Transitional Cell Carcinoma Of The Urothelium Research Articles

SOGUG-vexillum: Phase II non-randomized clinical trial of nivolumab/ipilimumab maintenance following first-line chemotherapy in unresectable locally advanced or metastatic urothelial cancer.

TPS4606 Background: The current standard of care in non-progressors to first-line platinum-based chemotherapy for unresectable locally advanced or metastatic urothelial carcinoma (UC) is maintenance treatment with avelumab plus best supportive care (BSC). The Checkmate 032 trial showed that the highest ORR (42.4%) was achieved by the combination of Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg in refractory mUC (1), with a manageable safety profile and better outcomes compared to other treatment arms. The trial aims to consolidate the clinical benefit achieved from first-line chemotherapy with the combination of nivolumab 1mg/kg plus ipilimumab 3mg/kg followed by nivolumab. Methods: This single arm, open-label, multicenter study evaluates the effectiveness of Ipilimumab and nivolumab followed by nivolumab maintenance therapy in delaying disease progression in patients with unresectable urothelial cancer that did not progress after first-line chemotherapy. Main eligibility criteria include: Male or female subjects ≥ 18 yrs old with written informed consent, ECOG performance status 0 or 1, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium (UCC), patient inclusion within 3-12 weeks after the last chemo dose, no progressive disease per RECIST v1.1, available tumor tissue at baseline, adequate normal organ and marrow function (Haemoglobin ≥ 9.0 g/dL, ANC > 1500 per mm3, platelets ≥ 100,000 per mm3, bilirubin ≤ 1.5 X ULN, transaminases ≤ 2.5X ULN, creatinine clearance > 30 mL/min). The primary endpoint is Progression Free Survival (PFS). Secondary objectives include: objective response rate (ORR), duration of response (DoR), overall survival (OS), chemotherapy overall survival (cOS), and chemotherapy progression-free survival (cPFS). Additionally, the study also has safety secondary objectives. Dynamic biomarker analysis will be performed. As of January 2023, 5 out of the planned 66 patients have been enrolled in the study. 1) Sharma P et al. J Clin Oncol. 2019. Clinical trial information: EudraCT 2021-005364-22 .

A phase III, randomized, open-label, multicenter, global study of first-line durvalumab plus standard of care (SoC) chemotherapy and durvalumab plus tremelimumab, and SoC chemotherapy versus SoC chemotherapy alone in unresectable locally advanced or metastatic urothelial cancer (NILE).

TPS504 Background: Despite high response rates with first-Line (1L), standard, platinum-based chemotherapy (CT) (gemcitabine + cisplatin or gemcitabine + carboplatin) for patients (pts) with locally advanced or metastatic urothelial cancer (mUC), prognosis remains poor. Studies of immune checkpoint inhibitors + CT in 1L mUC have demonstrated mixed results. In IMvigor130, an improvement in progression-free survival (PFS) with atezolizumab + CT vs placebo + CT reached statistical significance, although overall survival (OS) had not reached statistical significance at the interim analysis. A subgroup analysis suggested a possible larger effect size for PFS and OS for pts with high PD-L1 expression. In KEYNOTE-361, no improvement in either PFS or OS was observed with pembrolizumab + CT vs CT alone. The combination of durvalumab (anti–PD-L1 antibody) and tremelimumab (anti–CTLA-4 antibody) has shown activity in previously treated mUC. In the DANUBE trial of 1L mUC, the co-primary endpoints were OS compared between durvalumab and CT in pts whose tumor cells and/or tumor-infiltrating immune cells express high levels of PD-L1 (≥25%) and between durvalumab + tremelimumab and CT regardless of PD-L1 expression. While neither co-primary endpoint was met, durvalumab + tremelimumab showed evidence of activity, particularly in the PD-L1–high population (hazard ratio: 0.74 [95% CI 0.59–0.93]). Collectively, these results led to an update to the NILE protocol, focusing on pts with PD-L1–high expression. Methods: NILE (NCT03682068) is a randomized, open-label, multicenter, phase III global trial that will randomize ~1215 previously untreated pts with histologically or cytologically documented, unresectable, locally advanced, or metastatic transitional cell carcinoma of the urothelium. Eligible pts aged ≥18 years will be randomized 1:1:1 to durvalumab + CT (Arm 1), durvalumab + tremelimumab + CT (Arm 2), or CT (Arm 3). A tumor tissue sample for biomarker analysis is mandatory as PD-L1 status is a stratification factor. The original co-primary endpoints were PFS and OS for durvalumab + CT vs CT in the intention-to-treat population. However, based on the DANUBE trial results, the primary endpoint was revised to a co-primary endpoint OS in pts with high PD-L1 expression for Arm 1 vs Arm 3 and Arm 2 vs Arm 3. Secondary endpoints will include OS, OS rate at 24 months, PFS, objective response rate, proportion of pts alive and progression free at 12 months, duration of response, disease control rate, time from randomization to second progression, health-related quality of life, and safety. Pharmacokinetics, immunogenicity, and biomarkers are exploratory endpoints. The study opened for enrollment in September 2018. Clinical trial information: NCT03682068.

