Pembrolizumab as second-line therapy for advanced urothelial carcinoma

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

Research output: Contribution to journalArticleResearchpeer-review

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 .).

LanguageEnglish
Pages1015-1026
Number of pages12
JournalNew England Journal of Medicine
Volume376
Issue number11
Early online date17 Feb 2017
DOIs
Publication statusPublished - 16 Mar 2017

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Confidence Intervals
Carcinoma
Drug Therapy
Platinum
Neoplasms
Survival
docetaxel
Therapeutics
Disease-Free Survival
pembrolizumab
Paclitaxel
Population
Disease Progression
Cell Count
Research Personnel
Ligands
Antibodies

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Bellmunt, J., de Wit, R., Vaughn, D. J., Fradet, Y., Lee, J-L., Fong, L., ... Bajorin, D. F. (2017). Pembrolizumab as second-line therapy for advanced urothelial carcinoma. New England Journal of Medicine, 376(11), 1015-1026. https://doi.org/10.1056/NEJMoa1613683
Bellmunt, Joaquim ; de Wit, Ronald ; Vaughn, David J. ; Fradet, Yves ; Lee, Jae-Lyun ; Fong, Lawrence ; Vogelzang, Nicholas J. ; Climent, Miguel A. ; Petrylak, Daniel P. ; Choueiri, Toni K. ; Necchi, Andrea ; Gerritsen, Winald ; Gurney, Howard ; Quinn, David I. ; Culine, Stéphane ; Sternberg, Cora N. ; Mai, Yabing ; Poehlein, Christian H. ; Perini, Rodolfo F. ; Bajorin, Dean F. / Pembrolizumab as second-line therapy for advanced urothelial carcinoma. In: New England Journal of Medicine. 2017 ; Vol. 376, No. 11. pp. 1015-1026.
@article{cb49aaa31e47449ea6727dbcf7c495ea,
title = "Pembrolizumab as second-line therapy for advanced urothelial carcinoma",
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 .).",
author = "Joaquim Bellmunt and {de Wit}, Ronald and Vaughn, {David J.} and Yves Fradet and Jae-Lyun Lee and Lawrence Fong and Vogelzang, {Nicholas J.} and Climent, {Miguel A.} and Petrylak, {Daniel P.} and Choueiri, {Toni K.} and Andrea Necchi and Winald Gerritsen and Howard Gurney and Quinn, {David I.} and St{\'e}phane Culine and Sternberg, {Cora N.} and Yabing Mai and Poehlein, {Christian H.} and Perini, {Rodolfo F.} and Bajorin, {Dean F.}",
year = "2017",
month = "3",
day = "16",
doi = "10.1056/NEJMoa1613683",
language = "English",
volume = "376",
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Bellmunt, J, de Wit, R, Vaughn, DJ, Fradet, Y, Lee, J-L, Fong, L, Vogelzang, NJ, Climent, MA, Petrylak, DP, Choueiri, TK, Necchi, A, Gerritsen, W, Gurney, H, Quinn, DI, Culine, S, Sternberg, CN, Mai, Y, Poehlein, CH, Perini, RF & Bajorin, DF 2017, 'Pembrolizumab as second-line therapy for advanced urothelial carcinoma', New England Journal of Medicine, vol. 376, no. 11, pp. 1015-1026. https://doi.org/10.1056/NEJMoa1613683

Pembrolizumab as second-line therapy for advanced urothelial carcinoma. / Bellmunt, Joaquim; de Wit, Ronald; Vaughn, David J.; Fradet, Yves; Lee, Jae-Lyun; Fong, Lawrence; Vogelzang, Nicholas J.; Climent, Miguel A.; Petrylak, Daniel P.; Choueiri, Toni K.; Necchi, Andrea; Gerritsen, Winald; Gurney, Howard; Quinn, David I.; Culine, Stéphane; Sternberg, Cora N.; Mai, Yabing; Poehlein, Christian H.; Perini, Rodolfo F.; Bajorin, Dean F.

In: New England Journal of Medicine, Vol. 376, No. 11, 16.03.2017, p. 1015-1026.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pembrolizumab as second-line therapy for advanced urothelial carcinoma

AU - Bellmunt, Joaquim

AU - de Wit, Ronald

AU - Vaughn, David J.

AU - Fradet, Yves

AU - Lee, Jae-Lyun

AU - Fong, Lawrence

AU - Vogelzang, Nicholas J.

AU - Climent, Miguel A.

AU - Petrylak, Daniel P.

AU - Choueiri, Toni K.

AU - Necchi, Andrea

AU - Gerritsen, Winald

AU - Gurney, Howard

AU - Quinn, David I.

AU - Culine, Stéphane

AU - Sternberg, Cora N.

AU - Mai, Yabing

AU - Poehlein, Christian H.

AU - Perini, Rodolfo F.

AU - Bajorin, Dean F.

PY - 2017/3/16

Y1 - 2017/3/16

N2 - 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 .).

AB - 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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Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee J-L, Fong L et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. New England Journal of Medicine. 2017 Mar 16;376(11):1015-1026. https://doi.org/10.1056/NEJMoa1613683