The Association between a Decrease in On-Treatment Neutrophil-to-Eosinophil Ratio (NER) at Week 6 after Ipilimumab Plus Nivolumab Initiation and Improved Clinical Outcomes in Metastatic Renal Cell Carcinoma

SIMPLE SUMMARY: Immune checkpoint inhibitors (ICIs) have significantly changed the treatment paradigm in metastatic renal cell carcinoma (mRCC) and brought an unprecedented durable response. However, there is still a significant proportion of patients who do not response to ICIs, and there are no biomarkers to select responders. In this study, we investigated the change in neutrophil-to-eosinophil ratio (NER) during ipilimumab/nivolumab treatment and clinical response in mRCC. We found that mRCC patients who responded to immunotherapy had lower on-treatment NER during ipilimumab/nivolumab induction. In addition, after accounting for baseline tumor biological characteristics and patient sociodemographic factors, we found that the decrease in NER at week 6 was independently associated with improved outcomes in ipilimumab/nivolumab-treated mRCC. Given that the NER can be easily obtained through routine laboratory work-ups, our results provide initial evidence that the decrease in on-treatment NER during immunotherapy, as a biomarker to predict ICI treatment response, warrants further investigation in prospective studies. ABSTRACT: A lower baseline neutrophil-to-eosinophil ratio (NER) has been associated with improved responses to immune checkpoint inhibitors (ICI)-treated metastatic renal cell carcinoma (mRCC). This study investigated the decrease in NER at week 6 after ipilimumab/nivolumab (ipi/nivo) initiation and treatment responses in mRCC. A retrospective study of ipi/nivo-treated mRCC at two US academic cancer centers was conducted. A landmark analysis at week 6 was performed to assess the association between the change in NER and clinical responses (progression-free survival (PFS)/overall survival (OS)). Week 6 NER was modeled as a continuous variable, after log transformation (Ln NER), and a categorical variable by percent change. There were 150 mRCC patients included: 78% had clear cell histology, and 78% were IMDC intermediate/poor risk. In multivariable regression analysis, every decrease of 1 unit of Ln NER at week 6 was associated with improved PFS (adjusted hazard ratio (AHR): 0.78, p-value:0.005) and OS (AHR: 0.67, p-value: 0.002). When NER was modeled by percent change, decreased NER > 50% was associated with improved PFS (AHR: 0.55, p-value: 0.03) and OS (AHR: 0.37, p-value: 0.02). The decrease in week 6 NER was associated with improved PFS/OS in ipi/nivo-treated mRCC. Prospective studies are warranted to validate NER change as a biomarker to predict ICI responses.