Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy

Background: A subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria. Methods: Data from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Results: One thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors. Conclusions: Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.