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Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial

PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with... Full description

Journal Title: The lancet oncology 2021, Vol.22 (7), p.931-945
Main Author: Powles, Thomas
Other Authors: Oudard, Stephane , Vulsteke, Christof , Fléchon, Aude , Yu, Evan Y , Imai, Kentaro , Homet Moreno, Blanca , Alva, Ajjai , Lazzaro, Mauricio Fernandez , Gatica, Gabriela , Van Aelst, Filip , Machiels, Jean-Pascal , Schallier, Denis , Brust, Leandro , Soares, Joao Paulo Holanda , Cheng, Susanna , Leal, Jose Luis , Ibanez, Carolina , Laguerre, Brigitte , Flechon, Aude , Topart, Delphine , Huillard, Olivier , Gravis, Gwenaelle , Reichardt, Peter , Herden, Jan , Pfister, David , Niegisch, Guenter , Boegemann, Martin , Gakis, Georgios , Neisius, Andreas , Thomas, Christian , Kosa, Judit Erzsebet , Bodoky, Gyorgy , Geczi, Lajos , Frank, Stephen Jay , Kejzman, Daniel , Rosenbaum, Eli , Rouvinov, Keren , Arai, Gaku , Takayama, Tatsuya , Fujimoto, Kiyohide , Tanikawa, Toshiki , Tomita, Yoshihiko , Nishimura, Kazuo , Tsujihata, Masao , Takano, Toshimi , Joraku, Akira , Kobayashi, Kazuki , De Wit, Ronald , Aarts, Maureen , Beerepoot, Laurens , Alekseev, Sergey M , Zyryanov, Alexander , Oschepkov, Vasiliy Nikolaevich , Shidin, Vladimir Aleksandrovich , Karlov, Petr Alexandrovich , Cohen, Graham Lawrence , Ruff, Paul , Lee, Nari , Rodriguez-Vida, Alejo , Grande, Enrique , Munoz Langa, Jose , Montesa Pino, Alvaro , Su, Wen-Pin , Chang, Yen-Hwa , Huang, Yi-Hsiu , Srimuninnimit, Vichien , Abali, Huseyin , Sendur, Mehmet Ali Nahit , Ozguroglu, Mustafa , Ozdogan, Mustafa , Evans, Linda , Hussain, Syed , DiSimone, Christopher , Schlegel, Peter , Mamtani, Ronac , Wallace, James , Suh, Jason Jung-Gon , Burgess, Earle , Wong, John , Chaudhry, Arvind , Thomas, Christian A , Fitzharris, John T , Oliff, Ira A , Vuky, Jacqueline , Hauke, Ralph , Joshi, Monika , Bolemon, Britt H , Markus, Maurice , Pfanzelter, Nicklas , Lawler, William Eyre , Courtright, Jay G , Doshi, Gurjyot , Sartor, Oliver Alton , Mannuel, Heather D , Alva, Ajjai , Charles, Anthony , Ades, Steven , Yu, Evan , Fleming, Mark
Format: Electronic Article Electronic Article
Language: English
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Publisher: England: Elsevier Ltd
ID: ISSN: 1470-2045
Link: https://www.ncbi.nlm.nih.gov/pubmed/34051178
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title: Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial
format: Article
creator:
  • Powles, Thomas
  • Oudard, Stephane
  • Vulsteke, Christof
  • Fléchon, Aude
  • Yu, Evan Y
  • Imai, Kentaro
  • Homet Moreno, Blanca
  • Alva, Ajjai
  • Lazzaro, Mauricio Fernandez
  • Gatica, Gabriela
  • Van Aelst, Filip
  • Machiels, Jean-Pascal
  • Schallier, Denis
  • Brust, Leandro
  • Soares, Joao Paulo Holanda
  • Cheng, Susanna
  • Leal, Jose Luis
  • Ibanez, Carolina
  • Laguerre, Brigitte
  • Flechon, Aude
  • Topart, Delphine
  • Huillard, Olivier
  • Gravis, Gwenaelle
  • Reichardt, Peter
  • Herden, Jan
  • Pfister, David
  • Niegisch, Guenter
  • Boegemann, Martin
  • Gakis, Georgios
  • Neisius, Andreas
  • Thomas, Christian
  • Kosa, Judit Erzsebet
  • Bodoky, Gyorgy
  • Geczi, Lajos
  • Frank, Stephen Jay
  • Kejzman, Daniel
  • Rosenbaum, Eli
  • Rouvinov, Keren
  • Arai, Gaku
  • Takayama, Tatsuya
  • Fujimoto, Kiyohide
  • Tanikawa, Toshiki
  • Tomita, Yoshihiko
  • Nishimura, Kazuo
  • Tsujihata, Masao
  • Takano, Toshimi
  • Joraku, Akira
  • Kobayashi, Kazuki
  • De Wit, Ronald
  • Aarts, Maureen
