Randomized Phase 2 Study of Trebananib (AMG 386) with or without Continued Anti-Vascular Endothelial Growth Factor Therapy in Patients with Renal Cell Carcinoma Who Have Progressed on Bevacizumab, Pazopanib, Sorafenib, or Sunitinib - Results of NCI/CTEP Protocol 9048

Background: In renal cell carcinoma (RCC), angiopoietin (Ang) 2 is elevated at the time of progression on anti-vascular endothelial growth factor (VEGF) therapy and may contribute to resistance. Objective: We tested trebananib, an Ang 1 and 2 neutralizing peptibody in patients with RCC progressing on anti-VEGF treatment. Methods: Patients with measurable RCC progressing despite an anti-VEGF agent within 12 weeks, any number of prior treatments, and good PS were randomized to trebananib 15 mg/kg IV weekly without (Arm A) or with (Arm B) continuation of the prior anti-VEGF agent. The primary endpoint for each arm was tumor response (RECIST 1.1). Secondary endpoints included progression free survival and adverse events. Results: Of 41 enrolled patients, 35 were eligible and started treatment (17 Arm A, 18 Arm B) with median age 60 (46-76) and 3 prior treatments (1-8). Four died prior to documented progression and 27 progressed as their first event. Both arms were stopped after interim analysis, 2 responses (11%; 95% C.I. 1-35%) were observed in Arm B. Median PFS of 2.7 (95% C.I. 2.3-4.7) months in Arm A and 5.2 (95% C.I. 2.7-10.8) months in Arm B did not support continued study. Common adverse events including fatigue, nausea, and increased creatinine were generally grade 1-2 and numerically higher in Arm B. The most common grade 3 or higher adverse events were hypertension and dyspnea. Conclusions: While tolerable, trebananib either without or with continued anti-VEGF therapy did not showpromising activity in RCC patients who recently progressed on anti-VEGF therapy alone.