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Journal ArticleDOI

Maintenance therapy with vinflunine plus best supportive care versus best supportive care alone in patients with advanced urothelial carcinoma with a response after first-line chemotherapy (MAJA; SOGUG 2011/02): a multicentre, randomised, controlled, open-label, phase 2 trial.

01 May 2017-Lancet Oncology (Elsevier)-Vol. 18, Iss: 5, pp 672-681

TL;DR: In patients with disease control after first-line chemotherapy, progression-free survival exceeded the acceptable threshold with vinflunine maintenance therapy, and progression- free survival was longer with v influnines maintenance therapy than with best supportive care.
Abstract: Summary Background Maintenance therapy improves outcomes in various tumour types, but cumulative toxic effects limit the choice of drugs. We investigated whether maintenance therapy with vinflunine would delay disease progression in patients with advanced urothelial carcinoma who had achieved disease control with first-line chemotherapy. Methods We did a randomised, controlled, open-label, phase 2 trial in 21 Spanish hospitals. Eligible patients had locally advanced, surgically unresectable, or metastatic transitional-cell carcinoma of the urothelial tract, adequate organ function, and disease control after four to six cycles of cisplatin and gemcitabine (carboplatin allowed after cycle four). Patients were randomly assigned (1:1) to receive vinflunine or best supportive care until disease progression. We initially used block randomisation with a block size of six. Four lists were created for the two stratification factors of starting dose of vinflunine and presence of liver metastases. After a protocol amendment, number of cisplatin and gemcitabine cycles was added as a stratification factor, and eight lists were created, still with a block size of six. Finally, we changed to a minimisation procedure to reduce the risk of imbalance between groups. Vinflunine was given every 21 days as a 20 min intravenous infusion at 320 mg/m 2 or at 280 mg/m 2 in patients with an Eastern Cooperative Oncology Group performance status score of 1, age 75 years or older, previous pelvic radiotherapy, or creatinine clearance lower than 60 mL/min. The primary endpoint was median progression-free survival longer than 5·3 months in the vinflunine group, assessed by modified intention to treat. Comparison of progression-free survival between treatment groups was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01529411. Findings Between April 12, 2012, and Jan 29, 2015, we enrolled 88 patients, of whom 45 were assigned to receive vinflunine and 43 to receive best supportive care. One patient from the vinflunine group was lost to follow-up immediately after randomisation and was excluded from the analyses. One patient in the best supportive care group became ineligible for the study and did not receive treatment due to a delay in enrolment, but was included in the intention-to-treat efficacy analysis. After a median follow-up of 15·6 months (IQR 8·5–26·0), 29 (66%) of 44 patients in the vinflunine group had disease progression and 24 (55%) had died, compared with 36 (84%) of 43 patients with disease progression and 32 (74%) deaths in the best supportive care group. Median progression-free survival was 6·5 months (95% CI 2·0–11·1) in the vinflunine group and 4·2 months (2·1–6·3) in the best supportive care group (hazard ratio 0·59, 95% CI 0·37–0·96, p=0·031). The most common grade 3 or 4 adverse events were neutropenia (eight [18%] of 44 in the vinflunine group vs none of 42 in the best supportive care group), asthenia or fatigue (seven [16%] vs one [2%]), and constipation (six [14%] vs none). 18 serious adverse events were reported in the vinflunine group and 14 in the best supportive care group. One patient in the vinflunine group died from pneumonia that was deemed to be treatment related. Interpretation In patients with disease control after first-line chemotherapy, progression-free survival exceeded the acceptable threshold with vinflunine maintenance therapy. Moreover, progression-free survival was longer with vinflunine maintenance therapy than with best supportive care. Vinflunine maintenance had an acceptable safety profile. Further studies of the role of vinflunine are warranted. Funding Pierre-Fabre Medicament.
Topics: Vinflunine (66%), Maintenance therapy (53%), Clinical endpoint (50%)

