Phase II study of dual phosphoinositol‐3‐kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma. (11th February 2016)

• Record Type: Journal Article
• Authors: Seront, Emmanuel; Rottey, Sylvie; Filleul, Bertrand; Glorieux, Philippe; Goeminne, Jean‐Charles; Verschaeve, Vincent; Vandenbulcke, Jean‐Marie; Sautois, Brieuc; Boegner, Petra; Gillain, Aline; van Maanen, Aline; Machiels, Jean‐Pascal
• Is Part Of: BJU international. Volume 118:Number 3(2016:Aug.)
• Page Start: 408
• Page End: 415
• Publication Date: 2016-02-11
• Subjects: BEZ235 -- PI3K inhibitor -- mTOR inhibitor -- transitional cell carcinoma; Genitourinary organs -- Diseases -- Periodicals; Genitourinary organs -- Surgery -- Periodicals; Urology -- Periodicals; 616.6
• DOI: 10.1111/bju.13415
• Languages: English
• ISSNs: 1464-4096

Abstract

Abstract : Objective: To assess, in a multicentre phase II trial, the safety and efficacy of BEZ235, an oral pan‐class I phosphoinositol‐3‐kinase (PI3K) and mammalian target of rapamycin (mTOR) complex1/2 inhibitor, in locally advanced or metastatic transitional cell carcinoma (TCC) after failure of platinum‐based therapy. Patients and Methods: Patients with locally advanced or metastatic TCC progressing after platinum therapy were prospectively stratified by PI3K/Akt/mTOR pathway alterations, defined as PTEN loss and PIK3CA mutation. All patients received BEZ235 until progressive disease or unacceptable toxicity. The primary endpoint was the progression‐free survival (PFS) rate at 16 weeks. This study was, however, closed prematurely because BEZ235 was withdrawn from further development. Results: A total of 20 patients (18 without and two with PI3K/Akt/mTOR alterations) were enrolled and received BEZ235. One partial response (5%) and two cases of stable disease (10%) were observed, all in patients without PI3K/mTOR pathway alterations. The PFS rate at 8 and 16 weeks was 15 and 10%, respectively; the median (range) PFS was 62 (38–588) days (95% confidence interval [CI] 53–110); and the median (range) overall survival was 127 (41–734) days (95% CI 58–309). Among the 90% of patients who experienced drug‐related adverse events of any grade, 50% experienced grade 3–4 adverse events, including stomatitis (15%), fatigue (5%), nausea (5%), diarrhoea (5%), renal failure (5%), cutaneous rash (5%), hepatotoxicity (5%) and hypertension (5%). Conclusion: BEZ235 showed modest clinical activity and an unfavourable toxicity profile in patients with advanced and pretreated TCC; however, a minority of patients experienced a clinical benefit, suggesting that a complete blockade of the PI3K/mTOR axis could improve outcome in some specific patients. Furthermore, this study showed that molecular stratification of patients for personalized medicine before treatment is feasible.