  • Beerepoot, Laurens
  • Alekseev, Sergey M
  • Zyryanov, Alexander
  • Oschepkov, Vasiliy Nikolaevich
  • Shidin, Vladimir Aleksandrovich
  • Karlov, Petr Alexandrovich
  • Cohen, Graham Lawrence
  • Ruff, Paul
  • Lee, Nari
  • Rodriguez-Vida, Alejo
  • Grande, Enrique
  • Munoz Langa, Jose
  • Montesa Pino, Alvaro
  • Su, Wen-Pin
  • Chang, Yen-Hwa
  • Huang, Yi-Hsiu
  • Srimuninnimit, Vichien
  • Abali, Huseyin
  • Sendur, Mehmet Ali Nahit
  • Ozguroglu, Mustafa
  • Ozdogan, Mustafa
  • Evans, Linda
  • Hussain, Syed
  • DiSimone, Christopher
  • Schlegel, Peter
  • Mamtani, Ronac
  • Wallace, James
  • Suh, Jason Jung-Gon
  • Burgess, Earle
  • Wong, John
  • Chaudhry, Arvind
  • Thomas, Christian A
  • Fitzharris, John T
  • Oliff, Ira A
  • Vuky, Jacqueline
  • Hauke, Ralph
  • Joshi, Monika
  • Bolemon, Britt H
  • Markus, Maurice
  • Pfanzelter, Nicklas
  • Lawler, William Eyre
  • Courtright, Jay G
  • Doshi, Gurjyot
  • Sartor, Oliver Alton
  • Mannuel, Heather D
  • Alva, Ajjai
  • Charles, Anthony
  • Ades, Steven
  • Yu, Evan
  • Fleming, Mark
subjects:
  • Adverse events
  • Aged
  • Analysis
  • Antibodies
  • Antibodies, Monoclonal, Humanized - adverse effects
  • Antibodies, Monoclonal, Humanized - therapeutic use
  • Antimitotic agents
  • Antineoplastic agents
  • Antineoplastic Agents, Immunological - adverse effects
  • Antineoplastic Agents, Immunological - therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols - adverse effects
  • Antineoplastic Combined Chemotherapy Protocols - therapeutic use
  • Cancer
  • Cancer therapies
  • Carboplatin
  • Carboplatin - therapeutic use
  • Carcinoma
  • Carcinoma - drug therapy
  • Carcinoma - immunology
  • Carcinoma - mortality
  • Carcinoma - pathology
  • Care and treatment
  • Chemotherapy
  • Cisplatin
  • Cisplatin - therapeutic use
  • Colitis
  • Creatinine
  • Deoxycytidine - analogs & derivatives
  • Deoxycytidine - therapeutic use
  • Diarrhea
  • Disease Progression
  • FDA approval
  • Female
  • Gemcitabine
  • Heart
  • Hepatitis
  • Humans
  • Immune Checkpoint Inhibitors - adverse effects
  • Immune Checkpoint Inhibitors - therapeutic use
  • Intravenous administration
  • Male
  • Metastases
  • Metastasis
  • Middle Aged
  • Myocardial infarction
  • Patients
  • PD-1 protein
  • PD-L1 protein
  • Pembrolizumab
  • Platinum
  • Product development
  • Progression-Free Survival
  • Sepsis
  • Statistics
  • Survival
  • Time Factors
  • Urinary Bladder Neoplasms - drug therapy
  • Urinary Bladder Neoplasms - immunology
  • Urinary Bladder Neoplasms - mortality
  • Urinary Bladder Neoplasms - pathology
  • Urothelial carcinoma
  • Urothelium - drug effects
  • Urothelium - immunology
  • Urothelium - pathology
ispartof: The lancet oncology, 2021, Vol.22 (7), p.931-945
description: PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305. Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-fre
language: eng
source:
identifier: ISSN: 1470-2045
fulltext: no_fulltext
issn:
  • 1470-2045
  • 1474-5488
url: Link


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titlePembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial
creatorPowles, Thomas ; Oudard, Stephane ; Vulsteke, Christof ; Fléchon, Aude ; Yu, Evan Y ; Imai, Kentaro ; Homet Moreno, Blanca ; Alva, Ajjai ; Lazzaro, Mauricio Fernandez ; Gatica, Gabriela ; Van Aelst, Filip ; Machiels, Jean-Pascal ; Schallier, Denis ; Brust, Leandro ; Soares, Joao Paulo Holanda ; Cheng, Susanna ; Leal, Jose Luis ; Ibanez, Carolina ; Laguerre, Brigitte ; Flechon, Aude ; Topart, Delphine ; Huillard, Olivier ; Gravis, Gwenaelle ; Reichardt, Peter ; Herden, Jan ; Pfister, David ; Niegisch, Guenter ; Boegemann, Martin ; Gakis, Georgios ; Neisius, Andreas ; Thomas, Christian ; Kosa, Judit Erzsebet ; Bodoky, Gyorgy ; Geczi, Lajos ; Frank, Stephen Jay ; Kejzman, Daniel ; Rosenbaum, Eli ; Rouvinov, Keren ; Arai, Gaku ; Takayama, Tatsuya ; Fujimoto, Kiyohide ; Tanikawa, Toshiki ; Tomita, Yoshihiko ; Nishimura, Kazuo ; Tsujihata, Masao ; Takano, Toshimi ; Joraku, Akira ; Kobayashi, Kazuki ; De Wit, Ronald ; Aarts, Maureen ; Beerepoot, Laurens ; Alekseev, Sergey M ; Zyryanov, Alexander ; Oschepkov, Vasiliy Nikolaevich ; Shidin, Vladimir Aleksandrovich ; Karlov, Petr Alexandrovich ; Cohen, Graham Lawrence ; Ruff, Paul ; Lee, Nari ; Rodriguez-Vida, Alejo ; Grande, Enrique ; Munoz Langa, Jose ; Montesa Pino, Alvaro ; Su, Wen-Pin ; Chang, Yen-Hwa ; Huang, Yi-Hsiu ; Srimuninnimit, Vichien ; Abali, Huseyin ; Sendur, Mehmet Ali Nahit ; Ozguroglu, Mustafa ; Ozdogan, Mustafa ; Evans, Linda ; Hussain, Syed ; DiSimone, Christopher ; Schlegel, Peter ; Mamtani, Ronac ; Wallace, James ; Suh, Jason Jung-Gon ; Burgess, Earle ; Wong, John ; Chaudhry, Arvind ; Thomas, Christian A ; Fitzharris, John T ; Oliff, Ira A ; Vuky, Jacqueline ; Hauke, Ralph ; Joshi, Monika ; Bolemon, Britt H ; Markus, Maurice ; Pfanzelter, Nicklas ; Lawler, William Eyre ; Courtright, Jay G ; Doshi, Gurjyot ; Sartor, Oliver Alton ; Mannuel, Heather D ; Alva, Ajjai ; Charles, Anthony ; Ades, Steven ; Yu, Evan ; Fleming, Mark
creatorcontribPowles, Thomas ; Oudard, Stephane ; Vulsteke, Christof ; Fléchon, Aude ; Yu, Evan Y ; Imai, Kentaro ; Homet Moreno, Blanca ; Alva, Ajjai ; Lazzaro, Mauricio Fernandez ; Gatica, Gabriela ; Van Aelst, Filip ; Machiels, Jean-Pascal ; Schallier, Denis ; Brust, Leandro ; Soares, Joao Paulo Holanda ; Cheng, Susanna ; Leal, Jose Luis ; Ibanez, Carolina ; Laguerre, Brigitte ; Flechon, Aude ; Topart, Delphine ; Huillard, Olivier ; Gravis, Gwenaelle ; Reichardt, Peter ; Herden, Jan ; Pfister, David ; Niegisch, Guenter ; Boegemann, Martin ; Gakis, Georgios ; Neisius, Andreas ; Thomas, Christian ; Kosa, Judit Erzsebet ; Bodoky, Gyorgy ; Geczi, Lajos ; Frank, Stephen Jay ; Kejzman, Daniel ; Rosenbaum, Eli ; Rouvinov, Keren ; Arai, Gaku ; Takayama, Tatsuya ; Fujimoto, Kiyohide ; Tanikawa, Toshiki ; Tomita, Yoshihiko ; Nishimura, Kazuo ; Tsujihata, Masao ; Takano, Toshimi ; Joraku, Akira ; Kobayashi, Kazuki ; De Wit, Ronald ; Aarts, Maureen ; Beerepoot, Laurens ; Alekseev, Sergey M ; Zyryanov, Alexander ; Oschepkov, Vasiliy Nikolaevich ; Shidin, Vladimir Aleksandrovich ; Karlov, Petr Alexandrovich ; Cohen, Graham Lawrence ; Ruff, Paul ; Lee, Nari ; Rodriguez-Vida, Alejo ; Grande, Enrique ; Munoz Langa, Jose ; Montesa Pino, Alvaro ; Su, Wen-Pin ; Chang, Yen-Hwa ; Huang, Yi-Hsiu ; Srimuninnimit, Vichien ; Abali, Huseyin ; Sendur, Mehmet Ali Nahit ; Ozguroglu, Mustafa ; Ozdogan, Mustafa ; Evans, Linda ; Hussain, Syed ; DiSimone, Christopher ; Schlegel, Peter ; Mamtani, Ronac ; Wallace, James ; Suh, Jason Jung-Gon ; Burgess, Earle ; Wong, John ; Chaudhry, Arvind ; Thomas, Christian A ; Fitzharris, John T ; Oliff, Ira A ; Vuky, Jacqueline ; Hauke, Ralph ; Joshi, Monika ; Bolemon, Britt H ; Markus, Maurice ; Pfanzelter, Nicklas ; Lawler, William Eyre ; Courtright, Jay G ; Doshi, Gurjyot ; Sartor, Oliver Alton ; Mannuel, Heather D ; Alva, Ajjai ; Charles, Anthony ; Ades, Steven ; Yu, Evan ; Fleming, Mark ; KEYNOTE-361 Investigators
descriptionPD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305. Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.
