Differential prognostic effect of systemic inflammation in patients with non–small cell lung cancer treated with immunotherapy or chemotherapy: A post hoc analysis of the phase 3OAKtrial

Abstract

BACKGROUND:A proinflammatory diathesis, as measured by the neutrophil to lymphocyte ratio (NLR), heralds an adverse disease course for non-small cell lung cancer (NSCLC). METHODS: This post hoc analysis used data from the phase 3 OAK trial (NCT02008227), which randomized previously treated patients with NSCLC to atezolizumab or docetaxel. The main objective was assessing the differential impact of the pretreatment NLR on overall survival according to the treatment modality. In addition, patients' genomic characteristics were assessed according to their inflammatory status with a circulating free DNA (cfDNA) next-generation sequencing (NGS) analysis. RESULTS: In all, 600 and 575 patients with NLR data were included in the atezolizumab and docetaxel cohorts, respectively, with a median NLR of 4 (interquartile range, 2.6-6.7) for the pooled population. An NLR ≥4 was associated with a positive smoking status (88.6% vs. 78.1%; p < .01), male sex (66.4% vs. 57.6%; p = .01), a worse performance status (71.3% vs. 55.2%; p < .01), a higher number of metastatic sites (63.2% vs. 51.6%; p = .01), squamous histology (32.1% vs. 21.4%; p < .01), and tissue KRAS mutations (30% vs. 18.7%; p = .02) but not with programmed death ligand 1 (PD-L1) expression or the tissue epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) status. A pretreatment NLR ≥4 was more strongly associated with mortality after atezolizumab (adjusted hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.35-2.01) versus docetaxel (HR, 1.32; 95% CI, 1.08-1.60; multivariable [MVA] interaction p = .0869). The HR for an increased risk of death for PD-L1-negative/NLR ≥4 patients (compared with PD-L1-positive/NLR <4 patients) was significantly higher in the atezolizumab cohort (MVA interaction p = .01). The exclusion of EGFR/ALK-positive patients further increased the prognostic ability of the baseline NLR in favor of atezolizumab (MVA interaction p = .02). Pretreatment cfDNA data from NGS showed that patients with a high blood tumor mutation burden (cutoff, 16 mut/Mb) had a higher median NLR (4.6 vs. 3.7; p = .01). After adjustments for multiple comparisons, none of the selected variants of interest (EGFR, KRAS, TP53, KEAP1, STK11, SMARCA4, ARID1A, and targeted DNA damage response and repair genes) were significantly associated with the NLR. CONCLUSIONS: A low baseline NLR identified patients with NSCLC who derived a greater survival benefit from atezolizumab in comparison with those identified in the docetaxel cohort. The NLR could complement PD-L1 expression in tailoring treatment in this setting.

A novel immunotherapy prognostic score for patients with pretreated advanced urinary tract carcinoma from the subgroup analysis of the SAUL study. The urInary TrAct CArcinoma score (ITACA)

“…The negative prognostic value of NLR has been confirmed in several tumour types [17][18] , including the aUC treated with either immunotherapy 6,8,9 or chemotherapy [19][20] and other urological cancers treated with immunotherapy 21 . Recently, NLR was indicated as a possible predictive factor for advanced non-small-cell lung cancer treated with single-agent immunotherapy after progression to firstline chemotherapy 22 . In our previous analysis of the Italian SAUL patient cohort 8 , we found that the SII, with the receiving operating curve (ROC)-derived cut-off of 884, performed slightly better than NLR in terms of prognostic accuracy, which was confirmed in the current analysis.…”

Systemic and local immunosuppression in glioblastoma and its prognostic significance

“…High post-treatment NLR has also been associated with poor survival outcomes in cancer patients treated with immune checkpoint inhibitors ( 162 ). Combining NLR assessment with other biomarkers of response to immune checkpoint inhibitors, such as PD-L1 expression, tumor mutation burden, or lymphocyte infiltration, has been shown to provide additional predictive power in identifying patients who respond to treatment ( 164 – 169 ). Finally, in meta-analyses, lower baseline NLR was significantly associated with immune-related adverse events (irAEs) resulting from the use of immune checkpoint inhibitors in cancer patients ( 170 , 171 ).…”

Neutrophil-to-Lymphocyte Ratio (NLR) in NSCLC, Gastrointestinal, and Other Solid Tumors: Immunotherapy and Beyond

“…In patients with previously treated advanced NSCLC, the POPLAR and OAK randomized clinical trials established the superiority of atezolizumab, a PD-L1 inhibitor, over standard chemotherapy with docetaxel, leading to the approval of the PD-L1 inhibitor as a second-line treatment option after progression to first-line platinum-based chemotherapy, regardless of PD-L1 expression levels [124,125]. A post hoc analysis of these two studies was focused on the role of NLR as an additional biomarker other than PD-L1 expression [126]. The study found that the combination of the NLR and PD-L1 expression was more accurate in predicting the outcomes to atezolizumab compared to the single evaluation of PD-L1 expression.…”