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1
Randomized phase II study of maintenance vinflunine versus best supportive care after first
line chemotherapy in patients with advanced urothelial carcinoma: The MAJA study (SOGUG
2011/02)
Jesús García-Donas, MD*
1
; Albert Font, MD*
2
; Begoña Pérez-Valderrama, MD
3
; José Antonio
Virizuela, MD
4
; Miquel Ángel Climent, MD
5
; Susana Hernando Polo, MD
6
; José Ángel Arranz,
MD
7
; Maria del Mar Llorente, MD
8
; Nuria Lainez, MD
9
; José Carlos Villa Guzmán, MD
10
; Begoña
Mellado, MD
11
; Aránzazu González del Alba, MD
12
; Daniel Castellano, MD
13
; Enrique Gallardo,
MD
14
; Urbano Anido, MD
15
; Xavier García del Muro, MD
16
; Montserrat Domènech, MD
17
; Javier
Puente, MD
18
; Rafael Morales-Barrera, MD
19
; Jose Luis Perez-Gracia, MD
20
; Joaquim Bellmunt,
MD
21
*These authors contributed equally
1
Medical Oncology, HM Hospitales Centro Integral Oncológico HM Clara Campal,
Madrid/SPAIN;
2
Medical Oncology, Insitut Català d’Oncologia, Badalona/SPAIN;
3
Medical Oncology, Hospitales Universitarios Virgen del Rocío, Sevilla/SPAIN;
4
Medical Oncology, Hospital Universitario Virgen de Macarena, Sevilla/SPAIN;
5
Medical Oncology, Instituto Valenciano de Oncología, Valencia/SPAIN;
6
Medical Oncology, Hospital Universitario Fundación Alcorcón, Alcorcón/SPAIN;
7
Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid/SPAIN;
8
Medical Oncology, Hospital General Universitario de Elda, Alicante/SPAIN;
9
Medical Oncology, Complejo Hospitalario de Navarra, Pamplona/SPAIN;
10
Medical Oncology, Hospital General Universitario de Ciudad Real, Ciudad Real/SPAIN;
11
Medical Oncology, Hospital Universitari Clínic de Barcelona, Barcelona/SPAIN;
12
Medical Oncology, Hospital Universitario Son Espases, Palma de Mallorca/SPAIN;
13
Medical Oncology, Hospital Universitario 12 de Octubre, Madrid/SPAIN;
14
Medical Oncology, Corporació Sanitària Parc Taulí, Sabadell/SPAIN;
15
Medical Oncology, Complejo Hospitalario Universitario de Santiago, Santiago de
Compostela/SPAIN;
16
Medical Oncology, Institut Català d’Oncologia Hospitalet. IDIBELL. Universitat de Barcelona.
Hospitalet de Llobregat/SPAIN;
17
Medical Oncology, Althaia Xarxa Assitencial de Manresa, Manresa/SPAIN;
18
Medical Oncology, Hospital Clínico de San Carlos, Madrid/SPAIN;

2
19
Vall d’Hebron Institute of Oncology, Vall d’ Hebron University Hospital, Universitat
Autònoma de Barcelona, Barcelona, Spain ;
20
Medical Oncology, Clínica Universidad de Navarra, Pamplona/SPAIN;
21
Medical Oncology, Hospital del Mar, Barcelona/SPAIN.
Corresponding authors:
Joaquim Bellmunt, MD, PhD
Director, Bladder Cancer Center
Dana-Farber/Brigham and Women's Cancer Center
Associate Professor, Harvard Medical School
450 Brookline Ave, Boston, MA 02215 (DANA 1230)
E-mail: Joaquim_Bellmunt@dfci.harvard.edu
Tel. +1 857 205 4684 (US) or +34 600400548 (EU)
Dr. Jesús Garcia-Donas, MD, PhD
Medical Oncology,
HM Hospitales Centro Integral Oncológico HM Clara Campal,
Madrid/SPAIN
Email: jgarciadonas@gmail.com
Tel. +34 917 567 800