identifier
0ISSN: 1470-2045
1EISSN: 1474-5488
2DOI: 10.1016/S1470-2045(21)00152-2
3PMID: 34051178
languageeng
publisherEngland: Elsevier Ltd
subjectAdverse events ; Aged ; Analysis ; Antibodies ; Antibodies, Monoclonal, Humanized - adverse effects ; Antibodies, Monoclonal, Humanized - therapeutic use ; Antimitotic agents ; Antineoplastic agents ; Antineoplastic Agents, Immunological - adverse effects ; Antineoplastic Agents, Immunological - therapeutic use ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Cancer ; Cancer therapies ; Carboplatin ; Carboplatin - therapeutic use ; Carcinoma ; Carcinoma - drug therapy ; Carcinoma - immunology ; Carcinoma - mortality ; Carcinoma - pathology ; Care and treatment ; Chemotherapy ; Cisplatin ; Cisplatin - therapeutic use ; Colitis ; Creatinine ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - therapeutic use ; Diarrhea ; Disease Progression ; FDA approval ; Female ; Gemcitabine ; Heart ; Hepatitis ; Humans ; Immune Checkpoint Inhibitors - adverse effects ; Immune Checkpoint Inhibitors - therapeutic use ; Intravenous administration ; Male ; Metastases ; Metastasis ; Middle Aged ; Myocardial infarction ; Patients ; PD-1 protein ; PD-L1 protein ; Pembrolizumab ; Platinum ; Product development ; Progression-Free Survival ; Sepsis ; Statistics ; Survival ; Time Factors ; Urinary Bladder Neoplasms - drug therapy ; Urinary Bladder Neoplasms - immunology ; Urinary Bladder Neoplasms - mortality ; Urinary Bladder Neoplasms - pathology ; Urothelial carcinoma ; Urothelium - drug effects ; Urothelium - immunology ; Urothelium - pathology
ispartofThe lancet oncology, 2021, Vol.22 (7), p.931-945
rights
02021 Elsevier Ltd
1Copyright © 2021 Elsevier Ltd. All rights reserved.
2COPYRIGHT 2021 Elsevier B.V.
