Pembrolizumab Survival Advantage Upheld in Advanced Urothelial Carcinoma

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Joaquim Bellmunt, MD, PhD

Joaquim Bellmunt, MD, PhD

Patients with recurrent urothelial cancer had sustained improvement in overall survival at 2 years after they received second-line treatment with pembrolizumab (Keytruda) vs chemotherapy, according to an updated survival analysis of the phase III KEYNOTE-045 trial presented at the 2018 Genitourinary Cancers Symposium.1 In addition, at this median follow-up of 2 years, the median duration of response has not been reached in the pembrolizumab arm. These results mirror the initial results reported in The New England Journal of Medicine in 2017 and provide consistency to the prolonged duration of response observed with pembrolizumab in this patient population.2

At a median follow-up of 27.7 months, median survival was 10.3 months for the pembrolizumab-treated patients vs 7.3 months for those treated with investigator’s choice of chemotherapy. Pembrolizumab reduced the risk for death by 30% compared with chemotherapy as second-line treatment following disease progression on platinum-based chemotherapy (hazard ratio [HR] = 0.30; P = .00017). Both 12- and 24-month survival rates were significantly improved in patients who received pembrolizumab. Programmed cell death ligand 1 (PD-L1) expression status did not affect response to pembrolizumab treatment or the survival benefit.

“Pembrolizumab is the first immunotherapy to demonstrate superior survival over chemotherapy in patients with advanced urothelial carcinoma after failure of platinum-based therapy. This study provides level 1 evidence to support the use of pembrolizumab as standard of care in this patient population,” said lead author Joaquim Bellmunt, MD, PhD, Director of the Bladder Cancer Center at Dana-Farber Cancer Institute, Boston.

On the basis of the KEYNOTE-045 trial, pembrolizumab was approved in the United States by the U.S. Food and Drug Administration as second-line treatment of advanced urothelial carcinoma in unselected patients (for PD-L1 status). Pembrolizumab is also approved as front-line therapy for patients with urothelial carcinoma, based on the initial results of the phase II KEYNOTE-052 trial.

Study Details

KEYNOTE-045 enrolled patients with advanced urothelial carcinoma whose disease progressed on up to two previous therapies, including platinum-based therapy. Patients were randomized to receive pembrolizumab at 200 mg every 2 weeks (n = 270) or investigator’s choice of chemotherapy -(paclitaxel at 175 mg/m2, docetaxel at 75 mg/m2, or vinflunine at 320 mg/ m2 every 3 weeks, n = 272). Almost half the patients had two or more high-risk features.


  • Improved overall survival with pembrolizuamb compared with chemotherapy, regardless of the level of PD-L1 expression.
  • A survival advantage with pembrolizumab over chemotherapy initially reported in 2017 was sustained at 2-year
  • These data suggest pembrolizumab is the preferred second-line treatment over chemotherapy in patients with advanced urothelial carcinoma.

In the initial results, reported after a preplanned interim analysis with a median follow-up of 14 months, median overall survival was 10.3 months with pembrolizumab vs 7.4 months for chemotherapy (HR, 0.73; P = .0022), representing a 27% improvement in survival.2 The updated data, presented by Dr. Bellmunt, showed a 30% improvement in survival with pembrolizumab over chemotherapy (P = .00017). At 12 months, 44.4% of those in the pembrolizumab arm and 29.8% in the chemotherapy arm were alive; at 24 months, 27% vs 14.3%, respectively, were alive.

A consistent survival advantage for pembrolizumab was observed across all subgroups, including those with PD-L1–positive and PD-L1–negative tumors. PD-L1 positivity was defined as ≥ 10% PD-L1 expression in tumor cells, lymphocytes, and macrophages. In PD-L1–positive patients, median overall survival was 8 months with pembrolizumab and 4.9 months with chemotherapy. In PD-L1–negative patients, median overall survival was 10.8 months vs 7.7 months, respectively.

The objective response rate was almost double in the pembrolizumab group: 21% vs 11% with chemotherapy. The rate of complete response in the pembrolizumab arm improved to 9.3% but did not change in the chemotherapy arm. The median duration of response was not reached in the pembrolizumab arm and was 4.4 months with chemotherapy. Response rates were superior with pembrolizumab regardless of PD-L1 status.

Safety Profile

The toxicity profiles of the two treatment arms were similar to those reported in the initial publication of results. Pembrolizumab had a more favorable adverse-event profile. In the chemotherapy arm, the following adverse events were more frequent: fatigue, diarrhea, asthenia, anemia, constipation, peripheral neuropathy, decreased neutrophil count, neutropenia, and alopecia. Pembrolizumab was associated with more immune-related events, such as hypothyroidism, hyperthyroidism, pneumonitis, and colitis.

Treatment-related adverse events occurred less frequently in the pembrolizumab arm. The rate of adverse events of any grade was 60.9% with pembrolizumab vs 90.2% with chemotherapy; adverse events of grades 3 to 5 occurred in 15% vs 49.4%, respectively. Treatment discontinuation rates due to adverse events were 7.1% for those treated with pembrolizumab and 12.9% for those treated with chemotherapy. ■

DISCLOSURE: Dr. Bellmunt is on the advisory boards of MSD, BMS, Bayer, Pfizer, Merck, AstraZeneca, Sanofi, and Roche; has received honoraria from Pfizer and Pierre Fabre; and participated in clinical trials for Merck, Pfizer, and Roche.


1. Bellmunt J, De Wit R, Vaughn DJ, et al: Two-year follow-up from the phase 3 KEYNOTE-045 trial of pembrolizumab vs investigator’s choice (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer. 2018 Genitourinary Cancers Symposium. Abstract 410. Presented February 9, 2018.

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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