Phase II study of everolimus in metastatic urothelial cancer

Abstract

What's known on the subject? and what does the study add?: No recent advances have been made in the treatment of patients with advanced bladder cancer and, to date, targeted therapies have not resulted in an improvement in outcome. The mammalian target of rapamycin pathway has been shown to be up-regulated in bladder cancer and represents a rational target for therapeutic intervention. In the present phase II study of everolimus, one near-complete response, one partial response and several minor responses suggest that everolimus possesses biological activity in a subset of patients with bladder cancer. To maximize benefit from targeted agents such as everolimus, the preselection of patients based on molecular phenotype is required.

Objective: To assess the efficacy and tolerability of everolimus in advanced urothelial carcimoma (UC).

Patients and methods: The present study comprised a single-arm, non-randomized study in which all patients received everolimus 10 mg orally once daily continuously (one cycle = 4 weeks). In total, 45 patients with metastatic UC progressing after one to four cytotoxic agents were enrolled between February 2009 and November 2010 at the Memorial Sloan-Kettering Cancer Center. The primary endpoints were 2-month progression-free survival (PFS) and the safety of everolimus, with the secondary endpoint being the response rate. A Simon minimax two-stage design tested the null hypothesis that the true two month PFS rate was ≤ 50%, as opposed to the alternative hypothesis of ≥ 70%.

Results: The most common grade 3/4 toxicities were fatigue, infection, anaemia, lymphopaenia, hyperglycaemia and hypophosphataemia. There were two partial responses in nodal metastases, with one patient achieving a 94% decrease in target lesions and remaining on drug at 26 months. An additional 12 patients exhibited minor tumour regression. There were 23 of 45 (51%) patients who were progression-free at 2 months with a median (95% CI) PFS of 2.6 (1.8-3.5) months and a median (95% CI) overall survival of 8.3 (5.5-12.1) months. No clear association was observed between mammalian target of rapamycin pathway marker expression and 2-month PFS.

Conclusions: Although everolimus did not meet its primary endpoint, one partial response, one near-complete response and twelve minor regressions were observed. Everolimus possesses meaningful anti-tumour activity in a subset of patients with advanced UC. Studies aiming to define the genetic basis of everolimus activity in individual responders are ongoing.

Trial registration: ClinicalTrials.gov NCT00805129.

Keywords: bladder cancer; everolimus; mTOR; transitional cell carcinoma; urothelial cancer.

Conflict of interest statement

Conflict of Interest: Matthew I. Milowsky received research funding from Novartis Pharmaceuticals Corporation.

© 2013 BJU International.

Figures

Fig. 1

Kaplan–Meier plots of progression-free survival (PFS) and overall survival (OS) for (A) all 45 patients and (B) the 37 evaluable patients.

Fig. 2

CT scan showing near-complete response in para-aortic lymphadenopathy in a major responder treated with everolimus. Baseline imaging shows moderate para-aortic adenopathy (*); follow-up imaging shows a remaining sub-centimetre node (arrow). The change in appearance of the inferior liver and right kidney on the follow-up scan is the result of a combination of different inspiratory effort and interval mild right hydronephrosis with cortical scarring and atrophy.

Fig. 3

Pretreatment tumour sample with over-expression of phospho-S6 and phospho-4E-BP1 and an absence of phosphatase and tensin homologue (PTEN) staining in tumour cells (note retained PTEN staining in blood vessels – positive internal control). H&E, haematoxylin and eosin.