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

BJU Int. 2016 Sep;118(3):408-15. doi: 10.1111/bju.13415. Epub 2016 Feb 11.


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 This study was, however, closed prematurely because BEZ235 was withdrawn from further development.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.

Keywords: BEZ235; PI3K inhibitor; mTOR inhibitor; transitional cell carcinoma.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Transitional Cell / drug therapy*
  • Carcinoma, Transitional Cell / pathology
  • Carcinoma, Transitional Cell / secondary
  • Female
  • Humans
  • Imidazoles / therapeutic use*
  • Male
  • Middle Aged
  • Phosphoinositide-3 Kinase Inhibitors
  • Prospective Studies
  • Quinolines / therapeutic use*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Urologic Neoplasms / drug therapy*
  • Urologic Neoplasms / pathology


  • Antineoplastic Agents
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinolines
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • dactolisib