A phase III, randomized, open label, multicenter, global study of first-line (1L) durvalumab in combination with standard of care (SOC) chemotherapy and durvalumab in combination with tremelimumab and SOC chemotherapy versus SOC chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer (UC).

TPS4590 Background: Despite high response rates to 1L SoC for locally advanced or metastatic UC chemotherapy (gemcitabine + cisplatin or gemcitabine + carboplatin for patients who are cisplatin-ineligible [poor performance status, impaired renal function, comorbidities]), most patients experience disease progression. Novel strategies such as combining chemotherapy and immunotherapy offer hope for improving clinical outcomes. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a human IgG2 mAb directed against CTLA-4. The mechanisms of action of PD-1 and CTLA-4 are nonredundant, so targeting both checkpoint pathways may have additive or synergistic efficacy compared with monotherapy. Studies of platinum-based chemotherapy combined with checkpoint blockade in other tumor types have yielded improved efficacy with acceptable safety and support exploration of this approach for 1L locally advanced or metastatic UC. Methods: NILE (NCT03682068) is a randomized, open-label, multicenter, global trial that will enroll approximately 1265 patients with histologically or cytologically documented, unresectable, locally advanced, or metastatic transitional cell carcinoma of the urothelium. Patients will be randomized (1:1:1) to durvalumab + SoC chemotherapy, durvalumab + tremelimumab + SoC chemotherapy, or SoC chemotherapy as 1L therapy. Primary endpoints are progression-free survival using blinded independent central review assessments per RECIST 1.1 and overall survival (OS). Secondary endpoints include objective response rate, OS at 24 months, proportion of patients alive and progression free at 12 months, duration of response, disease control rate, time from randomization to second progression, and health-related quality of life. Safety, pharmacokinetics, immunogenicity, and biomarkers will also be assessed. The study opened for enrollment in September 2018. 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 Genitourinary Cancers Symposium. Clinical trial information: NCT03682068.

A phase III, randomized, open-label, multicenter, global study of first-line (1L) durvalumab in combination with standard of care (SoC) chemotherapy and durvalumab in combination with tremelimumab and soc chemotherapy versus soc chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer (UC).

TPS499 Background: Despite high response rates to 1L SoC for locally advanced or metastatic UC chemotherapy (gemcitabine +cisplatin or gemcitabine + carboplatin for patients who are cisplatin-ineligible [poor performance status, impaired renal function, comorbidities]), most patients experience disease progression. Novel strategies like combining chemotherapy and immunotherapy offer hope for improving clinical outcomes. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a human IgG2 mAb directed against CTLA-4. The mechanisms of action of PD-1 and CTLA-4 are nonredundant, so targeting both checkpoint pathways may have additive or synergistic efficacy compared to monotherapy. Studies in other tumor types of platinum-based chemotherapy combined with checkpoint blockade have yielded improved efficacy with acceptable safety and support exploration of this approach for 1L locally advanced or metastatic UC. Methods: NILE is a randomized, open-label, multicenter, global trial that will enroll approximately 1265 patients who will be randomized (1:1:1) to durvalumab + SoC chemotherapy, durvalumab + tremelimumab + SoC chemotherapy, or SoC chemotherapy as 1L-line therapy in patients with histologically or cytologically documented, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium. Primary endpoints are progression-free survival using blinded independent central review assessments per RECIST 1.1 and overall survival (OS). Secondary endpoints include objective response rate, OS at 24 months, proportion of patients alive and progression free at 12 months, duration of response, disease control rate, time from randomization to second progression, and HRQoL. Safety, pharmacokinetics, immunogenicity, and biomarkers will also be assessed. The study opened for enrollment in September 2018. Clinical trial information: NCT03682068.

