Angiokines associated with outcomes after sunitinib or everolimus treatment in patients with non-clear cell renal cell carcinoma

Purpose: Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib. Experimental Design: ASPEN (NCT01108445) was an international, randomized, open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1 criteria. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival. Results: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 89 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 87 PFS and 62 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), HGF, and VCAM-1, and these were also associated with poor risk disease. SDF-1 was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. OPN, HGF, TIMP-1, VCAM-1, PDGF-AA and IL-6 levels increased with progression on everolimus, while OPN, PlGF, TIMP-1, VEGF, and soluble VEGFR-2 and VCAM-1 increased with progression on sunitinib. Conclusions: In patients with metastatic non-clear cell RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN