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, KEYNOTE-045 Investigators, Elizabeth McCaffrey, Andrew Hill, Shahrokh Shariat, Wolfgang Loidl, Renate Pichler, Hellmut Samonigg, Brieuc Sautois, Jean-Pascal Machiels, Robyn Macfarlane, Cesar Sanchez, Luis Matamala, Mette Kempel, Mads Agerbaek, Lisa Sengelov, Helle Pappot, Sylvie Zanetta, Aude Flechon, Jerome Alexandre, Stephane Oudard, Andreas Neisius, Axel Merseburger, Martin Boegemann, Axel Merseburger, Lajos Geczi, Laszlo Mangel, Peter Nyirady, Agnes Ruzsa, Laszlo Landherr, Sean McDermott, Avishay Sella, Stephen Frank, Daniel Keizman, Raanan Berger, Keren Rouvinov, Eli Rosenbaum, Avivit Peer, Giovanni Lo Re, Enrico Cortesi, Rosa Tambaro, Francesco Ferrau, Satoshi Fukasawa, Akito Yamaguchi, Wataru Obara, Tatsuya Takayama, Hideki Enokida, Hidefumi Kinoshita, Mototsugu Oya, Akira Yokomizo, Minato Yokoyama, Naoto Sassa, Kiyohide Fujimoto, Toshihiro Saito, Kazuo Nishimura, Teruo Inamoto, Masafumi Oyama, Hiroshi Kitamura, Hiroomi Kanayama, Hiroyuki Nishiyama, Tomoyuki Kato, Yoshiaki Yamamoto, M P Hendriks, Fritha Hanning, David Gibbs, Svein Helle, Gunnar Tafjord, Silvia Neciosup, Tomasz Demkow, Antonio Quintela, Nuno Vau, Deana Hallman-Navarro, Michael Schenker, Dana Stanculeanu, Ravindran Kanesvaran, Bhumsuk Keam, Sun Young Rha, Jose Arranz, Daniel Castellano Gauna, Enrique Espinosa, Marta Lopez Brea, Javier Puente, Anna Laurell, Po-Hui Chiang, Hsi-Chin Wu, Wu-Chou Su, Chia-Chi Lin, Yen-Hwa Chang, Mahmut Gumus, Halit Karaca, Zeynep Turna, Arzu Yaren, Darren Mitchell, Vincent Khoo, Glenn Bubley, Petros Grivas, Matthew Galsky, Arjun Balar, Long Dang, Alexandra Drakaki, Christopher Hoimes, James Randall, Peter O'Donnell, Matthew Milowsky, Elizabeth Guancial, Bradley Somer, 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, KEYNOTE-045 Investigators, Elizabeth McCaffrey, Andrew Hill, Shahrokh Shariat, Wolfgang Loidl, Renate Pichler, Hellmut Samonigg, Brieuc Sautois, Jean-Pascal Machiels, Robyn Macfarlane, Cesar Sanchez, Luis Matamala, Mette Kempel, Mads Agerbaek, Lisa Sengelov, Helle Pappot, Sylvie Zanetta, Aude Flechon, Jerome Alexandre, Stephane Oudard, Andreas Neisius, Axel Merseburger, Martin Boegemann, Axel Merseburger, Lajos Geczi, Laszlo Mangel, Peter Nyirady, Agnes Ruzsa, Laszlo Landherr, Sean McDermott, Avishay Sella, Stephen Frank, Daniel Keizman, Raanan Berger, Keren Rouvinov, Eli Rosenbaum, Avivit Peer, Giovanni Lo Re, Enrico Cortesi, Rosa Tambaro, Francesco Ferrau, Satoshi Fukasawa, Akito Yamaguchi, Wataru Obara, Tatsuya Takayama, Hideki Enokida, Hidefumi Kinoshita, Mototsugu Oya, Akira Yokomizo, Minato Yokoyama, Naoto Sassa, Kiyohide Fujimoto, Toshihiro Saito, Kazuo Nishimura, Teruo Inamoto, Masafumi Oyama, Hiroshi Kitamura, Hiroomi Kanayama, Hiroyuki Nishiyama, Tomoyuki Kato, Yoshiaki Yamamoto, M P Hendriks, Fritha Hanning, David Gibbs, Svein Helle, Gunnar Tafjord, Silvia Neciosup, Tomasz Demkow, Antonio Quintela, Nuno Vau, Deana Hallman-Navarro, Michael Schenker, Dana Stanculeanu, Ravindran Kanesvaran, Bhumsuk Keam, Sun Young Rha, Jose Arranz, Daniel Castellano Gauna, Enrique Espinosa, Marta Lopez Brea, Javier Puente, Anna Laurell, Po-Hui Chiang, Hsi-Chin Wu, Wu-Chou Su, Chia-Chi Lin, Yen-Hwa Chang, Mahmut Gumus, Halit Karaca, Zeynep Turna, Arzu Yaren, Darren Mitchell, Vincent Khoo, Glenn Bubley, Petros Grivas, Matthew Galsky, Arjun Balar, Long Dang, Alexandra Drakaki, Christopher Hoimes, James Randall, Peter O'Donnell, Matthew Milowsky, Elizabeth Guancial, Bradley Somer
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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Source: PubMed