EV-201 study: A single-arm, open-label, multicenter study of enfortumab vedotin for treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor therapy.

TPS542 Background: The majority of patients with locally advanced or metastatic urothelial cancer (la/mUC) will not respond to immune checkpoint inhibitors (CPIs) given in the post-platinum or cisplatin ineligible setting, and there are currently no approved standard therapies after disease progression. Enfortumab vedotin (EV), an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is overexpressed in mUC. Preliminary results from an ongoing phase 1 study of EV monotherapy in pts with mUC (Petrylak ASCO 2017) showed that EV was well tolerated in pts with mUC. Nausea (36%), pruritus (31%), and fatigue (30%) were the most commonly reported treatment-related AEs. The most common grade ≥3 AEs (regardless of attribution) were urinary tract infection (11%) and hypophosphatemia (9%). EV showed an objective response rate (ORR) of 41% (29 out of 71 pts) across all dose levels and 53% (16 out of 30 pts) ORR at the recommended phase 2 dose of 1.25 mg/kg. The ORR was not diminished in pts with prior CPI use (44%), prior taxane use (41%) or in pts with liver metastases (47%). These encouraging results along with a favorable safety and tolerability profile warrant further investigation of EV as a monotherapy. Methods: This single-arm, open label, multicenter phase 2 study (NCT03219333) evaluates the antitumor activity and safety of EV monotherapy in ~120 pts with la/mUC. Pts must have previously received a CPI and either have received prior platinum or be ineligible for cisplatin. Pts must have histologically or cytologically documented transitional cell carcinoma of the urothelium that progressed during or following receipt of most recent therapy. The primary objective is to determine antitumor activity of EV as measured by ORR. Secondary objectives include assessment of duration of response, disease control rate, PFS, OS, and safety/tolerability of EV. Pts must have tumor tissue available for exploratory analyses. Response is assessed per RECIST v1.1. Study enrollment began in Sept 2017. Clinical trial information: NCT03219333.

EV-103 study: A phase 1b dose-escalation and dose-expansion study of enfortumab vedotin in combination with immune checkpoint inhibitor (CPI) therapy for treatment of patients with locally advanced or metastatic urothelial cancer.

TPS532 Background: Immune checkpoint inhibitors (CPIs) are approved for patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) who progress on prior platinum or are ineligible for first line cisplatin. However, only a minority of pts respond to CPI monotherapy and a combination approach may be beneficial. Enfortumab vedotin (EV), an antibody-drug conjugate (ADC), delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) to tumors expressing Nectin-4, which is overexpressed in mUC. Preliminary results from an ongoing phase 1 study of EV monotherapy in pts with mUC (Petrylak ASCO 2017) showed that EV was well tolerated in pts with mUC. EV showed a 41% (29 out of 71 pts) objective response rate (ORR) across all doses (24 wks median response duration). In pts with liver metastasis the ORR was 47% (9 out 19 pts) across all doses. Preclinical data show that an MMAE ADC, but not the unconjugated antibody, increases tumor immunogenicity by inducing immunogenic cell death, antigen presentation and tumor immune infiltration (Gardai 2015). Based on encouraging phase 1 study results and potential enhanced immune response, combining EV with a CPI may result in improved response rates with longer durability. Methods: This phase 1b study (NCT03288545) evaluates the safety/activity of EV + CPI in pts with la/mUC who have not previously received a CPI. The study has 2 parts: dose escalation (EV + pembrolizumab) and dose expansion (EV + CPI [pembrolizumab or atezolizumab]). Pts must have la/m transitional cell carcinoma of the urothelium, be eligible for treatment with a CPI, and be either ineligible for first-line cisplatin-based chemotherapy or have disease progression during or following treatment with ≥1 platinum-containing regimen. The primary objective is to assess the safety/tolerability of EV + CPI. Secondary objectives include determining a recommended dose of EV + CPI in pts with la/mUC, antitumor activity as measured by ORR, disease control rate, duration of response, PFS, and OS. Response is assessed per RECIST v1.1 and iRECIST. Study enrollment began in Oct 2017. Clinical trial information: NCT03288545.

