The antiangiogenic drug pazopanib has demonstrated clinicallymeaningful activity in patients with refractory urothelial cancer , according to results presented at the AACR Annual Meeting 2012,held here March 31 - April 4. The results also revealed thatincreases in interleukin-8 levels early after treatment withpazopanib may predict a lack of tumor response to the therapy. "Historically, prognosis of patients with relapsed or refractoryurothelial cancer is quite dismal," said Andrea Necchi, M.D.,faculty member in the department of medicine at Fondazione IRCCSIstituto Nazionale dei Tumori in Milan, Italy. "Patients who failto be cured after multiple chemotherapy regimens have a poorsurvival estimate, and palliative care is a reasonable trade-off." Data from the phase II proof-of-concept trial identified pazopanibas the first targeted compound to have clinically meaningfulactivity in patients with refractory urothelial cancer, accordingto Necchi. "Our data indicate that pazopanib seems to be a legitimate drug inthis disease," said Necchi. "Most interestingly, our biomarkeranalysis clearly pointed out the role of rising levels ofcirculating interleukin-8 as an early and potentiallypractice-changing indicator of tumor resistance and poor survival." The researchers assigned 41 patients with relapsing or progressingurothelial cancer between 2010 and 2011 to 800 mg once-dailypazopanib. All patients had at least one prior chemotherapy regimenfor metastatic disease. At follow-up, seven patients had a partial response to therapy and24 patients had stable disease - an overall clinical benefit of 76percent. Median progression-free survival was 2.6 months, andmedian overall survival was 4.7 months. However, 10 percent ofpatients had a long-term cure after a median follow-up of 19months. The researchers examined blood samples for predictive biomarkers atbaseline and every four weeks. They found that early rising levelsof interleukin-8 (e.g., after four weeks of pazopanib) wereassociated with tumor progression and shorter overall survival. "This trial gave a clear proof of concept that will requireconfirmation on a larger number of patients," Necchi said."However, the preliminary findings, mainly regarding the role ofinterleukin-8 levels, have the potential to change at least theconcept of new trial design with antiangiogenic agents in thisdisease." Notes Introduction: Discouraging results have been achieved withstandard and novel compounds in refractory urothelial cancer (UC).Promising interim results with PZP, a multitargeted drug withdistinct anti-angiogenic activity, were recently reported (ESMO2010, ASCO 2011). The final results corroborated by biomarkeranalysis is presented. Material and Methods: Eligible pts relapsing or progressing afterat least 1 chemotherapy regimen for metastatic disease underwentPZP 800 mg once daily until disease progression or unacceptabletoxicity. Whole-body contrast-enhanced CT scan with densitometricanalysis of target lesions and PET scan were planned at baselineand q4weeks thereafter. Independent review of all CT scans wasmade. 5 RECIST complete + partial responses (CR+PR) were requiredoverall to declare drug activity according to Simon's Optimal2-stage design. 50 mL of EDTA blood samples were collected atbaseline and q4wks (concurrently with CT-PET scans) in all pts toanalyze drug-induced changes in the amount of plasma VEGF,sVEGFR-1,-2 and -3, c-Kit, IL-6, 8 and 12 by multiplex ELISAplates. Results: 41 pts were enrolled from 02/2010 to 07/2011. Median agewas 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%) wereCDDP-refractory and 22 (54%) had hepatic metastases. 27 (66%) hadECOG PS 1-2. 7 pts (17%) had a confirmed RECIST-defined PR, 24 hada stable disease (76% clinical benefit). 20 pts (49%) had a clearnecrotic evolution of multiple metastases and/or a decreased SUV atPET consistent with PR. Median progression-free (PFS) and overallsurvival (OS) were 2 (1-14) and 4 mos (2-19), respectively but 7pts (17%) had long-term cure for 10mos (4/7 beyond 2nd line). 4cases of cavitation-fistulization of large tumor masses wereobserved. 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/dosereductions were needed. Significant increase from T0 (baseline) to T1 (+4wks) level wasobserved for VEGF (p 0.0001), IL6 (p 0.0129) and IL8(p 0.0013) and decrease for VEGFR2 and c-Kit (p 0.0001 each).Rising IL8(T1) levels significantly associated with RECISTprogression at covariance analysis (p=0.0104) and both elevatedIL8(T0) and IL8(T1) levels associated with shorter OS at Cox modelanalysis (p=0.0170 and 0.0107, respectively). Early (+4wks) PET anddensitometric response associated with longer PFS atGehan-Breslow-Wilcoxon test (p=0.008 and p=0.0472, respectively). Conclusions: This is the 1st trial ever presented to meet theprimary endpoint with a targeted drug in UC. A role forantiangiogenesis in UC has been set in a population of highlypre-treated pts. Increasing levels of IL8 were associated with PDand worse outcome. Future investigation should aim at targeting IL8to improve efficacy results by prolonging responses. Additional References Citations. 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