Elsevier

European Journal of Cancer

Volume 89, January 2018, Pages 56-63
European Journal of Cancer

Original Research
Neutrophil-lymphocyte ratio kinetics in patients with advanced solid tumours on phase I trials of PD-1/PD-L1 inhibitors

https://doi.org/10.1016/j.ejca.2017.11.012Get rights and content

Highlights

  • High neutrophil-lymphocyte ratio (NLR) at baseline and during treatment is adversely prognostic in patients receiving PD-1/PD-L1 blockade.

  • NLR does not correlate with risk of immune toxicity.

  • NLR decreases over time in responders to immunotherapy.

Abstract

Background

Although the neutrophil-lymphocyte ratio (NLR) is prognostic in many oncological settings, its significance in the immunotherapy era is unknown. Mechanistically, PD-1/PD-L1 inhibitors may alter NLR. We sought to characterise NLR kinetics in patients with advanced solid tumours treated with PD-1/PD-L1 inhibitors.

Methods

Electronic records of patients treated with PD-1/PD-L1 inhibitors on phase I trials across three sites were reviewed. A high NLR (hNLR) was predefined as >5. Univariate logistic regression models were used for toxicity, response analyses and Cox models for overall survival (OS) and progression-free survival analyses. Landmark analyses were performed (cycle two, three). Longitudinal analysis of NLR was performed utilising a mixed effect regression model.

Results

The median OS for patients with hNLR was 8.5 months and 19.4 for patients with low NLR, (hazard ratio [HR] = 1.85, 95% confidence interval [CI] 1.15–2.96, p = 0.01). On landmark analysis, hNLR was significantly associated with inferior OS at all time points with a similar magnitude of effect over time (p < 0.05). On multivariate analysis, NLR was associated with OS (HR 1.06, 95% CI 1.01–1.11, p = 0.01). NLR did not correlate with increased immune toxicity. Longitudinally, NLR correlated with response: NLR decreased by 0.09 (95% CI: −0.15 to −0.02; p = 0.01) per month in responders compared with non-responders.

Conclusions

hNLR at baseline and during treatment is adversely prognostic in patients with advanced malignancies receiving PD-1/PD-L1 blockade. Importantly, NLR reduced over time in responders to immunotherapy. Taken together, these data suggest that baseline and longitudinal NLR may have utility as a unique biomarker to aid clinical decision-making in patients receiving immunotherapy.

Section snippets

Background

The advent of new cancer immunotherapeutics has led to renewed optimism in clinically meaningful progress to improve cancer outcomes for patients. In particular, since a survival benefit was observed with ipilimumab, an immune checkpoint inhibitor (ICI), in patients with advanced melanoma [1], there has been an explosion in novel cancer immunotherapeutics. The most successful molecules to date have been inhibitors of the programmed-death 1 (PD-1) – programmed death-ligand 1 (PD-L1) checkpoint,

Study design

We conducted a retrospective multi-centre cohort study of consecutive patients with advanced solid tumours treated with PD-1/PD-L1 inhibitors in phase I clinical trials across three sites in the United Kingdom, Spain and Australia. At least one dose of experimental agent needed to be received to be eligible for inclusion on this study. Data collected included patient demographics and clinical data, haematology and biochemistry at baseline and before each cycle of therapy, toxicity data,

Results

Between May 2014 and May 2017, 165 patients were treated with PD-1 and PD-L1 inhibitors. Baseline characteristics are displayed in Table 1. Baseline characteristics were well balanced by baseline NLR status although patients with higher baseline NLR were more likely to have received previous radiotherapy treatment (p = 0.03). Patients with higher baseline NLR were observed to have lower baseline haemoglobin (p < 0.001) and lower baseline albumin (p < 0.001).

Overall, 79/165 (48%) achieved a CB.

Discussion

The NLR is a widely validated clinical biomarker of prognosis applicable to several clinical settings. Its role in the immunotherapy era is undefined, although studies have shown that for melanoma patients treated with the CTLA-4 inhibitor, ipilimumab, the NLR retains its prognostic significance [22]. This study suggests that baseline NLR is correlated with clinical benefit, and that it is significantly prognostic for OS in a population of patients with advanced solid tumours participating in

Conflict of interest statement

None declared.

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