Monoinstitutional real world experience in management of Vinflunine as second line therapy for transitional cell carcinoma of the urothelium.

Vinflunine is the only cytotoxic agent tested as a second line therapy in transitional cell carcinoma of the urothelium in a phase III trial. It is not largely employed in clinical practice because of the high incidence of grade 3–4 toxicity. We evaluated efficacy and safety of Vinflunine at the dose of 280 mg/m2 every 3 weeks associated with primary prophylaxis with granulocyte growth factors and laxatives for patients progressed after platinum + Gemcitabine. Overall survival was 8.5 months, progression-free survival 4.33 months and response rate 25%, with disease control rate 57.2%. Grade III-IV neutropenia occurred in 10.7% of the patients, grade III-IV anemia and grade III thrombocytopenia in 10.7% and 7.2%, respectively. Among non haematological toxicity, grade I-II constipation was reported in 14.2% of the patients, without grade III-IV adverse events. No discontinuation for toxicity was observed. This study underlines that Vinfluinine at a dose of 280 mg/m2 associated with primary prophylaxis for neutropenia and constipation is effective and with a favorable toxicity profile.

Real-life clinical practice results with vinflunine in patients with relapsed platinum-treated metastatic urothelial carcinoma: an Italian multicenter study (MOVIE-GOIRC 01\u20132014)

BackgroundVinflunine is the only chemotherapeutic agent shown to improve survival in platinum-refractory patients with metastatic transitional cell carcinoma of the urothelium (TCCU) in a phase III clinical trial, which led to product registration for this indication in Europe. The aim of this study was to assess the efficacy of vinflunine and to evaluate the prognostic significance of risk factors in a large, unselected cohort of patients with metastatic TCCU treated according to routine clinical practice.MethodsThis was a retrospective multicenter study. Italian cancer centers were selected if, according to the Registry of the Italian Medicines Agency (AIFA), at least four patients had been treated with vinflunine between February 2011 and June 2014, after first- or second-line platinum-based chemotherapy. The primary objective was to test whether the efficacy measured by overall survival (OS) in the registration study could be confirmed in routine clinical practice. Multivariate analysis was carried out using Cox proportional hazard model.ResultsA total of 217 patients were treated in 28 Italian centers. Median age was 69 years (IQR 62–76) and 84% were male; Eastern Cooperative Oncology Group performance status (ECOG PS) was ≥ 1 in 53% of patients. The median number of cycles was 4 (IQR 2–6); 29%, 35%, and 36% received an initial dose of 320 mg/m2, 280 mg/m2 or a lower dose, respectively. Median progression-free survival (PFS) and OS for the entire population was 3.2 months (2.6–3.7) and 8.1 months (6.3–8.9). A complete response was observed in six patients, partial response in 21, stable disease in 60, progressive disease in 108, with a disease control rate of 40%. Multivariate analysis showed that ECOG PS, number of metastatic sites and liver involvement were unfavorable prognostic factors for OS. Toxicity was mild, and grade 3–4 adverse effects were mainly: neutropenia (9%), anemia (6%), asthenia/fatigue (7%) and constipation (5%).ConclusionsIn routine clinical practice the results obtained with VFL seem to be better than the results of the registration trial and reinforce evidence supporting its use after failure of a platinum-based chemotherapy.

A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN)

Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second lines. Vinflunine is the only treatment approved in this setting by the European Medicines Agency and taxanes are also widely used in second line. Cabazitaxel is a taxane with activity in docetaxel-refractory cancers. A randomized study was conducted to compare its efficacy versus vinflunine. This is a multicenter, randomized, open-label, phase II/III study, following a Simon's optimal method with stopping rules based on an interim futility analysis and a formal efficacy analysis at the end of the phase II. ECOG Performance Status, anaemia and liver metastases were stratification factors. Primary objectives were overall response rate for the phase II and overall survival for the phase III. Seventy patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Three patients (13%) obtained a partial response on cabazitaxel (95% CI 2.7-32.4) and six patients (30%) in the vinflunine arm (95% CI 11.9-54.3). Median progression-free survival for cabazitaxel was 1.9 versus 2.9 months for vinflunine (P = 0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for overall survival benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3- to 4-related adverse events were seen in 41% patients with no difference between the two arms. This phase II/III second line bladder study comparing cabazitaxel with vinflunine was closed when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those known previously. NCT01830231.

