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Clinical Trial
. 2017 Mar 16;376(11):1015-1026.
doi: 10.1056/NEJMoa1613683. Epub 2017 Feb 17.

Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma

Joaquim Bellmunt  1 , Ronald de Wit  1 , David J Vaughn  1 , Yves Fradet  1 , Jae-Lyun Lee  1 , Lawrence Fong  1 , Nicholas J Vogelzang  1 , Miguel A Climent  1 , Daniel P Petrylak  1 , Toni K Choueiri  1 , Andrea Necchi  1 , Winald Gerritsen  1 , Howard Gurney  1 , David I Quinn  1 , Stéphane Culine  1 , Cora N Sternberg  1 , Yabing Mai  1 , Christian H Poehlein  1 , Rodolfo F Perini  1 , Dean F Bajorin  1 ; KEYNOTE-045 Investigators
Collaborators, Affiliations
Clinical Trial

Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma

Joaquim Bellmunt et al. N Engl J Med. .

Abstract

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 .).

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Figures

Figure 1
Figure 1. Overall Survival and Progression-free Survival in the Intention-to-Treat Population
Shown are Kaplan–Meier estimates of overall survival and progression-free survival according to treatment group. Tick marks represent patients who had data censored at the last time that they were known to be alive (Panel A) or who were known to be alive and without disease progression as assessed per Response Evaluation Criteria in Solid Tumors, version 1.1, by blinded, independent, central radiologic review (Panel B). The intention-to-treat population included all the patients who underwent randomization. The one-sided superiority thresholds for pembrolizumab were a P value of 0.0123 in the analysis of overall survival and a P value of 0.0151 in the analysis of progression-free survival. The median overall survival was 10.3 months (95% 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 (44.8 weeks [95% CI, 34.8 to 51.3] vs. 32.2 weeks [95% CI, 26.5 to 36.1]). The median progression-free survival was 2.1 months (95% CI, 2.0 to 2.2) in the pembrolizumab group and 3.3 months (95% CI, 2.3 to 3.5) in the chemotherapy group (9.1 weeks [95% CI, 8.7 to 9.6] and 14.3 weeks [95% CI, 10.0 to 15.2], respectively).
Figure 2
Figure 2. Analysis of Overall Survival in Key Subgroups
Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with 0 indicating no symptoms and higher scores indicating greater disability; a score of 2 indicates that the patient is ambulatory and capable of all self-care but is unable to carry out any work activities and is out of bed more than 50% of waking hours. The programmed death ligand 1 (PD-L1) combined positive score was defined as the percentage of tumor and infiltrating immune cells with PD-L1 expression out of the total number of tumor cells. The upper tract was defined as the renal pelvis or ureter, and the lower tract as the bladder or urethra. Risk factors include the Bellmunt risk factors of an ECOG performance-status score above 0, a hemoglobin concentration of less than 10 g per deciliter, and the presence of liver metastases, plus a time since the completion or discontinuation of previous therapy of less than 3 months. The number of patients in each of the subgroups of investigator’s choice of chemotherapy represents the number of patients who received at least one dose of that treatment (84 patients received docetaxel, 84 paclitaxel, and 87 vinflunine) plus the number of patients who received at least one dose of pembrolizumab (266). For all other subgroups, the intention-to-treat population was used. Data were missing as follows: ECOG performance-status score (10 patients), smoking status (4), histologic type (2), tumor PD-L1 combined positive score 1% cutoff (14), tumor PD-L1 combined positive score 10% cutoff (16), location of primary tumor (1), location of metastases (2), liver metastases (1), hemoglobin concentration (13), number of risk factors (15), context of most recent therapy received (2), time since most recent chemotherapy (2), and type of previous platinum therapy (2). Data for 2 patients with other histologic type and for 2 patients with other previous platinum therapy are also not shown. The dashed line indicates the rate of overall survival in the entire trial population.
Figure 3
Figure 3. Time to Response and Duration of Response in Patients with a Confirmed Objective Response
Response and disease progression were assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by blinded, independent, central radiologic review. Bars indicate the duration of response at the time of data cutoff.
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