Second-Line Pembrolizumab Extends Survival in Urothelial Cancer

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Ronald de Wit, MD, PhD

Ronald de Wit, MD, PhD

PEMBROLIZUMAB (KEYTRUDA) extended survival by about 3 months in patients with advanced urothelial cancer whose disease progressed on platinum-based chemotherapy vs investigator’s choice of therapy, according to the mature results of the KEYNOTE-045 trial presented at the European Society for Medical Oncology (ESMO) 2017 Congress.1 As other studies have shown, only about 20% to 30% of patients respond to checkpoint inhibitors, but responders tend to have durable responses. 

Advanced/metastatic urothelial cancer is aggressive. There is no internationally accepted standard of care after patients experience disease progression on platinum-based therapy. Median survival with second-line therapy tends to be about 6 to 7 months. Pembrolizumab’s tolerability and its durability of response make it an attractive option for second-line therapy. 

“Pembrolizumab is the first agent to improve survival over chemotherapy in the second-line setting for the treatment of urothelial cancer. Not all patients benefit from checkpoint inhibition, but a sizable proportion of those who respond have very durable responses, even longer than 1 year,” said study author Ronald de Wit, MD, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. “These results are striking in the setting of urothelial cancer, which is highly lethal in the metastatic state.” 

“Even in patients who respond to second-line chemotherapy, responses tend to be short-lived, and toxicity typically prevents prolonged treatment, whereas pembrolizumab tends to be well tolerated,” Dr. de Wit noted. 

Pembrolizumab was approved by the U.S. Food and Drug Administration (FDA) in May 2017 for the treatment of patients with locally advanced or metastatic urothelial carcinoma that has progressed during or after platinum-containing therapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing therapy. In July 2017, pembrolizumab gained accelerated approval from the FDA for front-line treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. 

Study Details 

KEYNOTE-045 was conducted at 120 sites in 29 countries and enrolled 542 patients with advanced urothelial cancer that progressed within 12 months of first-line platinum-based chemotherapy. Between November 2014 and November 2015, patients were randomized 1:1 to receive treatment with either pembrolizumab at 200 mg every 3 weeks (n = 272) or investigator’s choice of chemotherapy with paclitaxel at 175 mg/m2 every 3 weeks, docetaxel at 75 g/m2 every 3 weeks, or vinflunine at 320 mg/m2 every 3 weeks (n = 270). 

“Overall, the superior survival, better adverse-event profile, and better quality of life render pembrolizumab a new standard of care for second-line treatment of advanced urothelial cancer.”
— Ronald de Wit, MD, PhD

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Baseline characteristics were similar between the two treatment arms. Median age was around 66 years. Programmed cell death ligand 1 (PD-L1) composite positive score of ≥ 10% was found in 27.4% of those in the pembrolizumab arm and 33.1% in the chemotherapy arm. In this trial, responses were independent of PD-L1 expression on tumor or infiltrating immune cells. 

Survival Results 

MATURE RESULTS at 22.5 months of follow-up showed an approximately 3-month absolute difference in overall survival for pembrolizumab vs investigator’s choice of chemotherapy: median overall survival of 10.3 vs 7.4 months, respectively, with a hazard ratio (HR) of 0.70, reflecting a 30% improvement (P = .0003). These results confirm the interim analysis reported earlier this year.2 

Overall survival was longer with pembrolizumab compared with chemotherapy regardless of age, presence of liver metastases and visceral metastases, hemoglobin levels, and choice of chemotherapy. Eighteen-month overall survival rates were 33.2% for pembrolizumab compared with 19.7% for chemotherapy. 

Interestingly, although there was an overall survival difference at longer follow-up, median progression-free survival was not significantly different between the two study arms: 2.1 vs 3.3 months, respectively. 

Response Rates and Toxicity 

THE OBJECTIVE RESPONSE rate was approximately doubled with pembrolizumab over chemotherapy: 21.1% vs 11%. Response rates with pembrolizumab were more durable than those with chemotherapy. The median duration of response was not yet reached in the pembrolizumab arm vs 4.4 months in the chemotherapy arm. 


  • As second-line therapy, pembrolizumab improved overall survival compared with chemotherapy by an absolute difference of 3 months.
  • Pembrolizumab achieved durable responses, some lasting more than 1 year, and had a more favorable safety profile than chemotherapy.
  • This is the first agent to show a survival benefit for urothelial cancer in the second-line setting.

The toxicity profile of pembrolizumab was improved over that of chemotherapy, and no new safety signals for pembrolizumab were raised. Treatment-related adverse events of any kind were reported in 62% of the pembrolizumab group compared with 91% of those treated with second-line chemotherapy. Grade 3 or higher adverse events were reported in 16.5% of the pembrolizumab group compared with 50.2% of the chemotherapy group. Immune-related adverse events were reported in 19.5% of patients on pembrolizumab compared with 7.5% of patients on chemotherapy. Treatment discontinuation due to an adverse event occurred in 7.1% compared with 12.5%, respectively. 

Quality of life measured at week 15 showed better results in the pembrolizumab arm. 

“Overall, the superior survival, better adverse-event profile, and better quality of life render pembrolizumab a new standard of care for second-line treatment of advanced urothelial cancer,” Dr. de Wit concluded. ■

DISCLOSURE: Dr. de Wit is a steering committee member of the trial and a compensated consultant for Merck, Roche, and Lilly. 


1. de Wit R, Vaughn DJ, Fradet Y, et al: Pembrolizumab versus paclitaxel, docetaxel, or vinflunine for recurrent, advanced urothelial cancer: Mature results from the phase 3 KEYNOTE-045 trial. ESMO 2017 Congress. Abstract LBA37_PR. Presented September 10, 2017. 

2. Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376:1015-1026, 2017.

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