By Awais Zia

Urothelial carcinoma is a cancer of transitional epithelium that occurs in the urinary system including the renal pelvis, bladder, ureter, and/or urethra. Patients with urothelial carcinoma usually present with blood in the urine and frequency or urgency to urinate. Current management of metastatic urothelial carcinoma consists of first-line platinum-based chemotherapy, especially cisplatin. Cisplatin provides a median overall survival of 12 to 15 months. (Continue reading here.)

After cisplatin, second-line standard therapy consists of several drugs, and each have varied effects. These drugs include paclitaxel, docetaxel, and vinflunine. The median overall survival provided by second-line therapy is only about 6 to 7 months. This has led to investigations for a second-line therapy that is more effective than current regimens.1

In recent years, monoclonal antibodies have shown promise in combating cancer. New antibodies have been designed to prevent cancer cells from blocking the immune system, in turn allowing the immune cells to target cancer cells. An example of monoclonal antibodies that work as antitumor agents are PD-1inhibitors. Pembrolizumab is a humanized monoclonal IgG4K isotype antibody against PD-1 that binds to PD-1 receptor and prevents inhibitory signals in T cells, consequently allowing T cells to attack cancer cells. In phase 1 and phase 2 trials, pembrolizumab has shown antitumor activity in patients with advanced urothelial carcinoma. A phase 3 trial was conducted whose results were recently published in The New England Journal of Medicine. Pembrolizumab has shown to significantly increase the overall survival of patients with urothelial carcinoma as well as decrease the rate of treatment-related adverse events compared to other second-line therapy agents.1

KEYNOTE-045 was a randomized, open-label, international phase 3 trial. Patients 18 years or older with confirmed urothelial carcinoma that had progressed after platinum-based chemotherapy were eligible. A total of 542 patients were randomly assigned in a 1:1 ratio to receive either pembrolizumab or a choice of standard second-line chemotherapy (paclitaxel, docetaxel, or vinflunine). The primary endpoints were overall survival and progression-free survival. The secondary endpoints were the objective response rate, duration of confirmed response, and safety. Patients who took pembrolizumab showed a longer overall survival than patients who took standard chemotherapy (10.3 months vs. 7.4 months; hazard ratio for death, 0.73; P=0.002).

There was no significant difference in the duration of progression-free survival between the pembrolizumab group and the standard chemotherapy group. The objective response rate was significantly higher in the pembrolizumab group than the chemotherapy group (21.1% vs. 11.4%, P=0.001). The percentage of patients with a duration of response of at least 12 months was 68% in the pembrolizumab group and 35% in the standard chemotherapy group. There was a lower rate of treatment-related adverse events in the pembrolizumab group than the standard chemotherapy group (60.9% vs. 90.2%). The most common treatment-related adverse events were pruritis (19.5% of patients), fatigue (13.9%), and nausea (10.9%). Four deaths occurred in the pembrolizumab group that were attributed to treatment.1

These results suggest that pembrolizumab is an effective second-line agent that can be used to treat patients with advanced urothelial carcinoma previously treated with platin-based therapy. Pembrolizumab increased the overall survival by approximately 3 months and was less toxic than standard second-line chemotherapy. Although increased survival by 3 months may not appear high, it is still a meaningful increase for patients. Many patients with cancer get diagnosed suddenly, which comes as a shock in their lives. The period between treatment and potential recovery or death can be a painful and difficult period for many patients. Lengthening the overall survival time by even a few months can be comforting for patients as well as their families who may have to go through as much pain as patients themselves.1

The use of pembrolizumab in the clinic compared with standard second-line therapy should proceed with caution. Although pembrolizumab was less toxic than standard therapy, its use was associated with several adverse events including pruritis, fatigue, and nausea in certain patients. Moreover, four deaths were attributed to pembrolizumab use. Proper dosage and constant monitoring of patients may be necessary when administering pembrolizumab in the clinic. A patient’s past medical history and current problems should also be considered.1


  1. Bellmunt, J, de Wit R, Vaughn, DJ, et al. “Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.” N Engl J Med. DOI: 10.1056/NEJMoa1613683.

Awais is a freelance medical writer and contributor to Clinical Research Currents, living in Rockville, MD.

Citation:  Zia, Awais. Pembrolizumab increases the overall survival rate and reduces adverse events in patients with urothelial carcinoma. Clinical Research Currents March 1, 2017.