32021. Elsevier Ltd
lds50peer_reviewed
citesFETCH-LOGICAL-c372t-65904c6a6495976e04314eea8d5e374866dc52aa16c227b98d7c5fb50523f8f50
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creatorcontrib
0Powles, Thomas
1Oudard, Stephane
2Vulsteke, Christof
3Fléchon, Aude
4Yu, Evan Y
5Imai, Kentaro
6Homet Moreno, Blanca
7Alva, Ajjai
8Lazzaro, Mauricio Fernandez
9Gatica, Gabriela
10Van Aelst, Filip
11Machiels, Jean-Pascal
12Schallier, Denis
13Brust, Leandro
14Soares, Joao Paulo Holanda
15Cheng, Susanna
16Leal, Jose Luis
17Ibanez, Carolina
18Laguerre, Brigitte
19Flechon, Aude
20Topart, Delphine
21Huillard, Olivier
22Gravis, Gwenaelle
23Reichardt, Peter
24Herden, Jan
25Pfister, David
26Niegisch, Guenter
27Boegemann, Martin
28Gakis, Georgios
29Neisius, Andreas
30Thomas, Christian
31Kosa, Judit Erzsebet
32Bodoky, Gyorgy
33Geczi, Lajos
34Frank, Stephen Jay
35Kejzman, Daniel
36Rosenbaum, Eli
37Rouvinov, Keren
38Arai, Gaku
39Takayama, Tatsuya
40Fujimoto, Kiyohide
41Tanikawa, Toshiki
42Tomita, Yoshihiko
43Nishimura, Kazuo
44Tsujihata, Masao
45Takano, Toshimi
46Joraku, Akira
47Kobayashi, Kazuki
48De Wit, Ronald
49Aarts, Maureen
50Beerepoot, Laurens
51Alekseev, Sergey M
52Zyryanov, Alexander
53Oschepkov, Vasiliy Nikolaevich
54Shidin, Vladimir Aleksandrovich
55Karlov, Petr Alexandrovich
56Cohen, Graham Lawrence
57Ruff, Paul
58Lee, Nari
59Rodriguez-Vida, Alejo
60Grande, Enrique
61Munoz Langa, Jose
62Montesa Pino, Alvaro
63Su, Wen-Pin
64Chang, Yen-Hwa
65Huang, Yi-Hsiu
66Srimuninnimit, Vichien
67Abali, Huseyin
68Sendur, Mehmet Ali Nahit
69Ozguroglu, Mustafa
70Ozdogan, Mustafa
71Evans, Linda
72Hussain, Syed
73DiSimone, Christopher
74Schlegel, Peter
75Mamtani, Ronac
76Wallace, James
77Suh, Jason Jung-Gon
78Burgess, Earle
79Wong, John
80Chaudhry, Arvind
81Thomas, Christian A
82Fitzharris, John T
83Oliff, Ira A
84Vuky, Jacqueline
85Hauke, Ralph
86Joshi, Monika
87Bolemon, Britt H
88Markus, Maurice
89Pfanzelter, Nicklas
90Lawler, William Eyre
91Courtright, Jay G
92Doshi, Gurjyot
93Sartor, Oliver Alton
94Mannuel, Heather D
95Alva, Ajjai
96Charles, Anthony
97Ades, Steven
98Yu, Evan
99Fleming, Mark
100KEYNOTE-361 Investigators
title
0Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial
1The lancet oncology
addtitleLancet Oncol
descriptionPD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305. Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.
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3Antibodies
4Antibodies, Monoclonal, Humanized - adverse effects
5Antibodies, Monoclonal, Humanized - therapeutic use
6Antimitotic agents
7Antineoplastic agents
8Antineoplastic Agents, Immunological - adverse effects
9Antineoplastic Agents, Immunological - therapeutic use
10Antineoplastic Combined Chemotherapy Protocols - adverse effects
11Antineoplastic Combined Chemotherapy Protocols - therapeutic use
12Cancer
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14Carboplatin
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16Carcinoma
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18Carcinoma - immunology
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20Carcinoma - pathology
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22Chemotherapy
23Cisplatin
24Cisplatin - therapeutic use
25Colitis
26Creatinine
27Deoxycytidine - analogs & derivatives
28Deoxycytidine - therapeutic use
29Diarrhea
30Disease Progression
31FDA approval
32Female
33Gemcitabine
34Heart
35Hepatitis
36Humans
37Immune Checkpoint Inhibitors - adverse effects
38Immune Checkpoint Inhibitors - therapeutic use
