Pembrolizumab Improves Overall Survival vs Chemotherapy in Second-Line Therapy for Advanced Urothelial Carcinoma

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IN THE PHASE III KEYNOTE-045 trial reported in The New England Journal of Medicine, Joaquim Bellmunt, MD, PhD, of Dana-Farber Cancer Institute, and colleagues found that pembrolizumab (Keytruda) significantly improved overall survival vs investigator choice of chemotherapy as second-line treatment in patients with advanced urothelial cancer who had progression after platinum-based treatment.1 No significant difference in progression-free survival was observed. 

Study Details 

IN THE OPEN-LABEL TRIAL, 542 patients recruited from 120 sites in 29 countries were randomized between November 2014 and November 2015 to receive pembrolizumab (n = 270) or investigator’s choice of docetaxel, paclitaxel, or vinflunine (n = 272). Of them, 266 patients in the pembrolizumab group and 255 in the chemotherapy group received study treatment; in the chemotherapy group, 84 received docetaxel, 84 received paclitaxel, and 87 received vinflunine (a fluorinated vinca alkaloid that is European Medicines Agency approved but not approved by the U.S. Food and Drug Administration). 

The coprimary endpoints, assessed in the intent-to-treat population, were overall survival and progression-free survival among all patients and among patients with tumor programmed cell death ligand 1 (PD-L1) combined positive score (percentage of PD-L1–expressing tumor and infiltrating immune cells) of 10% or more. 

For the pembrolizumab vs chemotherapy groups: median age was 67 vs 65 years; 74% were male in both; Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1 in 97% in both; 61% vs 69% were current or former smokers; 28% vs 34% had a tumor PD-L1 score ≥ 10%; primary tumor was in the bladder or urethra in 86% in both; 89% vs 86% had visceral disease; 34% vs 35% had liver metastases; hemoglobin level was < 10 g/dL in 16% in both; the number of “Bellmunt risk factors” (ie, ECOG performance status > 0, hemoglobin level < 10 g/dL, presence of liver metastases), and time since completion or discontinuation of previous therapy < 3 months, was ≥ 2 in 41% vs 46%; and 38% of both had completed or discontinued prior therapy within 3 months before study entry. 

Overall and Progression-Free Survival 

AT A SECOND INTERIM ANALYSIS in October 2016, the data and safety monitoring committee recommended early termination of the trial on the basis of superiority of pembrolizumab for overall survival in the coprimary populations. The data in the current report are from the second interim analysis. 

Median follow-up was 14.1 months. Among all patients, median overall survival was 10.3 months (95% confidence interval [CI] = 8.0–11.8 months) in the pembrolizumab group vs 7.4 months (95% CI = 6.1–8.3 months) in the chemotherapy group (hazard ratio [HR] = 0.73, P = .002). Among patients with a tumor PD-L1 score ≥ 10%, median overall survival was 8.0 months (95% CI = 5.0–12.3 months) vs 5.2 months (95% CI = 4.0–7.4 months; HR = 0.57, P = .005). 

At 12 months, the overall survival rate was 43.9% vs 30.7%. Pembrolizumab was associated with a survival benefit in virtually all subgroups examined, including among patients with liver metastases and those with tumor PD-L1 scores < 1%. Benefit appeared to be greater in current (HR = 0.32, 95% CI = 0.15–0.68) and former smokers (HR = 0.71, 95% CI = 0.52–0.97) than in never smokers (HR = 1.06, 95% CI = 0.72–1.55). The survival benefit of pembrolizumab was similar in comparisons with each of the three study chemotherapy regimens. 


  • Pembrolizumab was associated with prolonged overall survival among all patients with advanced urothelial carcinoma and in those with a tumor PD‑L1 score ≥ 10%.
  • No difference in progression-free survival was observed.

Median progression-free survival was 2.1 months in the pembrolizumab group vs 3.3 months in the chemotherapy group (HR = 0.98, P = .42), with no significant difference observed among patients with a tumor PD-L1 score ≥ 10% (HR = 0.89, P = .24). Progression-free survival rates at 12 months were 16.8% vs 6.2%, with both progression-free survival curves starting to diverge at that time. Subsequent therapy was received by 25.2% of the pembrolizumab group and 33.5% of the chemotherapy group, including immunotherapy in 0.7% and 12.9%. 

Response Rates 

OBJECTIVE RESPONSE RATES were 21.1% vs 11.4% (P = .001). Median duration of response was not reached in the pembrolizumab group (range = 1.6+ to 15.6+ months) vs 4.3 months in the chemotherapy group (range = 1.4+ to 15.4+ months). At the time of data cutoff, responses were ongoing in 41 (72%) of 57 responders in the pembrolizumab group and 11 (35%) of 31 in the chemotherapy group. 

Adverse Events 

TREATMENT-RELATED adverse events of any grade were observed in 60.9% of the pembrolizumab group vs 90.2% of the chemotherapy group, including grade ≥ 3 adverse events in 15.0% vs 49.4%. The most common treatment-related adverse events of any grade were pruritus (19.5%), fatigue (13.9%), and nausea (10.9%) in the pembrolizumab group and alopecia (37.6%), fatigue (27.8%), and anemia (24.7%) in the chemotherapy group; no grade ≥ 3 adverse events occurred in ≥ 5% of pembrolizumab patients, compared with neutropenia (13.3%), anemia (7.8%), and febrile neutropenia (7.1%) in the chemotherapy group. 

Discontinuation of treatment due to treatment-related adverse events occurred in 5.6% vs 11.0% of patients. Treatment-related adverse events led to death in two pembrolizumab patients (pneumonitis, urinary tract obstruction, malignant neoplasm progression, and unspecified cause) and in four chemotherapy patients (sepsis in two, septic shock, and unspecified cause). 

The investigators concluded: “Pembrolizumab was associated with significantly longer overall survival [27% reduction in the risk of death] and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma.” ■

DISCLOSURE: The study was funded by Merck. For full disclosures of the study authors, visit 


1. 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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