1. 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
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Thomas Powles, Tibor Csőszi, Mustafa Özgüroğlu, Nobuaki Matsubara, Lajos Géczi, Susanna Y-S Cheng, Yves Fradet, Stephane Oudard, Christof Vulsteke, Rafael Morales Barrera, Aude Fléchon, Seyda Gunduz, Yohann Loriot, Alejo Rodriguez-Vida, Ronac Mamtani, Evan Y Yu, Kijoeng Nam, Kentaro Imai, Blanca Homet Moreno, Ajjai Alva, Diana Vera Cascallar, Mirta Varela, Mauricio Fernandez Lazzaro, Diego Lucas Kaen, Gabriela Gatica, David Hugo Flores, Agustin Falco, Matias Molina, Filip Van Aelst, Brieuc Sautois, Jean-Pascal Machiels, Denis Schallier, Leandro Brust, Liane Rapatoni, Sergio J Azevedo, Gisele Marinho, Joao Paulo Holanda Soares, Carlos Dzik, Jamile Almeida Silva, Andre Poisl Fay, Joel Gingerich, Cristiano Ferrario, Kylea Potvin, Marie Vanhuyse, Mahmoud Abdelsalam, Susanna Cheng, Christian Caglevic, Felipe Reyes, Jose Luis Leal, Francisco Francisco, Carolina Ibanez, Florence Joly, Brigitte Laguerre, Sylvain Ladoire, Aude Flechon, Delphine Topart, Olivier Huillard, Stéphane Oudard, Marine Gross-Goupil, Stephane Culine, Gwenaelle Gravis, Peter Reichardt, Margitta Retz, Jan Herden, David Pfister, Carsten Ohlman, Michael Stoeckle, Manfred Wirth, Anja Lorch, Guenter Niegisch, Peter J Goebell, Martin Boegemann, Axel Merseburger, Georgios Gakis, Jens Bedke, Andreas Neisius, Christian Thomas, Thomas Hoefner, Andras Telekes, Judit Erzsebet Kosa, Janos Revesz, Gyorgy Bodoky, Tibor Csoszi, Andras Csejtei, Lajos Geczi, Agnes Ruzsa, Zsuzsanna Kolonics, Jozsef Erfan, Ray McDermott, Richard Bambury, Avishay Sella, Stephen Jay Frank, Daniel Kejzman, Olesya Goldman, Eli Rosenbaum, Avivit Peer, Raanan Berger, Keren Rouvinov, David Sarid, Satoshi Fukasawa, Gaku Arai, Akito Yamaguchi, Akira Yokomizo, Tatsuya Takayama, Hidefumi Kinoshita, Eiji Kikuchi, Ryuichi Mizuno, Yasuhisa Fujii, Naoto Sassa, Yoshihisa Matsukawa, Kiyohide Fujimoto, Toshiki Tanikawa, Yoshihiko Tomita, Kazuo Nishimura, Masao Tsujihata, Masafumi Oyama, Naoya Masumori, Hiroomi Kanayama, Toshimi Takano, Yuji Miura, Jun Miyazaki, Akira Joraku, Tomokazu Kimura, Yoshiaki Yamamoto, Kazuki Kobayashi, Ronald De Wit, Maureen Aarts, Winald Gerritsen, Maartje Los, Laurens Beerepoot, Adel Izmailov, Sergey Igorevich Gorelov, Boris Yakovlevich Alekseev, Andrey Semenov, Vladimir Anatolyevich Kostorov, Sergey M Alekseev, Alexander Zyryanov, Vasiliy Nikolaevich Oschepkov, Vladimir Aleksandrovich Shidin, Vladimir Ivanovich Vladimirov, Rustem Airatovich Gafanov, Petr Alexandrovich Karlov, David Brian Anderson, Lucinda Shepherd, Graham Lawrence Cohen, Bernardo Louis Rapoport, Paul Ruff, Nari Lee, Woo Kyun Bae, Hyo Jin Lee, Urbano Anido Herranz, Enrique Grande, Teresa Alonso Gordoa, Josep Guma Padro, Daniel Castellano Gauna, Jose Angel Arranz, Jose Munoz Langa, Regina Girones Sarrio, Alvaro Montesa Pino, Maria Jose Juan Fita, Yu-Li Su, Yung-Chang Lin, Wen-Pin Su, Ying-Chun Shen, Yen-Hwa Chang, Yi-Hsiu Huang, Virote Sriuranpong, Phichai Chansriwong, Vichien Srimuninnimit, Pongwut Danchaivijitr, Huseyin Abali, Sinan Yavuz, Ozgur Ozyilkan, Mehmet Ali Nahit Sendur, Meltem Ekenel, Mustafa Ozguroglu, Cagatay Arslan, Mustafa Ozdogan, Alison Birtle, Robert Huddart, Maria de Santis, Anjali Zarkar, Linda Evans, Syed Hussain, Christopher DiSimone, Antonio F Muina, Peter Schlegel, Haresh S Jhangiani, Michael Harrison, Dennis E Slater, David Wright, Ivor J Percent, Jianqing Lin, Clara Hwang, Sumati Gupta, Madhuri Bajaj, Robert Galamaga, John Eklund, James Wallace, Mikhail Shtivelband, Jason Jung-Gon Suh, Nafisa Burhani, Matthew Eadens, Krishna Gunturu, Earle Burgess, John Wong, Arvind Chaudhry, Peter Van Veldhuizen, Stephanie Graff, Christian A Thomas, Ian D Schnadig, Benedito Carneiro, Maha Hussain, Alicia Morgans, John T Fitzharris, Ira A Oliff, Jacqueline Vuky, Ralph Hauke, Ari Baron, Monika Joshi, Britt H Bolemon, Peter Jiang, Anthony E Mega, Maurice Markus, Nicklas Pfanzelter, William Eyre Lawler, Patrick Wayne Cobb, Jay G Courtright, Sharad Jain, Gurjyot Doshi, Vijay K Gunuganti, Oliver Alton Sartor, Scott W Cole, Hani Babiker, Edward M Uchio, Alexandra Drakaki, Heather D Mannuel, Elizabeth Guancial, Chunkit Fung, Anthony Charles, Robert J Amato, Yull Arriaga, Isaac Bowman, Steven Ades, Robert Dreicer, Evan Yu, David I Quinn, Mark Fleming, University of Zurich, Powles, Thomas, KEYNOTE-361 Investigators, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Centre du cancer, and UCL - (SLuc) Unité d'oncologie médicale
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Male ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Population ,610 Medicine & health ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Deoxycytidine ,Gastroenterology ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,medicine ,Humans ,030212 general & internal medicine ,Progression-free survival ,education ,Immune Checkpoint Inhibitors ,Aged ,Chemotherapy ,education.field_of_study ,business.industry ,Carcinoma ,Hazard ratio ,Middle Aged ,Gemcitabine ,Progression-Free Survival ,Urinary Bladder Neoplasms ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,10032 Clinic for Oncology and Hematology ,Disease Progression ,Female ,2730 Oncology ,Human medicine ,Cisplatin ,Urothelium ,business ,medicine.drug - Abstract
Summary Background 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. Methods 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 . Findings 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. Interpretation 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. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.
- Published
- 2021
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