Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma
By J. Bellmunt, R. de Wit, D. Vaughn, Y. Fradet, Jae-Lyun Lee, L. Fong, N. Vogelzang, M. Climent, D. Petrylak, T. Choueiri and 10 more. New England Journal of Medicine, 2017
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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 ClinicalTrials.gov number, NCT02256436.)
Subfields: Oncology, Pulmonary and Respiratory Medicine, Surgery
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Citations in the corpus
- Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence (2020, positive): “This was based on improved 3 month OS, with a lower rate of toxicity noted in the Keynote-045 trial [60] (Category 2A).”
- Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic (2018, background): “PD-L1 expression by IHC is an FDA-approved companion diagnostic test for pembrolizumab in NSCLC, gastric / gastroesophageal junction adenocarcinoma, cervical cancer and UC [15-20], and has shown some predictive ability across several other cancer types including head and neck and small cell lung car”
- Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4 (2019, background): “(HNSCC) [15], non-small cell lung cancer (NSCLC) [16], metastatic urothelial carcinoma [17], cervical carcinoma [18] among others in a list that continues to grow.”