Randomized phase 2 study of trebananib (AMG 386) with or without continued anti-vascular endothelial growth factor (VEGF) therapy in patients (pts) with renal cell carcinoma (RCC) who have progressed on bevacizumab, pazopanib, sorafenib, or sunitinib

Background: In RCC, Angiopoietin (Ang) 2 is elevated at the time of progression on anti‐VEGF therapy and may contribute to resistance. We tested trebananib, an Ang 1 and 2 neutralizing peptibody in pts with RCC progressing on anti‐VEGF treatment. Methods: Pts with measurable RCC progressing despite an anti‐VEGF agent within 12 weeks, any number of prior treatments, good PS and adequate organ function, were randomized to trebananib 15 mg/kg IV weekly without (arm A) or with (arm B) continuation of the prior anti‐VEGF agent. After randomization, pts underwent a pre‐treatment tumor biopsy. The primary endpoint for each arm was tumor response (RECIST 1.1), evaluated every 12 weeks. Each arm was a Simon Optimum design planned for 39 pts, interim analysis after 17 pts, with alpha = 0.10 and beta = 0.10. Secondary endpoints included progression free survival (PFS) and adverse events (AEs). Results: Of 40 enrolled pts, 35 started treatment (17 arm A, 18 arm B) with median age 61 (39‐77) and 3 prior treatments (1‐8). Four died prior to documented progression and 24 progressed as their 1st event. At interim analysis, 1 response (in Arm B, trebananib + pazopanib) was observed. Median PFS of 2.7 (95% C.I. 2.3‐4.7) months in arm A and 3.4 (95% C.I. 2.7‐8.3) months in arm B did not support continued study. Common AEs, mostly grade 1‐2, included fatigue, hypertension, and edema, and were numerically higher in arm B. In arm A, 6/17 treated pts (35%) experienced a Grade 3+ AE attributed to trebananib. In Arm B 8/15 pts (53%) with follow up experienced a Grade 3+ AE attributed to combo treatment. The most common grade 3+ AEs were hypertension and dyspnea. A possibly related unwitnessed cardiac arrest occurred on arm B. Conclusions: While tolerable, trebananib either without or with continued anti‐VEGF therapy did not show promising activity in RCC pts who recently progressed on anti‐VEGF therapy alone. Analysis of pre‐treatment research tumor biopsies from this study will provide insights into anti‐VEGF therapy resistance, including the role of Ang signaling and the lack of efficacy of these regimens.