J Clin Oncol 27: by American Society of Clinical Oncology INTRODUCTION

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1 VOLUME 27 NUMBER 27 SEPTEMBER JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Phase III Trial of Vinflunine Plus Best Supportive Care Compared With Best Supportive Care Alone After a Platinum-Containing Regimen in Patients With Advanced Transitional Cell Carcinoma of the Urothelial Tract From the Vall d Hebron University Hospital; University Hospital del Mar-IMIM, Barcelona, Spain; Hopital Foch, Suresnes; Centre Oscar Lambret, Lille; Institut de Recherche Pierre Fabre, Boulogne; Hôpital Henri Mondor, Créteil, France; Marie Curie Institute, Warsaw; SPZ Pulmonologii Oddzial Onkologii, Olsztyn, Poland; City Polyprofile Hospital N2, Saint Petersburg; Medical Radiological Research Center, Kaluga Region, Russian Federation; Herlev University Hospital, Herlev; Rigshospitalet, Copenhagen, Denmark; and Department of Oncology, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada. Submitted November 10, 2008; accepted May 8, 2009; published online ahead of print at on August 17, Supported by Pierre Fabre, Paris, France. Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL, and at the 33rd Congress of the European Society for Medical Oncology, September 12-16, 2008, Stockholm, Sweden. Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Joaquim Bellmunt, MD, Department of Medical Oncology, University Hospital Del Mar, Passeig Marítim 25-29, E Barcelona, Spain; jbellmunt@imas.imim.es. The Appendix is included in the full-text version of this article, available online at It is not included in the PDF version (via Adobe Reader ) by American Society of Clinical Oncology X/09/ /$20.00 DOI: /JCO Joaquim Bellmunt, Christine Théodore, Tomasz Demkov, Boris Komyakov, Lisa Sengelov, Gedske Daugaard, Armelle Caty, Joan Carles, Agnieszka Jagiello-Gruszfeld, Oleg Karyakin, François-Michel Delgado, Patrick Hurteloup, Eric Winquist, Nassim Morsli, Yacine Salhi, Stéphane Culine, and Hans von der Maase A B S T R A C T Purpose Vinflunine (VFL) is a new microtubule inhibitor that has activity against transitional cell carcinoma of urothelial tract (TCCU). We conducted a randomized phase III study of VFL and best supportive care (BSC) versus BSC alone in the treatment of patients with advanced TCCU who had experienced progression after a first-line platinum-containing regimen. Patients and Methods The study was designed to compare overall survival (OS) between patients receiving VFL BSC (performance status [PS] 0: 320 mg/m 2, every 3 weeks; PS 0 with previous pelvic radiation and PS 1: 280 mg/m 2 subsequently escalated to 320 mg/m 2 ) or BSC. Results Three hundred seventy patients were randomly assigned (VFL BSC, n 253; BSC, n 117). Both arms were well balanced except there were more patients with PS more than 1 (10% difference) in the BSC arm. Main grade 3 or 4 toxicities for VFL BSC were neutropenia (50%), febrile neutropenia (6%), anemia (19%), fatigue (19%), and constipation (16%). In the intent-to-treat population, the objective of a median 2-month survival advantage (6.9 months for VFL BSC v 4.6 months for BSC) was achieved (hazard ratio [HR] 0.88; 95% CI, 0.69 to 1.12) but was not statistically significant (P.287). Multivariate Cox analysis adjusting for prognostic factors showed statistically significant effect of VFL on OS (P.036), reducing the death risk by 23% (HR 0.77; 95% CI, 0.61 to 0.98). In the eligible population (n 357), the median OS was significantly longer for VFL BSC than BSC (6.9 v 4.3 months, respectively), with the difference being statistically significant (P.040). Overall response rate, disease control, and progressionfree survival were all statistically significant favoring VFL BSC (P.006, P.002, and P.001, respectively). Conclusion VFL demonstrates a survival advantage in second-line treatment for advanced TCCU. Consistency of results exists with significant and meaningful benefit over all efficacy parameters. Safety profile is acceptable, and therefore, VFL seems to be a reasonable option for TCCU progressing after first-line platinum-based therapy. J Clin Oncol 27: by American Society of Clinical Oncology INTRODUCTION In Europe, transitional cell carcinoma of the urothelial tract (TCCU) is the fourth most frequent malignancy, accounting for 136,000 new cases and representing approximately 7% of all human neoplasms. Overall, approximately 49,000 deaths in Europe are related to this neoplasm, and epidemiologic data for this tumor are similar to the North American experience. 1-3 Untreated metastatic TCCU is associated with a median survival time rarely exceeding 3 to 6 months; it is a chemotherapy-sensitive tumor and cisplatin-based chemotherapy is the standard treatment, 4-7 without an approved or established option for second-line treatment. 8,9 Vinflunine (VFL; Pierre Fabre Médicament, Paris, France) is a novel microtubule inhibitor selected for its particular mechanism of action and its higher level of in vivo antitumour activity compared by American Society of Clinical Oncology

