Immunotherapy-based combinations have had a dramatic improvement in outcomes for patients with metastatic renal cell carcinoma, with some patients having deep and durable responses. Developing biomarkers to predict which patients are most likely to respond to immunotherapy may help limit the number of patients who require upfront and long-term exposure to VEGF-TKIs. Additionally, the identification of biomarkers may help further our understanding of the tumor microenvironment (TME), enabling new mechanisms and combinations to improve outcomes for patients.
Eosinophils, a potentially overlooked player in the TME, have been shown to correlate with improved outcomes for patients with metastatic melanoma treated with immunotherapy.1,2 Additionally, a retrospective analysis from the Cleveland Clinic showed that patients with metastatic renal cell carcinoma and high baseline eosinophils had a lower risk of progression when treated with nivolumab monotherapy than patients with low baseline eosinophils.3 Mechanistically, mouse models have shown that that tumor-associated eosinophils express chemokines, such as CCL5, CXCL9, and CXCL10, which promote the recruitment of tumor reactive CD8+ T cells into the tumor microenvironment.4
We decided to explore the role of eosinophils and immunotherapy further by evaluating the baseline neutrophil-to-eosinophil ratio (NER) and response to nivolumab plus ipilimumab in patients with mRCC. We decided to utilize a ratio as a biomarker instead of an absolute value to normalize potential differences between laboratory assays. Neutrophils, with extensively validated prognostic value in mRCC as part of the IMDC criteria, were chosen to complete the ratio. We hypothesized that patients with a low NER at baseline (ie: patients with relatively lower baseline neutrophils and relatively higher baseline eosinophils) would have improved outcomes to immunotherapy.
Patients with immunotherapy naïve mRCC treated with nivolumab plus ipilimumab at the Vanderbilt-Ingram Cancer Center or Duke Cancer Institute were included in this analysis. Patients were divided into two groups by the median NER at baseline. They were also divided by the median neutrophil-to-lymphocyte ratio (NLR) for comparison.
A total of 110 patients met our inclusion criteria; the median follow-up time was 19.6 months. When split by median NER (mNER), there were no significant differences between age, race, sex, IMDC criteria, or prior therapy between the groups at baseline. Patients with <mNER had longer PFS (8.6 mo vs 3.2 mo, HR 0.50, p < 0.01) compared with patients >mNER (Figure 1a). The median OS for patients with <mNER was not reached (NR), compared with 27.3 mo for patients with >mNER (HR 0.31, p < 0.01) (Figure 1b). For illustration purposes, patients were separated into quartiles showing favorable outcomes for patients with low NER (Figure 1 c-d). Additionally, patients with <mNER had improved ORR (40.0% vs 21.8%, OR 2.39, p = 0.04).
For comparison, there was no statistical difference in median PFS by baseline NLR (<mNLR: 5.6 mo vs 5.8 mo in patients with >mNLR; HR 0.97, p = 0.90) (Figure 3a), and there was no significant difference in ORR (30.9% vs 30.9%, OR 1.00, p = 1.00). However, patients with <mNLR did have longer OS (NR vs 31.8 mo; HR: 0.42, p = 0.02), likely driven by the known prognostic significance of baseline neutrophilia. We further evaluated NER and NLR in subgroups by IMDC risk and receipt of prior therapy, finding similar trends favoring patients with low NER in each subgroup. Our study has several limitations, including its retrospective nature. Therefore, these findings are hypothesis-generating and require prospective evaluation and validation prior to routine clinical use. This study may call attention to further assessment of NER, a widely available and cost-effective biomarker, for immunotherapy responses in mRCC.
Written by: Matthew D. Tucker, MD, Clinical Fellow, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
- Martens A, Wistuba-Hamprecht K, Geukes Foppen M, Yuan J, Postow MA, Wong P, et al. Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab. Clin Cancer Res. 2016;22(12):2908–18.
- Ferrucci PF, Gandini S, Cocorocchio E, Pala L, Baldini F, Mosconi M, et al. Baseline relative eosinophil count as a predictive biomarker for ipilimumab treatment in advanced melanoma. Oncotarget. 2017;8(45):79809–15.
- Zahoor H, Barata PC, Jia X, Martin A, Allman KD, Wood LS, et al. Patterns, predictors and subsequent outcomes of disease progression in metastatic renal cell carcinoma patients treated with nivolumab. J Immunother Cancer. 2018 10 17;6(1):107.
- Carretero R, Sektioglu IM, Garbi N, Salgado OC, Beckhove P, Hämmerling GJ. Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells. Nat Immunol. 2015;16(6):609–17.