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Urothelial Carcinoma Review of Vinflunine Data and Ongoing Developments in Urothelial Carcinoma Anders Ullén Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden Overview of Registration Trials Data in Urothelial Carcinoma In total, 450 patients were treated in two phase II trials and one phase III trial that together formed the basis for the registration of vinflunine monotherapy in urothelial carcinoma patients after failure of platinum- based therapy (see Table 1). 1–3 Similar data were reported in the two phase II trials, in terms of overall response rate (ORR, 5–18  %), median overall survival (OS, 6.6–8.2 months) and median progression-free survival (PFS, 2.8– 3.0 months). 2,3 of the total cohort, it may be interesting to characterise these patients in more detail. In terms of secondary endpoints, all results favoured the vinflunine arm. Significant and meaningful benefits were observed in all main efficacy parameters, including ORR, PFS and disease-control rate (DCR) (see Table 3). 4 Median PFS was doubled in the vinflunine arm compared with the BSC arm, and although the times are relatively short (3.0 versus 1.5 months, respectively), this improvement might be a clinically meaningful benefit in this patient population. Furthermore, patient quality of life (QoL) was not impaired by In the core phase III study, results from the first analysis were reported following 1.8 years of follow-up. 1 The objective of achieving a 2-month survival advantage was achieved. OS in the vinflunine plus best supportive care (BSC) arm was 6.9 months (95  % confidence interval [CI] 5.7–8.0) versus 4.6 months (95  % CI 4.1–7.0) in the BSC-only arm, although the data were not statistically significant (p=0.2868) in the intent-to-treat (ITT) population. However, after adjusting for prespecified prognostic factors that were outlined in the protocol (alkaline phosphatase and haemoglobin [Hb] levels, visceral involvement, performance status [PS], presence of lymph node [LN] metastases and pelvic radiotherapy), the difference in OS between the two arms reached statistical significance in the eligible patient population, defined by the exclusion of 13 patients with at least one major protocol violation at baseline. A statistically significant (p=0.04) 2.6 month difference in median OS was observed in the vinflunine arm: 6.9 months (95 % CI 5.7–8.0) versus 4.3 months in the BSC arm (95 % CI 3.8–5.4) (see Table 2). 1 A multivariate (ITT) analysis adjusting for prognostic factors, such as PS or alkaline phosphatase, confirmed the clearly statistically significant (p=0.036) impact of vinflunine treatment on OS, with a 23 % reduction in the risk of death compared with the BSC-only arm (hazard ratio [HR]=0.77, 95 % CI 0.61–0.98) (see Table 2). 1 An updated survival analysis of over 3.5 years’ median follow-up in the ITT population was presented at the European Association of Urology (EAU) 2010 conference. 4 The median survival advantage of 2.3 months was confirmed in the vinflunine plus BSC arm, although the difference was still not significant. In the eligible population, a statistically significant (p=0.0227) difference of 2.6 months in median survival was observed in the vinflunine arm, and risk of death was reduced by 22 %. Thus, the 2-month difference in OS was maintained for the ITT and eligible populations (statistically significant in the eligible population): 4 Of note, it was possible to observe patients in the vinflunine arm surviving over 40 months. Even though they were only a small fraction 4 vinflunine. Global health status measurements (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30) showed a tendency towards better QoL for vinflunine plus BSC compared with BSC alone, although differences between the two treatment arms were not significant (p=0.658). Importantly, a statistically significant evolution of the pain scale between the two treatment arms favouring the vinflunine arm was measured by week 12 of therapy (p=0.046). In addition, less palliative radiotherapy was used in the vinflunine arm compared with BSC alone (4 % versus 24 %). 4 Grade 3 and grade 4 adverse events (AEs) following vinflunine treatment in non-transitional cell carcinoma of the urothelial tract (non-TCCU) versus TCCU patients showed that myelosuppression was common and higher in TCCU patients than in non-TCCU patients. Non-haematological toxicity mainly included asthaenia/fatigue and constipation, and was also higher in TCCU patients compared with non-TCCU patients. Reasons for these differences between cancer patients may be related to age, previous treatment, aggressiveness of the disease or a combination of these factors (see Table 4). Overall, vinflunine has a good tolerability profile that is consistent with expected class effects. Additional Data Derived from the Pivotal Phase III Vinflunine Trial The pivotal phase III study produced interesting data demonstrating that the main adverse prognostic factors for OS in patients who have failed a platinum-based regimen were Hb <10  g/dl, the presence of liver metastases and PS >0. 5 Patients harbouring a combination of all three risk factors had a worse OS compared with those who had none (see Figure 1). These data are important because they shed some light on which patients would most benefit from vinflunine therapy. These results were corroborated by Niegisch et al., 6 who confirmed that accumulation of these adverse prognostic factors resulted in worse OS. This study also © TOUC H ME D IC A L ME D IA 2013