2 Vinflunine Second-Line Therapy in Advanced Urothelial Carcinoma with that of previous drugs of the same family VFL is distinguished from the other vinca-alkaloids because it binds relatively weakly to tubulin, suggesting an improved tolerance profile as a result of less neurotoxicity. 13,15,16 The activity of other vinca alkaloids in first-line TCCU formed the rationale for a phase II trial in 51 patients previously treated with a platinum-containing therapy who were treated with VFL 320 mg/m 2 every 3 weeks. The study achieved a 17% response rate and long-duration responses ranging from 4.2 to 15.0 months (median, 9.1 months). 16 A further phase II trial conducted in 151 patients with platinum-resistant disease confirmed these results (overall response rate [ORR], 15.9%; median duration of response, 6 months). 17 On the basis of the phase II data, a phase III study of VFL in second-line TCCU was initiated. This trial is a randomized, multinational study of VFL and best supportive care (BSC) in second-line treatment of patients with advanced TCCU who have experienced progression after a platinum-containing regimen. PATIENTS AND METHODS Eligibility Eligible patients required histologically confirmed locally advanced or metastatic TCCU, documented progression after first-line platinumcontaining chemotherapy, age 18 years, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Prior radiation was allowed if affecting less than 30% of the bone marrow and completed 30 days before random assignment with full recovery of related toxicity. Patients were required to have adequate hematologic, hepatic, and renal (calculated clearance of creatinine 40 ml/min by the Cockcroft-Gault formula) function. Treatment Plan Patients were randomly assigned 2:1 to either VFL BSC (study arm) or BSC alone (control arm). Random assignment was stratified by study site and by refractoriness to previous platinum treatment. Refractory patients were those who had disease progression within the first two cycles of chemotherapy administered in the first-line setting. The protocol was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. 18 All patients randomly assigned to the study arm were initially treated with VFL 320 mg/m 2 every 21 days as a 20-minute infusion. After the first 10 treated patients, serious hematologic adverse events occurred in three patients; all of these three patients had multiorgan involvement and large tumor burdens. Prior phase II experience also suggested that hematologic toxicity was exacerbated by prior pelvic irradiation. The protocol was amended so that patients with an ECOG PS of 0 and without previous irradiation of the pelvic area received VFL 320 mg/m 2 plus BSC. Patients with an ECOG PS of 1 and patients with an ECOG PS of 0 with previous irradiation of the pelvic area received VFL 280 mg/m 2 plus BSC at the first cycle, with dose escalating to VFL 320 mg/m 2 plus BSC if no hematologic toxicities causing treatment delay occurred. BSC was administered according to institutional standards (including palliative radiotherapy, antibiotics, analgesics, corticosteroids, and transfusion). VFL was to be delayed by 1 week or a maximum of 2 weeks in case of grade 3 or greater neutropenia or thrombocytopenia or nonhematologic toxicity on the day of VFL administration. If any of the following occurred, the dose was to be reduced to 280 mg/m 2 from the next cycle on: grade 4 neutropenia lasting more than 7 days and/or febrile neutropenia between two subsequent administrations of VFL; grade 2 mucositis and/or constipation lasting more than 5 days; or any other grade 3 toxicity related to VFL (except grade 3 vomiting or nausea). If, after a dose reduction, this toxicity was seen again, the dose was to be further reduced to 250 mg/m 2. If, at this dose level, the same event recurred, the treatment was to be discontinued. No dose re-escalation was allowed after dose reduction. For patients starting treatment at 280 mg/mg 2 and who were never escalated to a dose of 320 mg/m 2, only one dose reduction was allowed (250 mg/m 2 ). In the study arm, treatment was administered until documented progression, unacceptable toxicity, or patient refusal. In the control arm, visits were recorded until there was an inability to meet the 3-week schedule, progressive disease requiring systemic anticancer therapy, or patient refusal. Tolerance was assessed throughout the treatment period and before each administration according to the National Cancer Institute Common Toxicity Criteria (version 2.0). Clinical Assessment Preregistration assessments included a detailed medical history, computed tomography scan, magnetic resonance imaging, and physical examination (in case of superficial lymph node or skin nodule) for tumor assessment. All positive imaging procedures at entry had to be repeated every 6 weeks. Efficacy was assessed both by investigators and an independent review committee using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. 