Dataset Information

Vinflunine in routine clinical practice for the treatment of advanced or metastatic urothelial cell carcinoma - data from a prospective, multicenter experience.

ABSTRACT: Vinflunine is recommended in the European guideline for the treatment of advanced or metastatic urothelial cell carcinoma (UCC) after failure of platinum-based therapy.This prospective, non-interventional study investigated the safety and efficacy of vinflunine in platinum-pretreated UCC patients in routine clinical practice. Data were prospectively collected on patients with advanced or metastatic UCC undergoing vinflunine treatment in 39 German hospitals and medical practices. Dosing of vinflunine, tumor assessments and concomitant medications followed physician's routine clinical practice. Primary endpoints were toxicity and assessment of vinflunine treatment modalities. Secondary aims included overall response rate (ORR), overall survival (OS) time and a prognostic risk-model.Seventy-seven platinum-pretreated patients were recruited. Vinflunine was predominantly administered as second-line (66%) therapy or in subsequent treatment lines (21%). One third of the patients received at least six cycles of vinflunine and the average number was 4.7 cycles. A vinflunine starting dose of 320 mg/m2 was chosen in 48% of patients and 280 mg/m2 in 39%. Grade 3/4 toxicities were leucopenia 16.9%, anemia 6.5%, elevated liver enzymes 6.5% and constipation 5.2%. ORR was 23.4% and OS was 7.7 (CI 4.1 to 10.4) months. Patients with zero, one, two or??three risk factors displayed a median OS of 18.2, 9.5, 4.1 and 2.8 months, respectively (p=0.0005; HR=1.82).Vinflunine delivers a meaningful benefit to an unselected population of advanced platinum-pretreated UCC patients managed in routine clinical practice.

SUBMITTER: Retz M

PROVIDER: S-EPMC4455983 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Vinflunine in routine clinical practice for the treatment of advanced or metastatic urothelial cell carcinoma - data from a prospective, multicenter experience.

Retz Margitta M de Geeter Patrick P Goebell Peter J PJ Matz Ullrich U de Schultz Wito W Hegele Axel A

BMC cancer 20150604

<h4>Background</h4>Vinflunine is recommended in the European guideline for the treatment of advanced or metastatic urothelial cell carcinoma (UCC) after failure of platinum-based therapy.<h4>Methods</h4>This prospective, non-interventional study investigated the safety and efficacy of vinflunine in platinum-pretreated UCC patients in routine clinical practice. Data were prospectively collected on patients with advanced or metastatic UCC undergoing vinflunine treatment in 39 German hospitals and ...[more]

PMID: 26040470

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Project description:Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives. Formalin-fixed paraffin-embedded samples of mUC patients (n = 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months; n= 11) or responders (R: response ≥ 6 months; n = 12). Genomic characterization revealed that the most common alteration, TP53 mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in KTM2C (4/12; 33.3%), PIK3CA (3/12; 25%) and ARID2 (3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased MAGEA4 expression as a potential biomarker of non-responding tumours to vinflunine treatment. Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.

Project description:BackgroundA systematic review and meta-analysis of the use of systemic vinflunine (VIN) in the treatment of urothelial carcinoma (UC) was performed to evaluate its efficacy based on current available clinical data.MethodsThis review was prospectively registered at the International Prospective Register of Systematic Reviews, PROSPERO (registration CRD42016049294). Electronic databases including MEDLINE®, Embase®, Cochrane Central Register of Controlled Trials, and Web of Science were searched through December 2016. We performed a meta-analysis of the published data. Primary end points were progression-free survival (PFS) and overall survival (OS). Numerous secondary clinical outcomes were analyzed including response and toxicity data.ResultsWe identified 382 publications, of which 35 met inclusion criteria for this review representing 29 unique studies. A total of 2,255 patients received VIN for the treatment of UC in the included studies. OS and PFS were analyzed in a pooled Kaplan-Meier analysis. Response data were available for 1,416 VIN-treated patients with random effects proportion of complete response in 1%, partial response in 18%, and overall response rate of 21%. Toxicity analysis revealed fatigue (40.1%), nausea (33.9%), constipation (34.1%), and alopecia (26.0%) as the most prevalent overall non-hematologic adverse events (AEs). Most prevalent grade 3-4 AEs were fatigue (10.2%), abdominal pain (8.2%), myalgias (2.5%), and nausea (2.3%). Most common hematologic AEs of all grades were anemia (56.6%), neutropenia (46.0%), thrombocytopenia (25.5%), and febrile neutropenia (6.6%). Grade 3-4 hematologic AEs had the following pooled rates: neutropenia, 24.6%; anemia, 10.2%; febrile neutropenia, 5.4%; and thrombocytopenia, 3.0%.ConclusionVIN has been explored as a combination first-line treatment as well as a single-agent second-line, third-line, and maintenance therapy for advanced and metastatic UC. In first-line treatment of UC, either as a maintenance agent after cisplatin or as a primary combination therapy, VIN may be a promising alternative to current treatments. Further studies are needed to compare first-line combination VIN regimens to the current standard of care in order to assess long-term survival outcomes. Second- and third-line VIN monotherapy does provide a proven, although limited, survival benefit in platinum-refractory patients.

Project description:Urothelial cell carcinoma (UCC) is the fifth most common type of cancer in developed countries. Vinflunine, a third-generation semi-synthetic anti-microtubule agent, was approved in 2009 by the EMA for the treatment of patients with advanced UCC (aUCC) who have progressed after initial treatment with a platinum-based chemotherapy regimen. However, nowadays with the incorporation of immune-checkpoint blockade in the management of aUCC, vinflunine is considered as a third line treatment after immunotherapy failure. In the randomized phase II MAJA trial we demonstrated that maintenance therapy with vinflunine in patients with controlled disease after first-line platinum-based chemotherapy resulted in significantly longer progression-free survival as compared to best supportive care. However, at present, the mechanisms that underlying vinflunine resistance in UCC remain unclear. Thus, the objective of this study is to perform a pre-planned gene expression analyses aimed to identify new resistance mechanisms as well as biomarkers to predict response to maintenance vinflunine. We have compared the gene expression profiles of eight bad responders to vinflunine (<4 cycles) and nine good responders (>12 cycles). RNA was isolated from FFPE tumor tissue collected using the Covaris kit and gene expression levels were analyzed with Clariom S (Affymetrix). Differential expression, defined as p<0.05 and |FC|>1.5, was determined with linear models for microarray data included in the limma and sva packages. Pre-ranked Gene Set Enrichment Analysis (GSEA) was used for the functional classification of the differential expression genes. In vitro validation was performed using bladder cancer cell lines. Hierarchical clustering of genes showed a differential expression pattern between good and bad responders. In good responders, GSEA revealed that “Epithelial-to-mesenchymal transition” (EMT) and “IL-6 – JAK – STAT3” pathways were the top enriched negatively hallmarks. Mechanistically, we showed that the downregulation of mesenchymal markers using the polyphenol curcumin, a well-known EMT inhibitor, significantly sensitized mesenchymal-like bladder cancer cells to vinflunine treatment. In conclusion, our results demonstrated that EMT process mediates resistance to vinflunine and suggested that the combination of this anti-microtubule agent with an EMT inhibitor could be a good strategy of maintenance therapy in aUCC patients.

Dataset Information

Vinflunine in routine clinical practice for the treatment of advanced or metastatic urothelial cell carcinoma - data from a prospective, multicenter experience.

Publications

Vinflunine in routine clinical practice for the treatment of advanced or metastatic urothelial cell carcinoma - data from a prospective, multicenter experience.

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