Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma

BACKGROUND: Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.

METHODS: In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1–expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more.

RESULTS: The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%).

CONCLUSIONS: Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 number, NCT02256436.)

The New England Journal of Medicine. March 16, 2017; 376:1015-1026 [Epub]

Joaquim Bellmunt, MD, PhD,1,2 Ronald de Wit, MD, PhD,4 David J. Vaughn, MD,6 Yves Fradet, MD,7 Jae-Lyun Lee, MD, PhD,8 Lawrence Fong, MD,9 Nicholas J. Vogelzang, MD,10 Miguel A. Climent, MD,3 Daniel P. Petrylak, MD,11 Toni K. Choueiri, MD,1 Andrea Necchi, MD,12 Winald Gerritsen, MD, PhD,5 Howard Gurney, MD,13 David I. Quinn, MD, PhD,14 Stéphane Culine, MD, PhD,15 Cora N. Sternberg, MD,16 Yabing Mai, PhD,17 Christian H. Poehlein, MD,17 Rodolfo F. Perini, MD,17 and Dean F. Bajorin, MD18 for the KEYNOTE-045 Investigators

1. Dana–Farber Cancer Institute, Boston, Massachusetts
2. Parc de Salut Mar, Hospital del Mar Medical Research Institute, Barcelona, Spain
3. Fundación Instituto Valenciano de Oncología, Valencia, Spain
4. Erasmus MC Cancer Institute, Rotterdam, The Netherlands
5. Radboud University Medical Center, Nijmegen, The Netherlands;
6. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
7. Centre Hospitalier Universitaire de Québec–Université Laval, Quebec, QC, Canada
8. Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea
9. The University of California, San Francisco, San Francisco, California
10. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
11. Smilow Cancer Hospital, Yale University, New Haven, Connecticut
12. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
13. Westmead Hospital and Macquarie University, Sydney, Australia
14. The University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, California
15. Hôpital Saint-Louis, Paris, France
16. San Camillo and Forlanini Hospitals, Rome, Italy
17. Merck, Kenilworth, New Jersey
18. Memorial Sloan Kettering Cancer Center, New York, New York 

N Engl J Med 2017; 376:1015-1026; DOI: 10.1056/NEJMoa1613683