19 An assessment of symptoms was made at entry and then throughout treatment in both arms at the same intervals. Physical examination and vital signs were assessed on day 1 of each cycle. A CBC count and a biochemical assessment were taken at baseline and during treatment before each cycle. Quality-of-Life and Patient Benefit Assessment Clinical benefit was a composite end point based on PS (assessed every 3 weeks), weight, pain index (using McGill Pain Questionnaire), analgesic consumption, and use of palliative radiotherapy. Quality-of-life assessments were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 before random assignment and on days 21, 42, 84, and 126 in both arms of the study. Statistical Methods The estimated number of events was based on the following clinical hypothesis: median survival time of 6 months for the study arm and 4 months for the control arm. A total of 290 events would be needed for the detection of survival superiority with a type I error rate of 5% and a power of 90%, using a two-sided log-rank test and a 2:1 random assignment. Sample size estimation also took into account projected accrual time and losses to follow-up; thus, 364 patients were planned for inclusion. The primary end point was a comparison of overall survival between the two arms based on the stratified log-rank test performed at P.05 level in the intent-to-treat (ITT) population. Overall survival analysis was also carried out in the eligible population (post hoc analysis). The secondary end points were comparison of progression-free survival (PFS) and disease control rate (sum of complete response, partial response, and stabilization) between the two arms in an ITT population; estimation of ORRs in the VFL BSC arm was performed with a 95% CI in the evaluable population. A multivariate Cox analysis on survival taking into account the prespecified prognostic factors (alkaline phosphatase, hemoglobin, visceral metastases, PS, presence of lymph nodes metastases, and pelvic radiotherapy) was performed. Clinical benefit and quality-of-life questionnaires were analyzed. Time-to-event data used Kaplan- Meier curves and life-tables by treatment arm. Patient characteristics and safety were analyzed using descriptive methods. RESULTS Three hundred seventy patients (VFL BSC, n 253; BSC, n 117) were enrolled and randomly assigned between May 2003 and August 2006 at 83 active study sites in 21 countries. Demographics Baseline demographics were well balanced between the two arms (Table 1). However, 10% more patients having an ECOG PS of 1 were assigned to the VFL BSC arm compared with the BSC arm by American Society of Clinical Oncology 4455

3 Bellmunt et al Table 1. Patient Demographics and Clinical Characteristics VFL BSC (n 253) BSC (n 117) Patient Demographics and Clinical Characteristics No. of Patients % No. of Patients % All treated patients Eligible population Age, years ECOG PS Creatinine clearance in the treated population, ml/min Missing No. of organs involved Visceral involvement Patients experiencing relapse or progression within 6 months after the prior chemotherapy Prior pelvic/abdominal irradiation Prior therapy with platinum-based regimen Cisplatin and no other platinum Carboplatin and no other platinum Other platinum combination Abbreviations: VFL, vinflunine; BSC, best supportive care; ECOG PS, Eastern Cooperative Oncology Group performance status. Used for safety analysis. Excludes patients presenting at baseline with one or more of four significant protocol deviations ( one previous chemotherapy regimen, no locally advanced or metastatic histologically proven transitional cell carcinoma of urothelial tract at study entry, no progression after first-line platinum-containing chemotherapy for advanced disease, and patients having received a neoadjuvant or adjuvant chemotherapy). Percentages based on 250 patients in the BSC VFL arm and 108 patients in the BSC arm. The randomly assigned population corresponds to the ITT population, and all treated patients were used for safety analyses. The eligible population was defined by