AMG 386 in Combination With Sorafenib in Patients With Metastatic Clear Cell Carcinoma of the Kidney: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study

Upregulation of proangiogenic factors in response to inactivation of the von Hippel-Lindau (VHL) gene is a critical component in the development and progression of clear cell renal cell carcinoma (RCC).1 Several inhibitors of the vascular endothelial growth factor (VEGF) signaling pathway have been shown to improve outcomes in patients with metastatic RCC (mRCC).1 However, because almost all patients ultimately develop resistance to therapy, combination treatment strategies that may result in more complete angiogenesis inhibition are of interest.2 The angiopoietin-1/angiopoietin-2 and Tie2 (tyrosine kinase with immunoglobulin-like and EGF-like domains 2) receptor axis may be a legitimate target for inhibiting angiogenesis in mRCC. Preclinical studies have demonstrated that its components are regulated by VHL and are dysregulated in RCC cell lines.3 Plasma angiopoietin-2 concentrations are significantly elevated in patients with mRCC (compared with localized disease or healthy controls), and increase at the time of disease progression.4 Concurrent blockade of the angiopoietin and VEGF pathways augments inhibition of angiogenesis and tumor growth in tumor xenograft models.5 Hence, combinations of angiopoietin/Tie2 inhibitors and VEGF inhibitors might induce clinically meaningful activity. AMG 386 is an investigational recombinant peptide-Fc fusion protein that neutralizes the receptor-ligand interaction between Tie2 and angiopoietin-1/2.5 In Colo205 xenograft models, simultaneous antagonism of angiopoietin-1/2 with AMG 386 suppressed tumor growth more effectively than did selective inhibition of angiopoietin-1 or angiopoietin-2 alone.5 Interim results of a phase 1b study suggested that treatment of patients who have mRCC with sorafenib or sunitinib plus AMG 386 had an acceptable toxicity profile, distinct from that of VEGF inhibitors, and may have antitumor activity.6 We evaluated in a phase 2 study the tolerability and anti-tumor activity of AMG 386 plus sorafenib in previously untreated patients who have clear cell mRCC.