This study showed that the NLRs of non-responders at 4 weeks after the initiation of nivolumab tended to be higher than at baseline. We also found that an NLR of ≥3 at 4 weeks was significantly associated with poor PFS and OS. These results suggested that a decline in the NLR may predict a favorable clinical outcome in mRCC patients treated with nivolumab as a sequential therapy.
Cancer-related inflammation is well recognized to be associated with cancer development and a poor prognosis. Tumor-associated neutrophils (TANs) are key regulators of cancer-related inflammation. TANs have been shown to induce genetic instability through the release of reactive oxygen species (ROS) and to produce tumor necrosis factor, IL-1, IL-6 and VEGF, which contribute to tumor proliferation and immune escape [21,22]. TANs also activate and form neutrophil extracellular traps (NETs), which play a pro-tumor role in tumor progression. TANs are an important factor in the tumor microenvironment, and an increased number of TANs might play a pivotal role in treatment resistance .
Boissier et al. performed a meta-analysis to evaluate the prognostic role of the NLR in RCC and demonstrated that a high NLR was associated with a poor prognosis. In patients with both mRCC and localized RCC, an NLR of <3 predicted better OS and PFS . In non-metastatic clear cell RCC, recurrence-free survival in patients with an NLR of ≥2.7 was significantly shorter than that in patients with an NLR of <2.7 . Another study on mRCC showed that an NLR of ≥4.0 was an independent predictor of OS . Kobayashi et al. reported that patients with an NLR of <3.32 had longer PFS in comparison to those with an NLR of ≥3.32 after 1st-line targeted therapy .
Several reports have evaluated the role of NLR in the clinical outcomes of mRCC patients were treated with ICI. Jeyakumar et al. showed that an NLR of ≥3 was a predictor of a poor response, PFS and OS in patients with mRCC who were treated with nivolumab, ipilimumab, avelumab, pembrolizumab, or atezolizumab . Lalani et al. reported that a high NLR at baseline and at 6 weeks after the initiation of therapy were associated with short PFS, short OS and a poor response . In our study, the NLR at baseline was not a significant predictor of the response to nivolumab. This may be because all of the patients had received two or more TKI treatments and 63% of them had received three or more such therapies before the initiation of nivolumab treatment. Kobayashi et al. also reported that the NLR significantly decreased, even after treatment with TKIs, especially after sunitinib . However, the NLR before nivolumab treatment was not a significant factor in this study. These results suggested that a decline in the NLR after ICI treatment—rather than TKI treatment—is useful information for predicting a response to nivolumab treatment.
Numerous studies have investigated different cutoff values for the NLR. In mRCC patients, most studies have used a cutoff value of around 3 [15-19, 22, 24-26]. We adopted NLR ≥3 as a significant predictor of poor PFS and OS in patients undergoing sequential treatment with nivolumab, based on the results of the meta-analysis by Hu et al. [15, 18].
The present study is associated with some limitations. First, this was a multi-institutional retrospective study. The patients’ characteristics and treatment strategies might have differed among the institutions. The second limitation was the small number of patients included in this study. Despite these limitations, we believe that these results are clinically informative and will be useful for predicting the clinical outcomes of patients receiving nivolumab as a sequential treatment. However, a prospective study using a larger cohort is needed to confirm this.