excluding 13 noneligible patients who presented at least one major protocol violation at baseline (Table 1; Fig 1). Primary End Point: Survival Although the objective of the median 2-month survival advantage favoring VFL BSC versus BSC was achieved (6.9 v 4.6 months, respectively) and the risk of death was reduced by 12% in the study arm versus control arm (hazard ratio [HR] 0.88; 95% CI, 0.69 to 1.12), this difference was not statistically significant (P.287; Fig 2). However, the multivariate analysis of overall survival in the ITT population adjusting for prespecified prognostic factors demonstrated that VFL has a statistically significant treatment effect on overall survival (P.036; Table 2). With this model, VFL reduced the risk of death by 23% compared with BSC (HR 0.77; 95% CI, 0.61 to 0.98). In the eligible population (Fig 3), the objective of achieving a 2-month survival difference in OS between the VFL BSC and BSC arms was met (6.9 v4.3 months, respectively), and the risk of death was reduced by 22% (HR 0.78; 95% CI, 0.61 to 0.99); this difference is statistically significant (P.040). Thirty-four percent of the patients in the BSC arm received subsequent chemotherapy compared with 28.9% of patients in the VFL BSC arm (Appendix Table A1, online only). The median follow-up time for the analysis was 21.5 months (95% CI, 16.7 to 25.3 months) for the VFL BSC arm and 22.3 months (95% CI, 18.7 to 28.5 months) for the BSC arm. Secondary End Points All of the results (ORR, disease control rate and duration, and PFS) significantly favored patients treated with VFL BSC (Table 3). The ORR, disease control rate, and median PFS were significantly higher in the study arm versus the control arm (ORR: 8.6% v 0%, respectively; P.006; disease control rate: 41.1% v 24.8%, respectively; P.002; median PFS: 3.0 v 1.5 months, respectively; P.001; HR 0.68; 95% CI, 0.54 to 0.86). Study Drug Exposure and Global Tolerability The median duration of treatment was similar in the study and control arms (9.5 v 9.4 weeks, respectively). The extent of exposure to the study drug was satisfactory, with 58% of patients receiving 90% of the planned VFL dose-intensity. A total of 65 patients (36%) who were initially treated with VFL 280 mg/m 2 had a dose escalation to 320 mg/m 2 at cycle 2. Myelosuppression was common, with VFL resulting in grade 3 to 4 levels of neutrophils and/or leukocytes reported for approximately half of VFL-treated patients; however, this toxicity was reversible and only led to discontinuation of two patients (Table 4). One patient in by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

4 Vinflunine Second-Line Therapy in Advanced Urothelial Carcinoma Randomly allocated (n = 370) Allocated to VFL + BSC arm (n = 253) Received allocated treatment (n = 248) Did not receive allocated treatment (n = 5) Nontreated patients (n = 5) Discontinued before treatment due to unrelated AE (n = 4) Discontinued due to death from unrelated AE (n = 1) Allocated to BSC arm (n = 117) Received allocated treatment (n = 117) Receiving treatment at the cutoff date (n = 3) Discontinuation (n = 250) Progressive disease (n = 139) Related AE (n = 30) Unrelated AE (n = 23) Patient s refusal (n = 25) Death from progression (n = 5) Death from related AE (n = 1) Death from unrelated AE (n = 10) Deviation from protocol (n = 5) Other (n = 12) Lost to follow-up after study discontinuation (n = 4) Analyzed in ITT (n = 253) Excluded from analysis (n = 0) Analyzed in eligible population (n = 249) Excluded from analysis of eligible population due to major deviation at baseline (n = 4) No histologically proven TCC at study entry; no progression after first-line platinum-containing chemotherapy for advanced disease; patients having received a neoadjuvant or adjuvant chemotherapy (n = 1) No progression after first-line platinum-containing chemotherapy for advanced disease; patients having received a neoadjuvant or adjuvant chemotherapy (n = 2) Patients having received a neoadjuvant or adjuvant chemotherapy; more than one line of chemotherapy (n = 1) Analyzed in per-protocol population (n = 244) Excluded from analysis of per-protocol population (n = 9) Not treated (n = 5) Major deviation at baseline (n = 4) Receiving treatment at the cutoff date (n = 1) Discontinuation (n = 116) Completion of the 18-week period (n = 34) Progressive disease (n = 31) Unrelated AE (n = 7) Patient s refusal (n = 11) Death from progression (n = 19) Death from unrelated AE (n = 1) Deviation from protocol (n = 9) Lost to follow-up (n = 1) Other (n = 3) Analyzed in ITT (n = 117) Excluded from analysis (n = 0) Analyzed in eligible population (n = 108) Excluded from analysis of eligible population due to major deviation at