Multicentre randomised phase II trial of gemcitabine + platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2
Introduction
Urothelial carcinoma of the bladder is estimated to be the 5th most prevalent cancer in Europe, with a 3- to 4-fold higher likelihood of occurrence in men than in women. The estimated age-standardised rate per 100,000 was 14.4 for incidence and 4.5 for mortality in 2012 (data for both sexes in Europe) [1]. The prognosis of patients with advanced or metastatic urothelial carcinoma (UC) is poor. The standard first-line regimen for advanced UC is cisplatin-based combination therapy, initially MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) and, more recently, the combination gemcitabine + cisplatin (GC). MVAC and GC provide similar median overall survival (OS) (14 and 15.2 months, respectively) but GC has a more favourable toxicity profile [2]. A large proportion (30–50%) of patients, however, is deemed ineligible for cisplatin-based chemotherapy [3]. The alternative gemcitabine + carboplatin combination has given a 30–40% overall response rate (ORR) and a median 4- to 5-month progression-free survival (PFS) [4], [5], [6]. The only randomised phase III trial comparing two carboplatin-based chemotherapy regimens is EORTC study 30986 (gemcitabine + carboplatin versus methotrexate/carboplatin/vinblastine) in patients unfit for cisplatin chemotherapy. In the gemcitabine-carboplatin arm, median PFS and OS were 5.8 and 9.3 months, respectively [7].
It has been suggested that a way forward in the treatment of UC patients with advanced or metastatic disease may be on the lines of the advances made in the targeted treatment of metastatic breast and gastric carcinoma, where trastuzumab (Herceptin®) based therapy has shown substantial benefit in patients presenting tumours with overexpression and/or amplification of the ERBB2 gene, aka Her2 (from human epidermal growth factor receptor 2). Trastuzumab is a recombinant humanised anti-Her2 monoclonal antibody. Unfortunately, the reported incidence of Her2 protein overexpression and gene amplification in UC varies extremely widely (9–81% for overexpression; 0–32% for amplification) and its prognostic value has not been definitively established (Supplementary Table S1) [8], [9]).
Early case reports reported encouraging results in metastatic (m) UC patients with trastuzumab in combination with gemcitabine/carboplatin or cisplatin [10], [11]. These results were, however, not fully borne out in later open studies with either trastuzumab or the dual epidermal growth factor/Her2 tyrosine kinase inhibitor, lapatinib [12], [13]. No comparative randomised studies have been reported. Back in 2004, we decided to conduct a randomised phase II study comparing gemcitabine and platinum salt, with or without trastuzumab, in patients with advanced or metastatic UC with Her2 overexpression. The primary end-point was PFS. Secondary end-points were ORR, OS, toxicity, and quality of life.
Section snippets
Study design
This was an open-label comparative, randomised, multicentre phase II trial performed in 17 centres (16 in France and 1 in Belgium) (Registry number: NCT01828736). It was sponsored by ARTIC (Association pour la Recherche de Thérapeutiques Innovantes en Cancérologie) and approved by the French national ethics committee (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale) of Ile-de-France X and the Ethics Committee of the Catholic University of Leuven in Belgium. A signed
Patient characteristics
From February 2004 to October 2009, 563 patients were screened for Her2 status. Because of the lower than expected inclusion rate (1.1 patients/month), the independent Data Monitoring Committee decided to prematurely stop the study. Among the screened patients, 75 (13.3%) were Her2 positive (i.e. IHC 2+/3+ and FISH+). However, only 61 out of these 75 patients met all other required eligibility criteria and could thus be randomised to treatment (Fig. 1).
The main characteristics of the 61 included
Discussion
The main difficulty encountered in this trial was recruitment of UC patients with locally advanced or metastatic disease whose tumours overexpressed Her2. We screened 563 patients before realising that we would not reach the 338 patient threshold for a high-power study. Our power calculations were based on a 30% incidence of Her2 overexpression. Despite the wide range of reported values, this was a reasonable estimate at the time of the study design and, according to many published studies,
Funding
This work was supported by Roche SAS.
Conflict of interest statement
SO: Consultant/advisory role for Roche; honoraria from Roche; PB: Consultant/advisory role for Roche; honoraria from Roche; GD: Research funding from Roche; AR: Research funding from GlaxoSmithKline; SC, JLM, FG, CT, TN, EV, EB, AV, FP, GG, JMV, JPM, XM, MFP, JOB, RE, CT and FB: no conflicts of interest.
Acknowledgements
The authors thank all patients and their families for their participation and Adela Banu for data monitoring.
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Registry number: clinicaltrials.gov/ct/show/NCT01828736.