3
ABSTRACT
BACKGROUND: The purpose of this trial was to evaluate if maintenance vinflunine (VFL), a
microtubule inhibitor approved by EMA as treatment after failure to platinum-containing
regimen, delays progression following disease control with first-line platinum based
chemotherapy (CT).
METHODS: Open-label, randomised study in which patients from 21 Spanish hospitals with
locally advanced/metastatic transitional cell carcinoma of the urothelial tract and adequate
organ function, with radiological response or stabilization after 4-6 cycles of a cisplatin-
gemcitabine (CG) chemotherapy (carboplatin was allowed after cycle 4) were randomized 1:1
by block randomization and stratified based on three factors: initial dose of VFL, liver
metastases and number of prior CG cycles. Patients were centrally assigned and treatment
allocation was not masked. Patients received intravenous VFL 320 mg/m
2
(or 280 mg/m
2
in
case of ECOG performance status 1, age 75 years, prior pelvic radiotherapy or creatinine
clearance < 60ml/min) every 21 days or best supportive care (BSC), until disease progression.
Primary endpoint was progression free survival (PFS) in the intention-to-treat population
(NCT01529411).
FINDINGS: 88 patients were randomized from April 2012 to January 2015, to the VFL arm
(n=45) and to the BSC arm (n=43). After a median follow-up of all population of 158 months
(range 05-487), 29 (659%) patients had progressed and 24 (545%) had died in the VFL arm,
compared to 35 (833%) and 31 (738%) in the BSC arm respectively. Median PFS was 653
months (range 202-1105) in the VFL arm and 420 months (range 177-664) in the BSC arm
(Hazard Ratio 0600, 95%CI 037-098, p=0037). Most common G3/4 adverse events in the VFL
arm were neutropenia (n=8; 18∙2%), fatigue (n=7; 159%) and constipation (n=6; 136%).
Treatment discontinuation due to drug-related adverse events occurred in 3 patients (67%) in
the VFL arm. After progression, 16 (364%) patients received treatment at the VFL arm and 25
(595%) at the BSC arm.
INTERPRETATION: Maintenance therapy with VFL in patients with disease control after first
line cisplatin-based chemotherapy provides a significant improvement in PFS with a reduction
of 40% in the risk of progression, and with an acceptable tolerability profile.
FUNDING: Pierre-Fabre Médicament.
Keywords: maintenance therapy, vinflunine, advanced or metastatic transitional cell
carcinoma of urothelial tract

4
INTRODUCTION
Transitional cell carcinoma of the urothelial tract (TCCU) is the fifth most common type of
cancer in western countries
1
.
TCCU is considered a relatively chemosensitive tumour, and high objective response rates
(ORR) are obtained with first line treatment with platinum-based regimens, varying from 40 to
70%
2-4
. Nevertheless the duration of response is limited and when progression occurs the
prognosis of these patients is generally poor
5
.
In 2000, cisplatin-gemcitabine (CG) demonstrated similar efficacy to the MVAC scheme with
less toxicity, becoming the most used combination in first-line treatment
6
. Median overall
survival (OS) in these patients is about 14 months and ORR is 49%.
In order to improve global results, several regimens have been tested in the recurrent setting,
including single agents
7
and combinations
8-10
, but all of them showed modest activity, often
associated with significant toxicity. Even though gemcitabine-paclitaxel doublet demonstrated
activity in two phase II trials
11,12
, a standard second line treatment was inexistent before 2009.
Vinflunine (VFL) is an antineoplastic agent of the vinca alkaloids family, with higher inhibition
of microtubules dynamics than other antimicrotubule drugs, exposing patients to a minor risk
of neurotoxicity
13,14
. Efficacy of VFL after failure of platinum-based chemotherapy was proved
in two phase II trials
15,16
. Afterwards, a phase III trial comparing VFL vs. best supportive care
(BSC) after prior platinum-based chemotherapy was conducted
17
. Bellmunt et al.
demonstrated that VFL significantly improved PFS (3 vs. 15 months, P = 00012), ORR (16 vs.
0%, P = 00063) and DCR (411 vs. 248%, P = 00063). An improvement in the primary endpoint
of OS was achieved (69 vs. 46; p = 029) in the intention to treat population (ITT) (n = 365),
and was statistically significant (69 vs. 43; p = 004) in the eligible population (n = 357). These
data were confirmed after a long-term follow-up of more than 35 years
18
. Because of these
results, VFL received the approval from the European Medicine Agency (EMA) for treatment of
TCCU patients after progression to a prior platinum-based regimen in September 2009
19
.
Recent results prove activity of immunecheckpoint inhibitors in patients that have progressed
to platinum-based regimens
20,21
, and have led to accelerated approval of atezolizumab, an
anti-PDL1 antibody
22
. In a phase III trial
20
, Pembrolizumab, an anti-PD1 antibody, has
demonstrated compared to CT an improvement in OS (10·3 vs 7·4 months; p = 0·0022) and
ORR (21·1 vs 11·4 %; p = 0·0011), without improvement in PFS. In this scenario of limited
progress, optimizing the use of currently available chemotherapy could clearly improve the
outcomes of disease.
Thus, an attractive approach could be to introduce maintenance therapy following first-line

