Immunotherapy and mTOR inhibitors a new perspective in the treatment of advanced and metastatic urothelial carcinomas.

Bladder cancer is the seventh cause of cancer death in men and the tenth in women. In metastatic disease, the prognosis remains poor, with a median survival of 15 months. Chemotherapy has remained standard systemic therapy over the past 15 years for patients with recurrent or metastatic disease. The therapeutic regimens recommended by guides in metastatic disease, as the first treatment line, are the combination of gemcitabine and platinum salts or the MVAC combination. Currently, there is no second-line standard systemic therapy for patients with tumor relapse after first-line chemotherapy. Therefore, the treatment of advanced and metastatic urothelial tumors remains a challenge for oncologists. Following radical cystectomy, more than half of patients with invasive urothelial carcinoma will develop recurrent disease. The excellent results obtained in the treatment of other solid tumors using targeted therapies such as tyrosine kinase inhibitors or CTLA-4 anti-CTL-4 or PD1 inhibitor immunotherapy have led to the idea that these therapies could be used with promising results in the treatment of metastatic bladder cancer. The acquisition of mutations in the PI3K/AKT/mTOR intracellular signal transduction pathway has been demonstrated in over 40% of bladder cancers, suggesting that blocking the mTOR pathway would be a promising target therapy in this pathology. Starting from this idea, there are currently several phase I and II studies of mTOR inhibitors like temsirolimus or sirolimus, the preliminary results being encouraging. In terms of immunotherapy in metastatic bladder cancer, there are currently several phase I or phase II studies testing anti-CTLA-4 therapy (ipilimumab) or PD1 inhibitors (nivolumab). Besides these molecules, there are studies that test new molecules such as MPDL3280A, MEDI4736 and MK3475 (lambrolizumab). All preliminary data show the efficacy of these new therapies in metastatic urothelial carcinoma. Our paper aims to review these new therapies by presenting the undergoing studies for recurrent and metastatic urothelial carcinoma with the preliminary results and safety profile of these new agents. In the future, we will have a new standard in the systemic treatment of advanced and metastatic urothelial carcinomas. [ABSTRACT FROM AUTHOR]