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 (TCC).

BACKGROUND: Excessive activation of the PI3K/Akt/mTOR pathway is frequently observed in transitional cell carcinoma (TCC) due to a loss of PTEN and/or activating mutation of PIK3CA. Allosteric mTOR inhibition by everolimus resulted in modest efficacy in advanced TCC. In different TCC cell lines, it has been shown that PI3K inhibition enhanced the efficacy of mTOR inhibitors with a synergistic effect observed mainly in cells with PI3K/Akt/mTOR pathway alterations. OBJECTIVES: To assess in a multicenter phase II trial the safety and efficacy of BEZ235, an oral pan-class I PI3K and mTOR complex1/2 inhibitor, in locally advanced or metastatic 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 received BEZ235 until progressive disease (PD) or unacceptable toxicity. The primary endpoint was the progression free survival (PFS) rate at 16 weeks. This study was, however, closed prematurely due to BEZ235 being withdrawn from further development. RESULTS: Twenty 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 PFS was 62 days (95% confidence interval (CI) 53 - 110 days; range 38 - 588 days) and the median OS was 127 days (95% CI 58 - 309 days; range 41 - 734 days). Among the 90% of patients who presented with any grade drug-related adverse events, 50% presented with grade 3 - 4 adverse events including stomatitis (15%), fatigue (5%), nausea (5%), diarrhea (5%), renal failure (5%), cutaneous rash (5%), hepatotoxicity (5%) and hypertension (5%), CONCLUSIONS: BEZ235 showed modest clinical activity and an unfavorable toxicity in patients with advanced and pretreated TCC. However, a minority of patients presented 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. This article is protected by copyright. All rights reserved.