39Intravenous administration
40Male
41Metastases
42Metastasis
43Middle Aged
44Myocardial infarction
45Patients
46PD-1 protein
47PD-L1 protein
48Pembrolizumab
49Platinum
50Product development
51Progression-Free Survival
52Sepsis
53Statistics
54Survival
55Time Factors
56Urinary Bladder Neoplasms - drug therapy
57Urinary Bladder Neoplasms - immunology
58Urinary Bladder Neoplasms - mortality
59Urinary Bladder Neoplasms - pathology
60Urothelial carcinoma
61Urothelium - drug effects
62Urothelium - immunology
63Urothelium - pathology
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0Powles, Thomas
1Oudard, Stephane
2Vulsteke, Christof
3Fléchon, Aude
4Yu, Evan Y
5Imai, Kentaro
6Homet Moreno, Blanca
7Alva, Ajjai
8Lazzaro, Mauricio Fernandez
9Gatica, Gabriela
10Van Aelst, Filip
11Machiels, Jean-Pascal
12Schallier, Denis
13Brust, Leandro
14Soares, Joao Paulo Holanda
15Cheng, Susanna
16Leal, Jose Luis
17Ibanez, Carolina
18Laguerre, Brigitte
19Flechon, Aude
20Topart, Delphine
21Huillard, Olivier
22Gravis, Gwenaelle
23Reichardt, Peter
24Herden, Jan
25Pfister, David
26Niegisch, Guenter
27Boegemann, Martin
28Gakis, Georgios
29Neisius, Andreas
30Thomas, Christian
31Kosa, Judit Erzsebet
32Bodoky, Gyorgy
33Geczi, Lajos
34Frank, Stephen Jay
35Kejzman, Daniel
36Rosenbaum, Eli
37Rouvinov, Keren
38Arai, Gaku
39Takayama, Tatsuya
40Fujimoto, Kiyohide
41Tanikawa, Toshiki
42Tomita, Yoshihiko
43Nishimura, Kazuo
44Tsujihata, Masao
45Takano, Toshimi
46Joraku, Akira
47Kobayashi, Kazuki
48De Wit, Ronald
49Aarts, Maureen
50Beerepoot, Laurens
51Alekseev, Sergey M
52Zyryanov, Alexander
53Oschepkov, Vasiliy Nikolaevich
54Shidin, Vladimir Aleksandrovich
55Karlov, Petr Alexandrovich
56Cohen, Graham Lawrence
57Ruff, Paul
58Lee, Nari
59Rodriguez-Vida, Alejo
60Grande, Enrique
61Munoz Langa, Jose
62Montesa Pino, Alvaro
63Su, Wen-Pin
64Chang, Yen-Hwa
65Huang, Yi-Hsiu
66Srimuninnimit, Vichien
67Abali, Huseyin
68Sendur, Mehmet Ali Nahit
69Ozguroglu, Mustafa
70Ozdogan, Mustafa
71Evans, Linda
72Hussain, Syed
73DiSimone, Christopher
74Schlegel, Peter
75Mamtani, Ronac
76Wallace, James
77Suh, Jason Jung-Gon
78Burgess, Earle
79Wong, John
80Chaudhry, Arvind
81Thomas, Christian A
82Fitzharris, John T
83Oliff, Ira A
84Vuky, Jacqueline
85Hauke, Ralph
86Joshi, Monika
87Bolemon, Britt H
88Markus, Maurice
89Pfanzelter, Nicklas
90Lawler, William Eyre
91Courtright, Jay G
92Doshi, Gurjyot
93Sartor, Oliver Alton
94Mannuel, Heather D
95Alva, Ajjai
96Charles, Anthony
97Ades, Steven
98Yu, Evan
99Fleming, Mark
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titlePembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial
authorPowles, Thomas ; Oudard, Stephane ; Vulsteke, Christof ; Fléchon, Aude ; Yu, Evan Y ; Imai, Kentaro ; Homet Moreno, Blanca ; Alva, Ajjai ; Lazzaro, Mauricio Fernandez ; Gatica, Gabriela ; Van Aelst, Filip ; Machiels, Jean-Pascal ; Schallier, Denis ; Brust, Leandro ; Soares, Joao Paulo Holanda ; Cheng, Susanna ; Leal, Jose Luis ; Ibanez, Carolina ; Laguerre, Brigitte ; Flechon, Aude ; Topart, Delphine ; Huillard, Olivier ; Gravis, Gwenaelle ; Reichardt, Peter ; Herden, Jan ; Pfister, David ; Niegisch, Guenter ; Boegemann, Martin ; Gakis, Georgios ; Neisius, Andreas ; Thomas, Christian ; Kosa, Judit Erzsebet ; Bodoky, Gyorgy ; Geczi, Lajos ; Frank, Stephen Jay ; Kejzman, Daniel ; Rosenbaum, Eli ; Rouvinov, Keren ; Arai, Gaku ; Takayama, Tatsuya ; Fujimoto, Kiyohide ; Tanikawa, Toshiki ; Tomita, Yoshihiko ; Nishimura, Kazuo ; Tsujihata, Masao ; Takano, Toshimi ; Joraku, Akira ; Kobayashi, Kazuki ; De