Elsevier

Lung Cancer

Volume 106, April 2017, Pages 1-7
Lung Cancer

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

https://doi.org/10.1016/j.lungcan.2017.01.013Get rights and content

Highlights

  • NLR  5 is associated with inferior OS in nivolumab-treated patients with NSCLC.

  • It is unclear whether this marker is predictive or prognostic in this setting.

  • Additional studies are needed to validate the NLR as a marker of nivolumab outcomes.

  • ECOG PS  2 and liver metastases were also associated with inferior OS.

Abstract

Objectives

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.

Methods

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).

Results

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).

Conclusions

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.

Introduction

Two programmed death-1 (PD-1) checkpoint inhibitors, nivolumab and pembrolizumab, were recently approved by the US Food and Drug Administration (FDA) for previously treated advanced non-small-cell lung cancer (NSCLC). Nivolumab was approved first for squamous-cell NSCLC based on a phase III randomized controlled trial (RCT) demonstrating increased overall survival (OS) compared to standard second-line docetaxel [1], and was subsequently approved for non-squamous NSCLC after a parallel phase III trial yielded a similar OS benefit in this population [2]. Pembrolizumab was initially approved after phase I/II data demonstrated its efficacy in NSCLC patients with ≥ 50% programmed death ligand 1 (PD-L1) expression [3]. A second-line phase III study ultimately confirmed a survival advantage over docetaxel in this same subgroup of patients [4].

In light of the marked and durable responses observed in a subset of NSCLC patients treated with nivolumab, many studies have focused on identifying predictors of benefit. Use of PD-L1, the most studied biomarker, has been fraught with challenges. Trials of pembrolizumab demonstrated a correlation between increased PD-L1 expression and improved outcomes [4], with an FDA requirement of PD-L1 expression ≥50% for its use. The role for PD-L1 as a biomarker for nivolumab use, however, is less well defined. Although PD-L1 expression in tumor cells was associated with improved survival with nivolumab compared to docetaxel in patients with non-squamous histology [2], there was no association between PD-L1 expression and outcomes in a trial that enrolled patients with squamous-cell histology [1]. Even in non-squamous patients, responses to nivolumab were observed in patients with no discernible PD-L1 expression, highlighting the challenges with this biomarker.

Given the shortcomings of PD-L1 as a predictive biomarker for use of nivolumab, novel markers of outcomes are needed to define the select patient population who will derive durable benefit from this agent. The pretreatment neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation previously associated with outcomes in a variety of cancers [5], [6], [7], [8], [9], was recently shown to be associated with clinical benefit in metastatic melanoma patients treated with ipilimumab [10]. Our primary objective was to determine whether pretreatment NLR was associated with outcomes in patients with NSCLC who received nivolumab in routine clinical practice. Because patients with NSCLC treated off study protocols likely differ considerably from those enrolled in RCTs [11], [12], [13], [14], [15], our secondary objective was to describe the clinical and demographic characteristics, as well as effectiveness outcomes and toxicities, of a cohort of NSCLC patients treated with nivolumab outside the context of a clinical trial at an academic U.S. cancer center.

Section snippets

Patients, data collection, and study design

We conducted a retrospective cohort study of all patients with previously treated advanced NSCLC who initiated nivolumab (3 mg/kg intravenously every 2 weeks) at the Abramson Cancer Center of the University of Pennsylvania between March 4, 2015, the date that nivolumab was approved by the US FDA, and March 1, 2016. We focused exclusively on patients treated with nivolumab (and not other PD-1 inhibitors) given treatment practices at our institution during this time period, and to minimize

Results

Between March 1, 2015, and March 1, 2016, 175 patients were treated with nivolumab outside of a clinical trial and received a median of 5 cycles [range, 1–24; interquartile range (IQR), 3–9]. Baseline characteristics are listed in Table 1. Median baseline NLR was 5.5 (range, 0.9–117; IQR, 3.1–9.4), with NLR < 5 in 73 patients (42%) and NLR  5 in 102 patients (58%). The median age at the time of treatment was 68 years (range, 33–88; IQR, 60–74), 46% of the patients were men, and 75% were Caucasian.

Discussion

In this analysis of 175 patients with NSCLC who received nivolumab as a standard of care over a 12-month period, pretreatment NLR  5 was associated with inferior OS and PFS. In recent years, it has become increasingly apparent that cancer-associated inflammation is a key determinant of disease progression and survival in a multitude of solid tumors [20]. Accordingly, NLR, which captures alterations in peripheral blood leukocytes associated with inflammation [16], has been studied extensively as

Conflicts of interest

Dr. Langer and Dr. Bauml report research grants and personal fees unrelated to the submitted work, as described in the attached ICMJE conflict of interest forms. None of the other authors report conflicts of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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