Phase II study of everolimus in metastatic urothelial cancer
Article first published online: 23 JUL 2013
© 2013 The Authors. BJU International © 2013 BJU International
Volume 112, Issue 4, pages 427–428, August 2013
How to Cite
Smith, A. B. and Pruthi, R. S. (2013), Phase II study of everolimus in metastatic urothelial cancer. BJU International, 112: 427–428. doi: 10.1111/j.1464-410X.2012.11717.x
- Issue published online: 23 JUL 2013
- Article first published online: 23 JUL 2013
Advanced urothelial cancer (UC) is a disease with high mortality, limited treatment options and few significant improvements in the last 10–20 years. Second-line chemotherapy trials have thus far generated disappointing results [1, 2]. The authors of the present paper should be applauded for their willingness to tackle a difficult patient population with multiple comorbidities, rapid clinical progression and high mortality. They explore the benefit and safety of everolimus, a mammalian target of rapamycin inhibitor, in a phase II study, which enrolled patients with known metastatic UC who have progressed after first-line platinum-based chemotherapy. The findings reported in the present paper are in line with another recently published study investigating the effectiveness of everolimus in patients with palliative UC . The safety analysis of the drug did reveal an increased rate of toxicity (as compared with other treatment sites such as RCC ), but this may be reflective of an older population with more comorbidities. Despite these toxicities, the convenience of the drug must also be considered. In patients who may want to avoid further clinic and hospital visits, an orally administered drug may not only improve compliance but also provide an option that differs from the rigorous treatment visits that are often required with standard chemotherapy. Notwithstanding these safety and tolerability concerns, the primary endpoint for the study was 2-month progression-free survival (PFS) ≥70%. Although this was not reached, a small subset of patients experienced significant benefits from the drug, one of whom achieved a 94% decrease in target lesions and has remained on the drug for over 2 years.
The benefit seen in this subset of patients lends itself nicely to molecular medicine and the concept of genotypic treatment algorithms, and this is where we may see the true advantage of everolimus in the treatment of advanced UC. Associated biomarkers may not have been strongly observed in the present study, but a borderline associationobserved between phospho-4E-BP1 expression and PFS at 2 months may lead to further prospective studies that can outline the association more clearly. Defining these associations will be a logical ‘next step’ not only for UC but also for other genitourinary malignancies, such as prostate adenocarcinoma and RCC. Stratifying patients based on prognostic biomarkers may lead to the targeted use of drugs and ultimately create a patient-tailored approach in which the appropriate therapy is chosen based upon the patient's particular biomarkers. To this end, molecular screening of tumours in large research centres is essential with the creation of large biorepositories to identify candidate biomarkers and appropriately stratify patients, thereby linking to prognosis and treatment, an ultimately advancing the field of genitourinary oncology.