Wit, Ronald ; Aarts, Maureen ; Beerepoot, Laurens ; Alekseev, Sergey M ; Zyryanov, Alexander ; Oschepkov, Vasiliy Nikolaevich ; Shidin, Vladimir Aleksandrovich ; Karlov, Petr Alexandrovich ; Cohen, Graham Lawrence ; Ruff, Paul ; Lee, Nari ; Rodriguez-Vida, Alejo ; Grande, Enrique ; Munoz Langa, Jose ; Montesa Pino, Alvaro ; Su, Wen-Pin ; Chang, Yen-Hwa ; Huang, Yi-Hsiu ; Srimuninnimit, Vichien ; Abali, Huseyin ; Sendur, Mehmet Ali Nahit ; Ozguroglu, Mustafa ; Ozdogan, Mustafa ; Evans, Linda ; Hussain, Syed ; DiSimone, Christopher ; Schlegel, Peter ; Mamtani, Ronac ; Wallace, James ; Suh, Jason Jung-Gon ; Burgess, Earle ; Wong, John ; Chaudhry, Arvind ; Thomas, Christian A ; Fitzharris, John T ; Oliff, Ira A ; Vuky, Jacqueline ; Hauke, Ralph ; Joshi, Monika ; Bolemon, Britt H ; Markus, Maurice ; Pfanzelter, Nicklas ; Lawler, William Eyre ; Courtright, Jay G ; Doshi, Gurjyot ; Sartor, Oliver Alton ; Mannuel, Heather D ; Alva, Ajjai ; Charles, Anthony ; Ades, Steven ; Yu, Evan ; Fleming, Mark
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1Aged
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3Antibodies
4Antibodies, Monoclonal, Humanized - adverse effects
5Antibodies, Monoclonal, Humanized - therapeutic use
6Antimitotic agents
7Antineoplastic agents
8Antineoplastic Agents, Immunological - adverse effects
9Antineoplastic Agents, Immunological - therapeutic use
10Antineoplastic Combined Chemotherapy Protocols - adverse effects
11Antineoplastic Combined Chemotherapy Protocols - therapeutic use
12Cancer
13Cancer therapies
14Carboplatin
15Carboplatin - therapeutic use
16Carcinoma
17Carcinoma - drug therapy
18Carcinoma - immunology
19Carcinoma - mortality
20Carcinoma - pathology
21Care and treatment
22Chemotherapy
23Cisplatin
24Cisplatin - therapeutic use
25Colitis
26Creatinine
27Deoxycytidine - analogs & derivatives
28Deoxycytidine - therapeutic use
29Diarrhea
30Disease Progression
31FDA approval
32Female
33Gemcitabine
34Heart
35Hepatitis
36Humans
37Immune Checkpoint Inhibitors - adverse effects
38Immune Checkpoint Inhibitors - therapeutic use
39Intravenous administration
40Male
41Metastases
42Metastasis
43Middle Aged
44Myocardial infarction
45Patients
46PD-1 protein
47PD-L1 protein
48Pembrolizumab
49Platinum
50Product development
51Progression-Free Survival
52Sepsis
53Statistics
54Survival
55Time Factors
56Urinary Bladder Neoplasms - drug therapy
57Urinary Bladder Neoplasms - immunology
58Urinary Bladder Neoplasms - mortality
59Urinary Bladder Neoplasms - pathology
60Urothelial carcinoma
61Urothelium - drug effects
62Urothelium - immunology
63Urothelium - pathology
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0Powles, Thomas
1Oudard, Stephane
2Vulsteke, Christof
3Fléchon, Aude
4Yu, Evan Y
5Imai, Kentaro
6Homet Moreno, Blanca
7Alva, Ajjai
8Lazzaro, Mauricio Fernandez
9Gatica, Gabriela
10Van Aelst, Filip
11Machiels, Jean-Pascal
12Schallier, Denis
13Brust, Leandro
14Soares, Joao Paulo Holanda
15Cheng, Susanna
16Leal, Jose Luis
17Ibanez, Carolina
18Laguerre, Brigitte
19Flechon, Aude
20Topart, Delphine
21Huillard, Olivier
22Gravis, Gwenaelle
23Reichardt, Peter
24Herden, Jan
25Pfister, David
26Niegisch, Guenter
27Boegemann, Martin
28Gakis, Georgios
29Neisius, Andreas
30Thomas, Christian
31Kosa, Judit Erzsebet
32Bodoky, Gyorgy
33Geczi, Lajos
34Frank, Stephen Jay
35Kejzman, Daniel
36Rosenbaum, Eli
37Rouvinov, Keren
38Arai, Gaku
39Takayama, Tatsuya
40Fujimoto, Kiyohide
41Tanikawa, Toshiki
42Tomita, Yoshihiko
43Nishimura, Kazuo
44Tsujihata, Masao
45Takano, Toshimi