baseline (n = 9) No histologically proven TCC at study entry; no progression after first-line platinum-containing chemotherapy for advanced disease; patients having received a neoadjuvant or adjuvant chemotherapy (n = 1) No progression after first-line platinum-containing chemotherapy for advanced disease (n = 3) No progression after first-line platinumcontaining chemotherapy for advanced disease; patients having received a neoadjuvant or adjuvant chemotherapy (n = 5) Analyzed in per-protocol population (n = 107) Excluded from analysis of per-protocol population (n = 10) Major deviation at baseline (n = 9) Major deviation on study (n = 1) Fig 1. CONSORT diagram. VFL, vinflunine; BSC, best supportive care; AE, adverse event; ITT, intent to treat; TCC, transitional cell carcinoma. the BSC arm had grade 4 neutropenia. Febrile neutropenia was reported in 6% of patients in the VFL BSC and led to discontinuation of one patient. The most common nonhematologic adverse events reported with VFL treatment were fatigue, constipation, nausea, anorexia, weight loss, vomiting, abdominal pain, alopecia, and stomatitis. The most common grade 3 to 4 adverse events in BSC patients were fatigue, constipation, and abdominal pain. The frequency of peripheral sensory neuropathy was similar and low in both arms. In the study arm, 11% of patients died on study or within 30 days of the last VFL dose/visit compared with 23% of patients in the BSC arm; deaths were mainly a result of disease progression. Only one patient s death was drug related in the study arm (Table 4). Quality of Life and Clinical Benefit VFL did not induce a decrease in health-related quality of life when compared with BSC alone (P.66, repeated measures analysis). By week 18, there was a positive change in the global health status score in the study arm, whereas in the control arm, there was a continuous decrement in change from baseline through week 18. VFL did not produce a worsening of the clinical benefit of patients. More patients received at least one palliative radiotherapy treatment in the BSC arm (4% in the study arm v 24% in the control arm), and the palliative treatment was delivered significantly earlier in the BSC arm (at 6 months, administered to 5% patients in the study arm v 26% in the control arm) by American Society of Clinical Oncology 4457

5 Bellmunt et al Overall Survival (probability) VFL + BSC BSC VFL + BSC BSC n = 253 n = 117 No. of events No. censored 49 (19.4%) 14 (12.0%) Median OS (mo) (95% Cl) (5.7 to 8.0) (4.1 to 7.0) Hazard ratio (95% CI) 0.88 (0.69 to 1.12) Stratified log-rank P.2868 Overall Survival (probability) VFL + BSC BSC VFL + BSC BSC n = 249 n = 108 No. of events No. censored 47 (18.9%) 10 (9.3%) Median OS (mo) (95% Cl) (5.7 to 8.0) (3.8 to 5.4) Hazard ratio (95% CI) 0.78 (0.61 to 0.99) Stratified log-rank P Time (months) Time (months) Fig 2. Overall survival (OS) in the intent-to-treat population (n 370). VFL, vinflunine; BSC, best supportive care. Fig 3. Overall survival (OS) in the eligible population (n 357; 96.5% of intent-to-treat population). VFL, vinflunine; BSC, best supportive care. DISCUSSION This large multinational study of VFL BSC versus BSC alone shows that VFL treatment provides a 2-month prolongation in median survival. This advantage was not statistically significant in the ITT population (370 patients), whereas a multivariate analysis adjusted for prespecified covariates demonstrated a significant treatment effect of VFL (P.036). In the eligible population (357 patients), a statistically longer survival was achieved for patients in the VFL BSC arm versus patients in BSC arm (P.040), and furthermore, this survival benefit was observed without any detrimental effect on quality of life in patients receiving VFL. There is no established treatment for patients with advanced bladder cancer who experience progression after first-line platinumbased regimens, and second-line treatment in this setting is an unmet medical need. TCCU is a chemotherapy-sensitive tumor, and a large number of drugs, either alone or in combination, have been studied in the salvage setting. However, most series are typically small ( 60 patients) with substantial heterogeneity in terms of eligibility criteria, definition of second-line treatment, and patient characteristics, precluding any formal assumption of the potential benefit provided with the experimental drug. This is the case when comparing ORR and survival data obtained with other available agents like docetaxel and pemetrexed, Table 2. Multivariate Analysis of Overall Survival in All Randomly Assigned Patients Using a Cox Proportional Hazard Model Variables at Random Assignment Hazard Ratio 95% CI P Treatment group to Alkaline phosphatase to Hemoglobin to Visceral involvement to ECOG performance status to Pelvic irradiation to Abbreviation: ECOG, Eastern Cooperative Oncology Group. Wald 2 test. which seem to give better results than those reported with VFL 16,17,20-37 ; response rates of 13% and 28% and median survival times of 9 and 9.6 months, respectively, have been reported with these agents. 