Hypertension and Circulating Cytokines and Angiogenic Factors in Patients With Advanced Non‐Clear Cell Renal Cell Carcinoma Treated With Sunitinib: Results From a Phase II Trial

Background. We evaluated the significance of hypertension developing during vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (VEGFR‐TKI) treatment and a group of cytokines and angiogenic factors (CAFs) in advanced non‐clear cell renal cell carcinoma (nccRCC) patients treated with sunitinib in a phase II study. Materials and Methods. Using multiplex assays, we analyzed the levels of 38 CAFs in plasma at baseline and after 4 weeks of sunitinib therapy. Sunitinib benefit was defined as a partial response or stable disease using the Response Evaluation Criteria in Solid Tumors lasting ≥4 months. Cox proportional hazards regression models were used to assess the associations among hypertension, CAFs, and progression‐free (PFS) and overall survival (OS). Results. Fifty‐seven patients were evaluable; 53 had baseline CAF levels available. The median PFS and OS were 2.9 months (95% confidence interval [CI], 1.4–5.5) and 16.8 months (95% CI, 10.7–27.4), respectively. Sunitinib benefit was observed in 21 patients (37%). However, 33 patients (60%) developed hypertension during treatment, although no association was found with survival or response. Elevated baseline soluble tumor necrosis factor (TNF) receptor I, interleukin‐8, growth‐regulated oncogene, transforming growth factor‐α, and VEGFR‐2 levels were associated with an increased risk of death on multivariate analysis. Conclusion. We found no association between the development of hypertension and survival or sunitinib benefit in advanced nccRCC. TNF and angiogenic/immunomodulatory mediators were identified for evaluation as markers of prognosis and VEGFR‐TKI benefit in future studies. Implications for Practice: The present study describes the first analysis of hypertension and a relatively large set of circulating cytokines and angiogenic factors in patients with advanced non‐clear cell renal cell carcinoma (nccRCC) treated with sunitinib. No association was found between hypertension and patient outcomes. However, a group of candidate circulating biomarkers was identified, in particular, those associated with tumor necrosis factor and CXCR1/2 signaling, with probable biological and clinical significance in nccRCC, warranting confirmation in future studies. The significance of hypertension developing during vascular endothelial growth factor receptor tyrosine kinase inhibitor treatment and a group of cytokines and angiogenic factors in advanced non‐clear cell renal cell carcinoma pati