A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN).

285 Background: Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first line. Vinflunine is EMA approved and used in several European countries. Docetaxel is widely used in second line. Cabazitaxel is a taxane with clinical activity in docetaxel-refractory cancers. A randomised study was conducted to compare its efficacy vs vinflunine. Methods: This was a multicenter, randomised, open-label, phase II/III study, following a Simon’s optimal method with early stopping rules based on an interim futility analysis. The study (NCT01830231) was supported by a research grant from Sanofi. The trial was aiming at superiority of cabazitaxel compared to vinflunine in patients progressing to platinum. ECOG, anemia and liver metastases were stratification factors. The primary objective for the phase II study was overall response rate (ORR), and overall survival (OS) for the phase III. Secondary objectives included safety and progression free survival (PFS). Results: 70 patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Mean age 63 years; 56 (80%) were men. No statistically significant differences were detected between arms for ORR (p=0.26). Three patients (13%) obtained a partial response on cabazitazel (95% CI, 2.7–32.4) and six patients (30%) in the vinflunine arm (95% CI, 11.9–54.3). Median PFS for cabazitaxel was 1.9 months versus 2.9 months for vinflunine (p=0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for OS benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3-4 related adverse events were seen in 41% patients with no difference between arms. The most frequent toxicities associated with cabazitaxel were asthenia, diarrhea, anemia and febrile neutropenia. Conclusions: This phase II/III second line bladder trial comparing cabazitaxel with vinflunine was closed early when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those observed in the phase III. Clinical trial information: NCT01830231.

A multicohort phase I study of ramucirumab (R) plus pembrolizumab (P): Interim safety and clinical activity in patients with urothelial carcinoma.

349 Background: Hallmarks of tumor growth include immunosuppression and angiogenesis. This is the first study to combine R (anti-VEGFR2) with P (anti-PD-1) to simultaneously target both processes in the urothelial tumor microenvironment. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02443324) enrolled patients (pts) with histologically confirmed transitional cell carcinoma of the urothelium (bladder, urethra, or renal pelvis) with prior progression on platinum-based systemic therapy, measurable disease, ECOG PS 0-1, and baseline tumor tissue. Eligible pts received R at 10 mg/kg on Day 1 given with P 200 mg on Day 1 q3W. PD-L1 was classified as positive (≥1%) or negative using the DAKO PD-L1 22C3 IHC pharmDx assay. Tumor response was assessed every 6 wks (RECIST v1.1). The primary objective was to assess safety and tolerability of adding R to P and preliminary efficacy will be assessed as a secondary objective. Results: As of 23-June-2016, 24 pts have been treated. The median age was 63 years, 58% were male, 50% had ECOG PS 0, 50% were PD-L1 positive and 67% received study treatment as third or subsequent regimen. Median duration of treatment was 2.14 mo and 2.37 mo for R and P, respectively. All grades treatment-related AEs (TRAE) occurred in 13 (54%) pts; TRAEs occurring in ≥10% of pts were fatigue (21%), nausea (17%), pyrexia (13%), elevated alanine aminotransferase (13%) and elevated aspartate aminotransferase (13%). Three (13%) pts had grade 3 TRAEs (hypertension, colitis, pulmonary embolism; n=1 each). No treatment-related grade 4 or 5 events occurred. Preliminary efficacy data showed two (8%) PD-L1 positive pts had confirmed partial response, 10 (42%) pts had stable disease, and 10 (42%) had progressive disease as their best response. Two (8%) pts were not evaluable for response at the time of analysis. Median duration of response has not been reached (>2.92 mo). Median PFS was 1.87 mo (95% CI, 1.28 to 3.38). Five (21%) pts remain on treatment. Conclusions: R plus P generated no new safety signals and demonstrated antitumor activity in pts with previously treated advanced urothelial carcinoma. Clinical trial information: NCT02443324.