5
treatment in patients who obtain disease control, as has been done in other tumours, such as
non-small cell lung cancer
23
. VFL is an attractive agent to explore in this setting since it has a
favourable toxicity profile without cumulative toxic effects.
Therefore, we designed a randomized phase II study with the primary objective of improving
progression-free survival (PFS) with VFL used as maintenance monotherapy in patients with
advanced TCCU who have reached an objective response or stabilization disease after
completing a minimum of 4 cycles of CG in first line.
METHODS
Study design
This was an open-label, 1:1, randomized phase II trial, performed at 21 institutions members of
the Spanish Oncology Genitourinary Group (SOGUG) in Spain. The Spanish Agency for Drugs
and Sanitary Products (AEMPS) and the Ethical committees approved the protocol in all
participating hospitals. The study was conducted according to the Declaration of Helsinki and
was registered in ClinicalTrials.gov (NCT01529411).
Patients
Patients were enrolled after completion of first line chemotherapy with 6 cycles of CG
(carboplatin was allowed after cycle 4), only if they had radiological response or stabilization
according to Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. Once
recruitment had started, the protocol was ammended to allow to include patients that had
received a minimum of 4 cycles of CG. Patients provided written informed consent before
inclusion in the study and for those already recruited, also after the amendment.
Enrolment should occur no later than 6 weeks from the last dose of the first line treatment.
Inclusion criteria included age between 18 and 80 years; life expectancy 12 weeks; an Eastern
Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; at least one
measurable or evaluable lesion prior to first line treatment with CG; confirmed advanced
surgically unresectable or metastatic TCCU; adequate bone marrow and organ function, with a
creatinine clearance (CrCl) 40 ml/min, according to Cockcroft-Gault formula; neutrophil count
15 x 10
9
/L; haemoglobin ≥10 g/dl; platelet count 10
12
/L; bilirubin 15 x upper limit of the
normal range (ULN); aspartate transaminase and alanine aminotransferase 25 x ULN; alkaline
phosphatase ≤5 x ULN. Neoadjuvant or adjuvant chemotherapy based on cisplatin was
allowed, provided it had been administered more than six months before the beginning of first
line chemotherapy for advanced or metastatic disease.

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Cites result from "Maintenance therapy with vinflunine..."

  • ...In a recent phase 2 study of 88 patients with advanced urothelial carcinoma who achieved stable disease after first-line cisplatin and gemcitabine treatment (MAJA, SOGUG 2011/02; NCT01529411), maintenance vinflunine resulted in longer PFS compared to BSC.(59) Median PFS was 6....

    [...]

  • ...In a recent phase 2 study of 88 patients with advanced urothelial carcinoma who achieved stable disease after first-line cisplatin and gemcitabine treatment (MAJA, SOGUG 2011/02; NCT01529411), maintenance vinflunine resulted in longer PFS compared to BSC.59 Median PFS was 6.5 months in patients treated with maintenance vinflunine compared to 4.2 months in those patients receiving BSC (hazard ratio of 0.59)....

    [...]


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H. von der Maase1, S.W. Hansen1, J.T. Roberts1, Luigi Dogliotti1  +14 moreInstitutions (1)
TL;DR: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability, and this better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.
Abstract: PURPOSE: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8, and 15; cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles. RESULTS: Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI, 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm a...

1,748 citations


Journal ArticleDOI
Joaquim Bellmunt1, Ronald de Wit2, David J. Vaughn3, Yves Fradet4  +16 moreInstitutions (11)
TL;DR: Pembrolizumab was associated with significantly longer overall survival and with a lower rate of treatment‐related adverse events than chemotherapy as second‐line therapy for platinum‐refractory advanced urothelial carcinoma.
Abstract: BackgroundPatients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options. MethodsIn this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1–expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more. ResultsThe median overall survival in the total population was 10.3 months (95% confidence interval [C...

1,697 citations