46Joraku, Akira
47Kobayashi, Kazuki
48De Wit, Ronald
49Aarts, Maureen
50Beerepoot, Laurens
51Alekseev, Sergey M
52Zyryanov, Alexander
53Oschepkov, Vasiliy Nikolaevich
54Shidin, Vladimir Aleksandrovich
55Karlov, Petr Alexandrovich
56Cohen, Graham Lawrence
57Ruff, Paul
58Lee, Nari
59Rodriguez-Vida, Alejo
60Grande, Enrique
61Munoz Langa, Jose
62Montesa Pino, Alvaro
63Su, Wen-Pin
64Chang, Yen-Hwa
65Huang, Yi-Hsiu
66Srimuninnimit, Vichien
67Abali, Huseyin
68Sendur, Mehmet Ali Nahit
69Ozguroglu, Mustafa
70Ozdogan, Mustafa
71Evans, Linda
72Hussain, Syed
73DiSimone, Christopher
74Schlegel, Peter
75Mamtani, Ronac
76Wallace, James
77Suh, Jason Jung-Gon
78Burgess, Earle
79Wong, John
80Chaudhry, Arvind
81Thomas, Christian A
82Fitzharris, John T
83Oliff, Ira A
84Vuky, Jacqueline
85Hauke, Ralph
86Joshi, Monika
87Bolemon, Britt H
88Markus, Maurice
89Pfanzelter, Nicklas
90Lawler, William Eyre
91Courtright, Jay G
92Doshi, Gurjyot
93Sartor, Oliver Alton
94Mannuel, Heather D
95Alva, Ajjai
96Charles, Anthony
97Ades, Steven
98Yu, Evan
99Fleming, Mark
100KEYNOTE-361 Investigators
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0Powles, Thomas
1Oudard, Stephane
2Vulsteke, Christof
3Fléchon, Aude
4Yu, Evan Y
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6Homet Moreno, Blanca
7Alva, Ajjai
8Lazzaro, Mauricio Fernandez
9Gatica, Gabriela
10Van Aelst, Filip
11Machiels, Jean-Pascal
12Schallier, Denis
13Brust, Leandro
14Soares, Joao Paulo Holanda
15Cheng, Susanna
16Leal, Jose Luis
17Ibanez, Carolina
18Laguerre, Brigitte
19Flechon, Aude
20Topart, Delphine
21Huillard, Olivier
22Gravis, Gwenaelle
23Reichardt, Peter
24Herden, Jan
25Pfister, David
26Niegisch, Guenter
27Boegemann, Martin
28Gakis, Georgios
29Neisius, Andreas
30Thomas, Christian
31Kosa, Judit Erzsebet
32Bodoky, Gyorgy
33Geczi, Lajos
34Frank, Stephen Jay
35Kejzman, Daniel
36Rosenbaum, Eli
37Rouvinov, Keren
38Arai, Gaku
39Takayama, Tatsuya
40Fujimoto, Kiyohide
41Tanikawa, Toshiki
42Tomita, Yoshihiko
43Nishimura, Kazuo
44Tsujihata, Masao
45Takano, Toshimi
46Joraku, Akira
47Kobayashi, Kazuki
48De Wit, Ronald
49Aarts, Maureen
50Beerepoot, Laurens
51Alekseev, Sergey M
52Zyryanov, Alexander
53Oschepkov, Vasiliy Nikolaevich
54Shidin, Vladimir Aleksandrovich
55Karlov, Petr Alexandrovich
56Cohen, Graham Lawrence
57Ruff, Paul
58Lee, Nari
59Rodriguez-Vida, Alejo
60Grande, Enrique
61Munoz Langa, Jose
62Montesa Pino, Alvaro
63Su, Wen-Pin
64Chang, Yen-Hwa
65Huang, Yi-Hsiu
66Srimuninnimit, Vichien
67Abali, Huseyin
68Sendur, Mehmet Ali Nahit
69Ozguroglu, Mustafa
70Ozdogan, Mustafa
71Evans, Linda
72Hussain, Syed
73DiSimone, Christopher
74Schlegel, Peter
75Mamtani, Ronac
76Wallace, James
77Suh, Jason Jung-Gon
78Burgess, Earle
79Wong, John
80Chaudhry, Arvind
81Thomas, Christian A
82Fitzharris, John T
83Oliff, Ira A
84Vuky, Jacqueline
85Hauke, Ralph
86Joshi, Monika
87Bolemon, Britt H
88Markus, Maurice
89Pfanzelter, Nicklas
90Lawler, William Eyre
91Courtright, Jay G
92Doshi, Gurjyot
93Sartor, Oliver Alton
94Mannuel, Heather D
95Alva, Ajjai
96Charles, Anthony
97Ades, Steven
98Yu, Evan
99Fleming, Mark
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atitlePembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial
jtitleThe lancet oncology
addtitleLancet Oncol
date2021-07
risdate2021
volume22
issue7
spage931
epage945
pages931-945
issn1470-2045
eissn1474-5488
abstractPD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305. Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.
copEngland
pubElsevier Ltd
pmid34051178
doi10.1016/S1470-2045(21)00152-2