VICTOR: Vinflunine in advanced metastatic transitional cell carcinoma of the urothelium: A retrospective analysis of the use of vinflunine in multi-centre real life setting as second line chemotherapy through Free of Charge Programme for patients in the UK and Ireland.

There is no standard of care in the UK or Ireland for second-line chemotherapy for patients with advanced transitional cell carcinoma (TCCU). Vinflunine is approved for TCCU patients who have failed a platinum-based regimen, and is standard of care in Europe but is not routinely available in the UK. Data were collected retrospectively on patients who received vinfluine as a second-line treatment. The aims were to document the toxicity and efficacy in a real life setting. Data were collected on 49 patients from 9 sites across the UK and Ireland [median age, 64 (IQR, 57–70) years, 33 males]. All patients had advanced metastatic TCCU. Thirteen patients had bone or liver metastases, 4 patients had PS 2 and 11 patients had HB <10. Median vinflunine administration was 3.5 cycles (range 1–18). Most common grade 3–4 toxicities were constipation (4 patients) and fatigue (3 patients). Partial response rate was 29% (14 PR, 11 SD, 19 PD, 4 NE, 1 not available). Median OS was 9.1 (6.0, 12.7) months. Results are consistent with real life data from Europe. Toxicity is further reduced with prophylactic laxative and oral antibiotics. Vinflunine is an efficient and tolerable second line treatment in advanced TCCU.

800P - VICTOR: Vinflunine in advanced metastatic transitional cell carcinoma of the urothelium (TCCU): a retrospective analysis of the use of vinflunine in multi-centre real life setting as second line chemotherapy through free of charge programme (FOCP) for patients in the UK and Ireland

800P - VICTOR: Vinflunine in advanced metastatic transitional cell carcinoma of the urothelium (TCCU): a retrospective analysis of the use of vinflunine in multi-centre real life setting as second line chemotherapy through free of charge programme (FOCP) for patients in the UK and Ireland

2632 VICTOR: Vinflunine in advanced metastatic transitional cell carcinoma of the urothelium (TCCU): A retrospective analysis of the use of Vinflunine in a multi-centre real life setting as second line chemotherapy through the free of charge programme (FOCP) for patients in the UK

2632 VICTOR: Vinflunine in advanced metastatic transitional cell carcinoma of the urothelium (TCCU): A retrospective analysis of the use of Vinflunine in a multi-centre real life setting as second line chemotherapy through the free of charge programme (FOCP) for patients in the UK

VICTOR: Vinflunine (Vin) in advanced metastatic transitional cell carcinoma of the urothelium (TCCU)—A retrospective analysis of use of Vin in multicenter, real life setting as second-line chemotherapy (ChT) through free-of charge-programme (FOCP) for patients (pts) in the UK.

352 Background: There is no standard of care currently in UK for second line ChT for pts with advanced TCC. Vin is approved for TCCU for pts who have failed a platinum-based regimen and is now the standard ChT in 2nd line in Europe based on large phase III randomised trial data showing 2.6 months survival advantage. ESMO guidelines recommended it as the only option for pts in the 2nd line setting. Vin is not currently available in NHS practice in UK as it is not on the approved list of drugs on cancer drug fund. Methods: Data are collected retrospectively on pts who received Vin as a 2nd line treatment through FOCP. The dose of Vin was 240-320 mg/m2 every 3 weeks. The aim was to document the toxicity, radiological RR and OS for pts treated with Vin in real life setting within the FOCP. Results: At the time of analysis data from 37 pts from 6 sites were available. Median pts age was 64 years(range: 57-69), 24m; 13 f. All pts had advanced metastatic TCC. 9 pts had bone or liver mets, 3 pts had PS 2 and 5 pts had HB &lt;10, all known poor prognostic indicators in palliative ChT setting. Total of 179 cycles have been delivered (median 3 ; mean 5; range1-16). Grade 3 / 4 toxicity: Anaemia 2/179, Neutropenia 2/179, Neutropenic infection 2/179, Constipation 4/179, Fatigue 3/179. Grade 2 toxicity; Anaemia 5/179, Neutropenia 13/179, Thrombocytopenia 2/179, Febrile infection 1/179, Constipation 9/179, Fatigue 20/179, Abdominal pain 2/179, Vomiting 8/179. 30 pts were evaluable for response. 11 pts had PR, 6 had SD, 13 had PD and 7 were not evaluable. Partial RR was 30 % with ITT and 37% for evaluable pts. Median OS was 9.5 (95% CI; 5.9- 16.9) months. Conclusions: Real life data showing a median OS of 9.5 m by ITT for all pts are encouraging and consistent with real life data from Europe (Spanish, German and French) presented at ESMO 2013. Toxicity has further improved with the use of prophylactic laxatives and oral antibiotics.

