Phase II study of everolimus in metastatic urothelial cancer

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. Keywords: bladder cancer, everolimus, mTOR, transitional cell carcinoma, urothelial cancer Introduction In the USA, urothelial carcinoma (UC) of the bladder is a common malignancy, with over 70 000 cases and 14 000 deaths occurring in 2010 [1]. Although representing a chemosensitive malignancy, the median survival of patients with metastatic UC is ≈ 15 months [2]. Second-line chemotherapy trials have yielded discouraging response rates in the range 10–30% with a progression-free survival (PFS) of between 2 and 3 months and a median survival of 6–9 months [3]. In Europe, vinflunine, a novel fluorinated vinca alkaloid, is approved for previously treated patients with advanced UC based on a modest improvement in survival compared to best supportive care alone seen in the eligible (6.9 vs 4.3 months; P = 0.040) but not in the intent-to-treat population [4]. No agent approved by the Food and Drug Administration exists for this setting because conventional chemotherapy has shown no survival benefit in patients with metastatic UC progressing after first-line platinum-based chemotherapy. The development of novel agents for advanced UC is desperately needed. Targeted therapies have shown activity in multiple tumour types, including genitourinary cancers. Two agents that inhibit mammalian target of rapamycin (mTOR), temsirolimus and everolimus, are approved for treating patients with advanced kidney cancer [5,6]. mTOR is a ubiquitous serine-threonine kinase and a downstream component of the phosphoinositol 3-kinase (PI3K)/Akt/phosphatase and tensin homologue (PTEN) signalling pathway, playing a critical role in the regulation of protein synthesis, cell growth, proliferation, survival and angiogenesis [7]. mTOR is comprised of two structurally and functionally distinct multiprotein signalling complexes: mTOR-complex 1 (mTORC1) and mTOR-complex 2 (mTORC2) [8]. mTORC1 is predominantly activated through the PI3K/Akt pathway [9] and mTORC1-mediated signalling is sensitive to rapamycin and its derivatives, including everolimus [10]. A major function of mTOR relates to its regulation of mRNA translation through the downstream intermediates: eukaryotic initiation factor 4E binding protein (4E-BP1) and the 40S ribosomal S6 kinase (p70S6K1) [10]. To gauge the potential for mTOR-targeted therapy in UC, we performed an immunohistochemical analysis of phospho-S6 and phospho-4E-BP1 expression in a tissue microarray prepared from 92 cases of ≥ pT2 UC of the bladder [11]. Grade 2–3+ expression of phospho-4E-BP1 and phospho-S6 was shown in 58% and 34% of the tumours, respectively, including a moderate correlation with immunoreactivity observed between mTOR pathway markers, suggesting that the pathway is active in UC and providing the rationale for a trial targeting mTOR in this disease. Everolimus is an oral derivative of rapamycin that selectively inhibits mTOR and has shown activity in multiple malignancies, leading to its approval by the Food and Drug Administration for advanced kidney cancer, advanced pancreatic neuroendocrine tumours and subependymal giant cell astrocytomas [6,12,13]. Everolimus inhibits the growth of bladder cancer cell lines in vitro and has activity in nude mouse models in vivo, including the inhibition of protein synthesis through S6K and 4E-BP1, as well as inhibition of angiogenesis [14,15]. Based on the above observations supporting a potential role for mTOR inhibition in UC, the present trial evaluated everolimus in patients with advanced UC who have progressed after first-line therapy.