with nivolumab efficacy in advanced non-small-cell lung cancer (NSCLC). Advanced/metastatic NSCLC patients treated with nivolumab monotherapy for second-line or further-line treatment at Jilin Cancer Hospital between March 2016 and July 2018 were enrolled in this retrospective study. The optimal cutoff values of SII, NLR, and PLR for predicting efficacy and prognosis were determined according to receiver operating characteristic (ROC) curve and the areas under the ROC curve. Progression-free survival (PFS) and overall survival (OS) were calculated and compared using Kaplan-Meier method and log-rank test. Prognostic values of each variable were evaluated with univariate and multivariate Cox proportional hazard regression (PHR) analyses. A total of 44 patients with advanced NSCLC were included; the median age was 60 (range: 43-74). The optimal cutoff value of SII/NLR/PLR predicted PFS and OS was 603.5, 3.07, and 144. Low SII, NLR, and PLR were associated with longer PFS (HR for SII = 0.34, 95%CI 0.15-0.76, P = 0.006; HR for NLR = 0.46, 95%CI 0.22-0.99, P = 0.048; HR for PLR = 0.39, 95%CI 0.17-0.94, P = 0.025) and OS (HR for SII = 0.16, 95%CI 0.05-0.51, P = 0.005; HR for NLR = 0.20, 95%CI 0.06-0.62, P = 0.002; HR for PLR = 0.20, 95%CI 0.06-0.73, P = 0.008). NLR ≤ 3.07, PLR ≤ 144, SII ≤ 603.5 were independently associated with longer PFS and OS. The SII, NLR, and PLR are promising prognostic predictor for patients with metastatic NSCLC patients.

Liu J ，Li S ，Zhang S ，Liu Y ，Ma L ，Zhu J ，Xin Y ，Wang Y ，Yang C ，Cheng Y ... -  《-》

Pretreatment advanced lung cancer inflammation index (ALI) for predicting early progression in nivolumab-treated patients with advanced non-small cell lung cancer.

Programmed death-ligand 1 (PD-L1) expression status is inadequate for indicating nivolumab in patients with non-small cell lung cancer (NSCLC). Because the baseline advanced lung cancer inflammation index (ALI) is reportedly associated with patient outcomes, we investigated whether the pretreatment ALI is prognostic in NSCLC patients treated with nivolumab. We retrospectively reviewed the medical records of all patients treated with nivolumab for advanced NSCLC between December 2015 and May 2016 at three Japanese institutes. Multivariate logistic regression and Cox proportional hazards models were used to assess the impact of the pretreatment ALI (and other inflammation-related parameters) on progression-free survival (PFS) and early progression (i.e., within 8 weeks after starting nivolumab). A total of 201 patients were analyzed; their median age was 68 years (range, 27-87 years), 67% were men, and 24% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher. An ECOG performance status ≥2, serum albumin <3.7 g/dL, neutrophil-to-lymphocyte ratio ≥4, and ALI <18 were significantly associated with poor PFS and early progression on univariate analysis. Multivariate analyses revealed that pretreatment ALI <18 was independently associated with inferior PFS (median, 1.4 vs. 3.7 months, P < 0.001) and a higher likelihood of early progression (odds ratio, 2.76; 95% confidence interval 1.44-5.34; P = 0.002). The pretreatment ALI was found to be a significant independent predictor of early progression in patients with advanced NSCLC receiving nivolumab, and may help identify patients likely to benefit from continued nivolumab treatment in routine clinical practice.

Shiroyama T ，Suzuki H ，Tamiya M ，Tamiya A ，Tanaka A ，Okamoto N ，Nakahama K ，Taniguchi Y ，Isa SI ，Inoue T ，Imamura F ，Atagi S ，Hirashima T ... -  《Cancer Medicine》