Pazopanib versus paclitaxel in relapsed urothelial tumors: A randomized phase II study investigating pazopanib versus weekly paclitaxel in relapsed or progressive transitional cell carcinoma of the urothelium (PLUTO).

TPS4589 Background: Urothelial cancer (UC) is a chemosensitive disease. There is a clear role for first line, platinum-based chemotherapy in advanced disease, response rates being around 40-50%. Ho...

Outcome of Metastasectomy for Urothelial Carcinoma: A Multi-Institutional Retrospective Study in Japan

We determined prognostic factors associated with prolonged survival after metastasectomy for urothelial carcinoma. A total of 42 patients who underwent resection of urothelial carcinoma metastases with curative intent at 4 Japanese university hospitals were included in analysis. Of the patients 41 of 42 underwent systemic chemotherapy before and/or after metastasectomy. Overall survival was analyzed using the Kaplan-Meier method. The relationship between clinical characteristics and survival was analyzed using the log rank test. Metastasectomy included lymph node dissection in 20 cases, pulmonary resection in 12, pelvic exenteration in 3, resection of local recurrence in 2, resection of subcutaneous metastasis in 2, liver resection in 1 and other in 2. Median overall survival was 29 months (IQR 19-80) from the initiation of treatment for metastases and 26 months (IQR 11-90) from metastasectomy. The overall 5-year survival rate after metastasectomy was 31%. On univariate analysis patients treated with metastasectomy for a solitary lung or solitary lymph node metastasis had significantly longer survival than the others who underwent metastasectomy (81 vs 19 months, log rank test p = 0.0296). Long-term cancer control could be achieved in a subgroup of patients who undergo metastasectomy, especially those with a solitary lung or solitary lymph node metastasis.

Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy

BackgroundTo compare long-term, updated overall survival (OS) of patients with advanced transitional cell carcinoma of the urothelium (TCCU) treated with vinflunine plus best supportive care (BSC) or BSC alone, after failure of platinum-based chemotherapy. Patients and methodsThree hundred and seventy patients were randomly assigned in a phase III trial and allocated (2:1) to vinflunine (320 or 280 mg/m2) plus BSC or BSC alone. The first report (Bellmunt J, Theodore C, Demkov T et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinumcontaining regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 2009; 27(27): 4454–4461) had a median follow-up of 22.1 m and the current report has a follow-up of 45.4 m. ResultsThree hundred and fifty-two patients had died (censoring rate 5%). In the intention-to-treat (ITT) population, the median OS was 6.9 m and 4.6 m for vinflunine plus BSC versus BSC alone, respectively (n.s.). In multivariate Cox analysis, the addition of vinflunine was independently correlated with improved survival (HR: 0.719; 95% CI:0.570–0.906, P = 0.0052). In the eligible population, the median OS in both the arms was 6.9 and 4.3 m, respectively (HR: 0.78; 95% CI:0.61–0.96; P = 0.0227), indicating an estimated 22% reduction in the risk of death. ConclusionsThe updated OS data confirm the positive treatment effect of vinflunine on survival that was previously reported. These results are consistent over time and confirm that vinflunine is a valuable option for second-line treatment in patients with advanced TCCU after failure of platinum-based regimens.

