Abstract LB-433: Biomarker analysis and final results of INT70/09 Phase II proof-of-concept study of Pazopanib (PZP) in refractory urothelial cancer (UC)
Authors: Necchi Andrea , Zaffaroni Nadia , Mariani Luigi , Nicolai Nicola , Crippa Flavio , Morosi Carlo , Daidone Maria Grazia , Gianni Alessandro Massimo , Braud Filippo De , Salvioni Roberto 
Published: August 2012

Abstract
Introduction: Discouraging results have been achieved with standard and novel compounds in refractory UC. Promising interim results with PZP, a multitargeted drug with distinct anti-angiogenic activity, were recently reported (ESMO 2010, ASCO 2011). The final results corroborated by biomarker analysis is presented. Material and Methods: Eligible pts relapsing or progressing after at least 1 chemotherapy regimen for metastatic disease underwent PZP 800 mg once daily until disease progression or unacceptable toxicity. Whole-body contrast-enhanced CT scan with densitometric analysis of target lesions and PET scan were planned at baseline and q4weeks thereafter. Independent review of all CT scans was made. ≥5 RECIST complete + partial responses (CR+PR) were required overall to declare drug activity according to Simon's Optimal 2-stage design. 50 mL of EDTA blood samples were collected at baseline and q4wks (concurrently with CT-PET scans) in all pts to analyze drug-induced changes in the amount of plasma VEGF, sVEGFR-1,-2 and -3, c-Kit, IL-6, 8 and 12 by multiplex ELISA plates. Results: 41 pts were enrolled from 02/2010 to 07/2011. Median age was 67 yrs (40-84). 15 pts (37%) had UC of the upper urinary tract. 20/41 pts were treated in 3rd line or beyond. 19 pts (46%) were CDDP-refractory and 22 (54%) had hepatic metastases. 27 (66%) had ECOG PS 1-2. 7 pts (17%) had a confirmed RECIST-defined PR, 24 had a stable disease (76% clinical benefit). 20 pts (49%) had a clear necrotic evolution of multiple metastases and/or a decreased SUV at PET consistent with PR. Median progression-free (PFS) and overall survival (OS) were 2 (1-14) and 4 mos (2-19), respectively but 7 pts (17%) had long-term cure for &gt;10mos (4/7 beyond 2nd line). 4 cases of cavitation-fistulization of large tumor masses were observed. G3 hypertension occurred in 2 pts, G1-2 asthenia in 11, diarrhoea in 5, anemia and hand-foot syndrome in 3 pts each. No discontinuations/dose reductions were needed. Significant increase from T0 (baseline) to T1 (+4wks) level was observed for VEGF (p&lt;0.0001), IL6 (p&lt;0.0129) and IL8 (p&lt;0.0013) and decrease for VEGFR2 and c-Kit (p&lt;0.0001 each). Rising IL8(T1) levels significantly associated with RECIST progression at covariance analysis (p=0.0104) and both elevated IL8(T0) and IL8(T1) levels associated with shorter OS at Cox model analysis (p=0.0170 and 0.0107, respectively). Early (+4wks) PET and densitometric response associated with longer PFS at Gehan-Breslow-Wilcoxon test (p=0.008 and p=0.0472, respectively). Conclusions: This is the 1st trial ever presented to meet the primary endpoint with a targeted drug in UC. A role for antiangiogenesis in UC has been set in a population of highly pre-treated pts. Increasing levels of IL8 were associated with PD and worse outcome. Future investigation should aim at targeting IL8 to improve efficacy results by prolonging responses.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-433. doi:1538-7445.AM2012-LB-433