Recent advances in medical therapy for metastatic urothelial cancer

Abstract

Cytotoxic chemotherapy has been the mainstay of medical therapy for metastatic urothelial cancer. Currently, the gemcitabine/cisplatin regimen is widely used worldwide as the standard first-line medical treatment. Very recently, in 2017, pembrolizumab, a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1, was approved as a second-line treatment to be used after platina-based chemotherapy for metastatic urothelial cancer in Japan. Based on its promising anti-tumor efficacy and manageable safety profile as demonstrated in the phase III KEYNOTE-045 trial, pembrolizumab therapy is expected to be rapidly introduced for treating metastatic urothelial cancer in clinical practice. The paradigm of medical treatment for patients with metastatic UC is dramatically changing through the introduction of this and other immune-checkpoint inhibitors. In this article, we provide a brief overview of these immune-checkpoint inhibitors and a comprehensive summary of the use of cytotoxic chemotherapy for metastatic urothelial cancer, including ongoing clinical trials.

Pembrolizumab versus chemotherapy in recurrent, advanced urothelial cancer in Japanese patients: a subgroup analysis of the phase 3 KEYNOTE-045 trial

“…According to the National Comprehensive Cancer Network, pembrolizumab is the preferred second-line therapy for patients with advanced/metastatic bladder cancer and may also be recommended as first-line therapy for patients whose tumors express PD-L1 CPS ≥ 10 or who are ineligible to receive platinum-based therapy [23]. Pembrolizumab is approved for second-line treatment of patients with advanced/metastatic UC in Japan [12]; however, there are no clear guidelines on choosing second-line therapy for these patients. In clinical practice, a variety of combination and single-agent therapies are prescribed [9,10,28].…”

“…The potential of immunotherapy in bladder cancer treatment has been known for approximately 30 years, since the efficacy of using intravesical bacillus Calmette-Guérin to provoke an immune response to treat certain types of bladder cancer was identified [11]. Programmed death ligand 1 (PD-L1) expression on tumor cells can suppress immune responses against tumors by binding to programmed death 1 (PD-1) receptors on T cells [11,12]. Monoclonal antibodies against this pathway have been developed to promote antitumor immune responses in patients with advanced or metastatic cancers; results of phase 1/2 studies showed that monoclonal antibodies have promising efficacy and manageable tolerability in management of UC [13][14][15][16][17].…”

“…Monoclonal antibodies against this pathway have been developed to promote antitumor immune responses in patients with advanced or metastatic cancers; results of phase 1/2 studies showed that monoclonal antibodies have promising efficacy and manageable tolerability in management of UC [13][14][15][16][17]. As a result, 3 anti-PD-L1 and 2 anti-PD-1 antibodies have been approved by the US Food and Drug Administration for the treatment of patients with platinum-refractory bladder cancer [11,12].…”

“…Pembrolizumab is currently the only immune checkpoint inhibitor approved in Japan for treating platinum-refractory UC [12]. A subgroup analysis of the KEYNOTE-045 study was performed to compare pembrolizumab with chemotherapy in Japanese patients with progressive UC.…”

Timing of changing therapy from gemcitabine and cisplatin chemotherapy based on real‑world data of advanced urothelial carcinoma

“…Pembrolizumab, a humanized monoclonal antibody that targets programmed death receptor-1, was associated with a significant overall survival (OS) benefit when compared with docetaxel, paclitaxel and vinflunine in the second-line treatment of metastatic UC in the Phase III trial KEYNOTE-045 (4). Since December 2017, pembrolizumab has been approved in Japan as a second-line treatment for radical unresectable UC that has become exacerbated after chemotherapy (5). However, cisplatin-based systemic chemotherapy is still the gold-standard approach for patients with advanced or metastatic UC in the first line (6)(7)(8)(9).…”