Vinflunine (VFL) as second-line chemotherapy for patients with transitional cell carcinoma of the urothelium (TCCU): A multicenter retrospective study.

e15620 Background: VFL is the standard chemotherapy in second-line advanced TCCU in Europe (EMA approval 21/09/2009). We set up a multicenter retrospective study to evaluate the efficacy and toxicity of VFL in patients (pts) with advanced TCCU after platinum failure within the framework of routine practice. Methods: Descriptive and retrospective study in pts who had demonstrated prior progression to a platinum-containing chemotherapy regimen at 7 centers. VFL standard dose (280-320/m2 every three weeks) was administered until progression or unacceptable toxicity. Objective response was evaluated according to RECIST criteria v.1.1. Results: Between April 2010 and December 2012, a total of 45 pts with median age of 68 years (range 47-83) were analyzed. Main characteristics: ECOG 0-1-2 in 7pts (15.6%), 33pts (73.3%), 5pts (11.1%). Mean creatinine clearance was 59 ml/min. Primary sites of disease were bladder 39pts (86.7%), renal pelvis 5pts (11.1%) and prostatic urethra 1pt (2.2%). All pts had previously received platinum-based chemotherapy as a first-line treatment (cisplatin in 45% of pts). Metastatic locations were: 27pts (60%) lymph nodes, 18pts (40%) lung, 13pts (29%) bone and 10pts (22%) liver. The median number of cycles of VFL was 5 (1-18). All pts were assessed for response, one (2.2%) patient presented complete response (CR), 11pts (24.4%) partial response (PR), 18pts (40%) stable disease (SD) and 15pts (33.4%) progressive disease (PD). Median progression-free survival was 4 months (95% CI, 2.2-5.7). Median overall survival (OS) was 11 months (95% CI, 3.5-18). OS at 6 months was 45%. Liver metastasis was the main prognostic factor for OS (p=0.04). Grade 3/4 adverse events included neutropenia 6pts (13%), constipation 4pts (9%), abdominal pain 4pts (9%) and nausea/vomiting 3pts (6%). Conclusions: This retrospective analysis confirm VFL as an active agent in pts progressing after platinum-based combination for advanced TCCU in a daily clinical practice in Spain. As ESMO (Bellmunt J, 2011) and Spanish (Castellano D, 2012) guidelines recommend vinflunine, it should be offered in this setting or alternatively, treatment within a clinical trial.

Phase I/II study of biweekly pemetrexed plus cisplatin in patients with locally advanced, nonresectable or metastatic urothelial cancer: Safety and efficacy results from phase II.

4550 Background: Pemetrexed (P) plus cisplatin (C) combination is effective against several malignant tumors. Single-agent P has shown antitumor activity in advanced urothelial cancer; we performed a phase I/II study to define the maximum tolerated dose of biweekly P plus C combination. Here, we report the final results of the phase II study. Methods: Eligible patients (pts) had locally advanced or metastatic transitional cell carcinoma of the urothelium not suitable for curative therapy, performance status (PS) 0-2, estimated life expectancy of at least 12 weeks, and adequate organ function. P and C were administered on days 1 and 15 of each 28-day cycle, up to a maximum of 6 cycles. Pts received the recommended dose from phase I, with P at 400 mg/m2 plus C at 50 mg/m2 (folic acid and vitamin B12 supplementation were also administered). Primary objective was overall response rate (ORR) according to RECIST 1.0. Results: Thirty-eight pts were recruited, 32 (84.2%) pts had bladder cancer with a mean diagnosis time of 1 (range 0-7) year and 30 (78.9%) had metastatic disease; 19 (50%) pts had visceral metastasis and 2 (5.3%) pts had a PS 2. Only 2 pts did receive adjuvant systemic therapy. Median number of cycles was 3 (range 0-7). Twelve (31.6%) pts discontinued the study treatment due to toxicity. The most common treatment-related AEs (&gt; 20%) were asthenia (n=27 pts), nausea and vomiting (n=21, respectively), diarrhea (n=18), anorexia (n=17), mucosal inflammation (n=14), and constipation (n=8). Most treatment-related AEs were of mild or moderate severity. Neutropenia (n=5) and asthenia (n=3) were the most frequent Grade 3 or 4 treatment-related AEs. Serious related AEs were observed in 8 (21.1%) pts. ORR was 39.5% (95% CI 24.0-56.6): 2 (5.3%) pts achieved complete response and 13 (34.2%) pts, partial response. Median progression free survival was 6.7 months, and median overall survival was 10.5 months. Conclusions: In this study, biweekly P (400 mg/m2) plus C (50 mg/m2) combination showed anti-tumor activity in pts with advanced urothelial cancer, with an acceptable safety profile. Clinical trial information: NCT00374868.