23,36 However, patient heterogeneity, patient selection, and eligibility criteria Table 3. Efficacy Results: Secondary End Points End Point VFL BSC BSC P No. of randomly assigned patients Overall response in evaluable patients No. of patients Complete response No. of patients 0 0 % 0 0 Partial response No. of patients 16 0 % Stable disease No. of patients % Objective response rate.0063 No. of patients 16 0 % % CI, % 5.0 to 13.7 Disease control.0024 No. of patients % % CI, % 35.0 to to 33.6 Duration of response, months Median % CI 4.5 to 17.0 Duration of disease control, months Median % CI 5.0 to to 4.9 PFS, months.0012 Median % CI 2.1 to to 2.3 Abbreviations: VFL, vinflunine; BSC, best supportive care; PFS, progressionfree survival by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

6 Vinflunine Second-Line Therapy in Advanced Urothelial Carcinoma Table 4. Most Common Treatment-Related Adverse Events and Hematologic Abnormalities VFL BSC BSC Overall Incidence Grade 3 or 4 Overall Incidence Grade 3 or 4 Adverse Event No. of Patients % No. of Patients % No. of Patients % No. of Patients % Fatigue/asthenia Nausea Vomiting Stomatitis/mucositis Abdominal pain Constipation Myalgia Neuropathy sensory Alopecia Infusion/injection site reaction Anemia Neutropenia Thrombocytopenia Febrile neutropenia Abbreviations: VFL, vinflunine; BSC, best supportive care. One pancytopenia drug-related death. (mixing first- and second-line treatment) need to be taken into account when establishing indirect comparisons. For example, in the pemetrexed trial, six of the responding patients had received only prior neoadjuvant therapy. 36 Additionally, the heterogeneity in reported results calls for caution; for example, in a trial studying pemetrexed as second-line therapy, the trial was closed prematurely because of insufficient activity. 37 Therefore, the lack of consensus for standard secondline therapy, the efficacy results observed with VFL in a well-defined second-line TCCU population, 16,17 and their clinical relevance, combined with an acceptable safety profile, prompted a phase III randomized study comparing VFL BSC versus BSC. To our knowledge, this is the first and only randomized study ever conducted in the TCCU second-line setting of patients previously treated with a platinum-based regimen. This was a pure second-line trial requiring confirmed progression of advanced disease for inclusionandexcludingpatientswhohadreceivedpriorpreoperativechemotherapy. The possibility for patients to be allocated to the BSC arm favored the enrollment of a population with unfavorable disease characteristics. As matter of fact, 40% of patients had bulky disease ( three metastatic locations), more than 70% had visceral involvement, and more than 80% experienced relapse or progression within 6 months after prior chemotherapy. The efficacy and safety results observed in the VFL BSC arm are consistent with the previous results of the two phase II studies conducted in Europe and the United States achieving, irrespective of the characteristics of the second-line TCCU patients, a median survival time of at least 6 months and a PFS time of approximately 3 months. VFL achieved response rates of 15.9% and 17% in two phase II studies; these rates are in the range of the those observed with the best contemporary single agents, 16,17,20-37 whereas the lower response rate (8.6%) observed in the phase III trial compared with phase II data reflects the large disease burden of the patients included. Although the objective of a median survival advantage of 2 months favoring VFL BSC versus BSC was achieved in the ITT population (6.9 v 4.6 months, respectively), the log-rank test was not statistically significant. Plausible explanations should be sought by examining some limitations of the trial. In this study, an imbalance of 10% was noticed for PS favoring the control arm. This trial was initially not stratified by PS, which has proved to be an important prognostic factor in the first-line setting 38 ; patients were only stratified by study site and refractoriness to previous platinum treatment. A multivariate analysis using a Cox proportional hazards model adjusted for prespecified prognostic factors showed that VFL BSC reduced the risk of death by 23% compared with BSC alone (P.036). This analysis now allows recognition of those