Intrinsic resistance to sunitinib in patients with metastatic renal cell carcinoma

Aim: Although targeting angiogenesis with vascular endothelial growth factor receptor (VEGFR) inhibitors has demonstrated efficacy in the treatment of renal cell carcinoma, primary, intrinsic resistance to the VEGFR inhibitor sunitinib is not fully understood in a subset of metastatic RCC (mRCC) patients. Methods: Between 2008 and 2012, a total of 134 patients with mRCC were treated with first-line sunitinib at one of six tertiary centers. Patients in whom progressive disease was the best response were classified as the intrinsic resistance group. Univariate and multivariate analyses were performed on the recognized baseline parameters. Results: Among 134 patients, 33 (25%) intrinsically resistant to sunitinib were identified. Multivariate logistic regression analyses revealed that the number of metastatic sites (OR = 3.6) and neutrophilia (OR = 7.4) were independently associated with development of intrinsic resistance. There were significant differences with regard to overall survival (P = 0.001) and progression-free survival (P < 0.0001) between the patients with and without intrinsic resistance. Conclusions: Intrinsic resistance to first-line sunitinib treatment is associated with a dismal prognosis in mRCC patients. Patients with known high-risk factors (poor performance, neutrophilia, elevated lactate dehydrogenase) and multiple metastatic sites including the liver may experience a limited benefit from sunitinib. Greater understanding of the underlying mechanism and molecular biomarkers for detecting intrinsically resistant disease is needed.