Interleukin-8 (IL8) and transforming growth-factor beta (TGF-β) as drugable biomarkers of response, progression-free survival (PFS), and overall survival (OS) with pazopanib (PZP): A phase II study in relapsed urothelial cancer (UC).

Abstract

78 Background: Final results of INT70/09 trial of PZP in 41 multi-relapsed patients (pts) with UC reported one of the highest response-rates as 7 pts (17%) had a confirmed PR, 14 a confirmed SD (51% clinical benefit) after independent review (AACR and ASCO 2012). Final achievements on circulating biomarkers are presented. Methods: From 02/2010 to 07/2011, pts received PZP 800 mg once daily until PD or unacceptable toxicity. 50 mL of EDTA blood samples were collected at baseline (T0) and after 4wks (T1) together with disease restaging in all pts to analyze plasma levels of VEGF, sVEGFR-1,-2 and -3, c-Kit, HGF, TGF-β, IL-6, 8 and 12 by multiplex ELISA plates. Changes in marker levels were analysed with the Wilcoxon signed-rank test and matched with RECIST response with the covariance analysis. A logistic regression and Cox regression model evaluated the association with response probability, PFS and OS. Biomarker level was modelled as a continuous time varying covariate. Results: Significant increase from T0 to T1 was observed for VEGF (p<0.0001), HGF (p=0.017), IL6 (p<0.0129) and IL8 (p<0.0013) and decrease for VEGFR2 and c-Kit (p<0.0001 each). Increasing IL8T1 level associated with lower response probability at covariance analysis (p=0.0104). Both TGF-βT0 (p=0.0019) and TGF-βT1 (p=0.0017) levels associated with PFS while elevated IL8T0 (p=0.0170), IL8T1 (p=0.0107) as well as TGF-βT0 (p=0.0472) and TGF-βT1 (p=0.0013) levels associated with OS. Elevated VEGFT1 also associated with shorter OS (p=0.0084) but significance was lost when jointly modelling biomarkers. Pts having IL8T1 levels < 80 pg/ml had greater response (80%) and 6-month OS (60%) probability than those with a level ≥ 80, for whom a dramatic fall was observed. Conclusions: Both IL8 and TGF-β had a prognostic value while IL8 modulation was also associated with response probability. These markers may serve to select pts most likely to get a benefit from PZP. There is a rationale for a sequence/combination with PZP and a phase II study of an anti-TGF-β receptor ALK1 moAb (PF-03446962) for refractory UC is currently recruiting (NCT01620970).