prognostic factors that are important in the second-line setting and thus will help in the design of future trials. Major clinical deviations from the eligibility criteria were observed in the ITT population. Thirteen noneligible patients presented at least one major protocol violation at baseline. The overall survival analysis conducted in the eligible population (96.5% of randomly assigned population) showed a median survival advantage of 2 months favoring the VFL BSC arm versus the BSC arm (6.9 v 4.3 months, respectively), and a statistically significant survival difference between the two arms was achieved (P.040), with the risk of death being reduced by 22%. The eligible population corresponds to the population targeted by the protocol, and the overall survival analysis conducted in this population is acceptable as being a comparison of randomly assigned groups because the violations cannot be a result of treatment. As expected, VFL-treated patients presented more toxicities than BSC alone patients. The most frequent grade 3 or 4 toxicity was neutropenia (50%), with neutropenic fever occurring in 6% of patients. Constipation was the second most frequent grade 3 or 4 toxicity reported (16%); this could be of concern for such a frail population if prophylaxis is not routinely prescribed, but this toxicity was observed mainly in the first and second cycles, suggesting that it was not a cumulative event. Constipation is a class effect of vinca alkaloids but was also reported by one fourth of the patients in the control arm. Abdominal pain, asthenia, and sensory neuropathy were present with by American Society of Clinical Oncology 4459

7 Bellmunt et al similar frequency in both arms, consistent with the advanced stage of the disease and the impact of previous platinum treatment. Finally, and to support phase III survival data results, the clinical benefits demonstrated with VFL in the TCCU second-line phase II studies are confirmed. The statistically significant better response rate, disease control, and PFS reported with VFL BSC highlight the intrinsic activity of VFL and provide a meaningful control of the disease, which is recognized as being of great importance for patients in such setting. Furthermore, the results of the quality-of-life assessments show that VFL, despite being a cytotoxic drug, does not alter the quality-of-life parameters when compared with BSC alone. Both findings confirm the efficacy of VFL on the symptoms of the disease and are more impressive by being achieved in a fragile population with advanced disease. The safety profile is acceptable, manageable, and without cumulative toxicity. Given these results, VFL seems to be a reasonable option for patients with TCCU who experience progression after first-line platinum-based chemotherapy and should be considered in the future for incorporation into combination therapy. Meanwhile, efforts should be directed to invest resources wisely and efficiently in identifying novel agents/combinations to be definitively tested in a phase III setting. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCO s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: François-Michel Delgado, Pierre Fabre (C); Patrick Hurteloup, Pierre Fabre (C); Nassim Morsli, Pierre Fabre (C); Yacine Salhi, Pierre Fabre (C) Consultant or Advisory Role: Joaquim Bellmunt, Pierre Fabre (C); Stéphane Culine, Pierre Fabre (C); Hans von der Maase, Pierre Fabre (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Joaquim Bellmunt, François-Michel Delgado, Patrick Hurteloup, Stéphane Culine, Hans von der Maase Financial support: François-Michel Delgado, Patrick Hurteloup Administrative support: François-Michel Delgado, Patrick Hurteloup, Eric Winquist Provision of study materials or patients: Joaquim Bellmunt, Christine Théodore, Tomasz Demkov, Boris Komyakov, Lisa Sengelov, Gedske Daugaard, Armelle Caty, Joan Carles, Agnieszka Jagiello-Gruszfeld, Oleg Karyakin, Eric Winquist, Stéphane Culine, Hans von der Maase Collection and assembly of data: Joaquim Bellmunt, François-Michel Delgado, Patrick Hurteloup, Stéphane Culine, Hans von der Maase Data analysis and interpretation: Joaquim Bellmunt, François-Michel Delgado, Patrick Hurteloup, Nassim Morsli, Yacine Salhi, Stéphane Culine, Hans von der Maase Manuscript writing: Joaquim Bellmunt Final approval of manuscript: Joaquim Bellmunt, Christine Théodore, Tomasz Demkov, Boris Komyakov, Lisa Sengelov, Gedske Daugaard, Armelle Caty, Joan Carles, Agnieszka Jagiello-Gruszfeld, Oleg Karyakin, François-Michel Delgado, Patrick Hurteloup, Eric Winquist, Nassim Morsli, Yacine Salhi, Stéphane Culine, Hans von der Maase REFERENCES 1. 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