Dynamic biomarker and imaging changes from a phase II study of pre- and post-surgical sunitinib.

OBJECTIVE To explore translational biological and imaging biomarkers for Sunitinib treatment prior to and after debulking nephrectomy. METHODS Treatment-naive patients with metastatic renal cell carcinoma (mRCC) received 50mg OD Sunitinib for 12 days pre-surgically, then post-surgery on 4 week-on, 2 week-off, repeating 6 week cycles until disease progression in a single arm phase II trial. Structural and dynamic contrast-enhanced MR imaging (DCE-MRI) and research blood sampling were performed at baseline and after 12 days. CT Imaging was performed at baseline and post-surgery then every 2 cycles. The primary endpoint was objective response rate (RECIST) excluding the resected kidney. Secondary endpoints included changes in DCE-MRI of the tumour following pre-surgery Sunitinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Translational and imaging endpoints were exploratory. RESULTS 14 patients received pre-surgery Sunitinib, 71% (10/14) took the planned 12 doses. All underwent nephrectomy, and 13 recommenced Sunitinib post-operatively. 58.3% (7/12) of patients achieved partial or complete response (PR or CR) (95% CI: 27.7 - 84.8%). Median OS was 33.7months and median PFS was 15.7months. Amongst those achieving PR or CR, median response duration was 8.7months. No unexpected surgical complications, Sunitinib-related toxicities, or surgical delays occurred. Within the translational endpoints, pre-surgical Sunitinib significantly increased necrosis, and reduced CD31, Ki67, circulating VEGF-C, and Ktrans (measured using DCE-MRI) (all p<0.05). There was a trend for improved OS in patients with high baseline plasma VEGF-C expression (p=0.02). Reduction in radiological tumour volume after pre-surgical Sunitinib correlated with high percentage of solid tumour components at baseline (Spearman's coefficient ρ=0.69, p=0.02). Conversely, percentage tumour volume reduction correlated with lower baseline percentage necrosis (coefficient=-0.51, p=0.03). CONCLUSION Neoadjuvant studies such as NeoSun can safely and effectively explore translational biological and imaging endpoints.