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Background The identification of biomarkers to select patients with metastatic renal cell carcinoma (mRCC) most likely to respond to combination immunotherapy (IO) is needed. We sought to investigate an association of the baseline neutrophil-to-eosinophil ratio (NER) with outcomes to nivolumab plus ipilimumab for patients with mRCC. Methods We performed a retrospective review of patients with clear cell mRCC treated with nivolumab plus ipilimumab from Vanderbilt-Ingram Cancer Center and Duke Cancer Institute. Patients with prior receipt of immunotherapy and those without available baseline complete blood count with differential were excluded. Patients were divided into groups by the median baseline NER and analyzed for overall survival (OS), progression free survival (PFS), and objective response rate (ORR). Patients were also divided by median baseline neutrophil-to-lymphocyte ratio (NLR) and analyzed for clinical outcome. Further analyses of patients above/below the median NER and NLR were performed in subgroups of IMDC intermediate/poor risk, IMDC favorable risk, and treatment naïve patients. Results A total of 110 patients were included: median age was 61 years and 75% were treatment naïve. The median NER (mNER) at baseline was 26.4. The ORR was 40% for patients with mNER (OR 2.39, p = 0.04). The median PFS for patients with mNER (HR 0.50, p mNER (HR 0.31, p p = 0.02), PFS and ORR did not differ compared with patients in the >mNLR group. Conclusions A lower baseline NER was associated with improved clinical outcomes (PFS, OS, and ORR) in patients with mRCC treated with nivolumab plus ipilimumab, and prospective validation of the baseline NER as a predictive biomarker for response to immunotherapy-based combinations in mRCC is warranted.

4541 Background: Immunotherapy (IO) has become the standard of care in patients with metastatic renal cell carcinoma (mRCC), yet clinical biomarkers of outcome remain elusive. Preclinical and clinical studies have demonstrated that a lower tumor volume burden is associated with better response to IO in melanoma and lung cancer. Methods: Retrospective chart review of mRCC patients treated with Immunotherapy/Immunotherapy or Immunotherapy/Tyrosine kinase inhibitors (TKI) combinations at Vanderbilt Ingram Cancer Center was conducted. Baseline target tumor lesions including primary kidney tumors and treatment response were assessed by RECIST 1.1 criteria. The association between baseline tumor burden and outcomes of interest [progression-free survival (PFS) and overall survival (OS)] were assessed with multivariable Cox regression model. Results: 79 patients with mRCC were included in the cohort. The median age was 64, 80% were male, 82% had clear cell histology, and 73% were IMDC intermediate/poor risk group. 53% received IO/IO and 39% received IO/TKI. 71% had prior nephrectomy and 14% had prior systemic therapy. The median baseline tumor burden was 87 mm (range: 16-363 mm). After adjusting for age, gender, histology, prior nephrectomy/systemic therapy and IMDC risk, baseline tumor burden was not associated with either PFS (p-value: 0.42) or OS (p-value: 0.99). At the initial follow-up scan (median time of 3.1 months from treatment initiation) 22 (28%) patients had an objective response and 41 (52%) patients had stable disease. Among patients with tumor shrinkage, every 10% decrease seen in the sum of the target lesions was associated with improved PFS (AHR: 0.77, 95%CI: 0.63-0.94, p-value:0.009) and OS (AHR: 0.62, 95%CI: 0.42-0.93, p-value:0.02). Conclusions: While baseline tumor burden volume was not associated with clinical outcome to immunotherapy-based therapy in patients with metastatic RCC; however, the degree of early tumor shrinkage was significantly associated with better outcomes. Large tumor burden does not preclude response and good outcome to immunotherapies.

4527 Background: Low baseline NER has been associated with improved response to immunotherapy in mRCC (PMID:34732251). The current study aimed to investigate the early decline of NER at week 6 after ipilimumab/nivolumab (ipi/nivo) initiation and treatment responses in mRCC. Methods: Retrospective chart review of ipi/nivo-treated mRCC patients at Vanderbilt-Ingram Cancer Center and Duke Cancer Institute was conducted. Landmark analysis at week 6 after ipi/nivo initiation was performed to assess the association between change in NER and clinical responses [progression-free survival (PFS)/overall survival (OS)]. Results: There were 150 mRCC patients included in the analysis: 78% had clear cell histology, 78% were IMDC intermediate/poor risk, and 74% were male. The median follow-up time was 11.9 months. After ipi/nivo initiation, the median NER decreased from 23.8 (interquartile range: 15.0-57.1) at baseline to 19.8 (10.6-40.8) at week 6; 102 (68%) patients had decreased NER. The NER at week 6 was grouped by percent change (≥ 50% decrease vs

4563 Background: Previous reports have shown that the baseline neutrophil-to-lymphocyte ratio (NLR) is associated with prognosis in patients with mRCC. However, NLR has not been shown to reliably predict for response to IO. Retrospective analyses in metastatic melanoma and mRCC have shown an association of eosinophilia with improved outcomes to single agent immunotherapy. We sought to evaluate and compare the baseline NLR and NER with response to ipi/nivo in patients with mRCC. Methods: A retrospective review of patients with mRCC treated at the Vanderbilt-Ingram Cancer Center or Duke Cancer Institute with ipi/nivo was performed. Patients with clear cell histology and a baseline complete blood count with differential were included. Patients previously treated with IO were excluded. Patients were separated into groups (above and below the median) based on baseline median NER and baseline median NLR. Analyses of progression free survival (PFS) and overall survival (OS) were conducted using the log rank test. The odds ratio (OR) for objective response rate (ORR) was analyzed using Fisher’s exact test. Results: 111 patients met inclusion criteria. The median age was 60, 77% of patients were male, 68% had prior nephrectomy, 74% were naïve to systemic therapy, and 84% were IMDC intermediate/poor risk. The median NER was 25.0 and median NLR was 3.4. Patients with < median baseline NER had significant improvement in PFS, OS, and ORR (see table). Patients with < median baseline NLR had significant improvement in OS but not in PFS or ORR. Conclusions: Baseline NER was associated with improved outcomes with ipi/nivo. While both NER and NLR were associated with improved OS, only NER was additionally associated with both improved PFS and ORR. With multiple first-line treatment options for mRCC, baseline NER may serve as an early non-invasive predictor for response to ipi/nivo.[Table: see text]

Background Pazopanib is an oral tyrosine-kinase inhibitor that is approved by the U.S. Food and Drug Administration for treatment of metastatic renal cell carcinoma (mRCC). Pharmacokinetic data have shown that concomitant administration of pazopanib and esomeprazole, a proton pump inhibitor (PPI), leads to decreased area under the curve and thus decreased exposure of pazopanib by 40%. Despite the pharmacokinetic data published to date, the clinical significance and impact on patient outcomes resulting from decreased pazopanib exposure remains unknown. Materials and Methods In this retrospective, observational, cohort study, 90 patients with mRCC who either received pazopanib in combination with a PPI or histamine 2 receptor antagonist (H2RA; concurrent PPI/H2RA group) or who did not take concurrent pH-elevating medications (no PPI/H2RA group) were compared to determine if there was an impact on progression-free survival (PFS), the primary endpoint, and secondary endpoints, overall survival (OS) and safety. Results The differences between the PFS of 9.0 months and OS of 28.0 months for the concomitant PPI/H2RA group versus 11.0 months and 30.1 months, respectively, for the no PPI/H2RA group were not statistically significant. Rates of adverse events were similar between the concomitant PPI/H2RA and no PPI/H2RA groups. Conclusion Concomitant PPI or H2RA usage was not shown to be associated with a reduction in PFS or OS for patients receiving pazopanib for mRCC, with a similar toxicity profile in each group. Based on the results of this retrospective cohort study and the palliative nature of the treatment of patients with mRCC, clinicians should consider allowing patients to remain on concomitant pazopanib and acid-reducing therapy. Implications for Practice Pazopanib is a preferred category-one first-line treatment for predominant clear cell metastatic renal cell carcinoma (mRCC). However, because of an aging demographic, coupled with patients with mRCC presenting with multiple comorbidities, including symptomatic dyspepsia or gastroesophageal reflux disease, patients are commonly required to take pazopanib concomitantly with a proton pump inhibitor (PPI) or a histamine 2 receptor antagonist (H2RA). Despite earlier pharmacokinetic reports suggesting that an alkaline pH may result in poorer absorption, this institutional retrospective study found no effect on clinical outcomes. These data suggest that concurrent treatment of mRCC with pazopanib and a PPI or H2RA may be safe in everyday practice.