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Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

2022; Elsevier BV; Volume: 23; Issue: 9 Linguagem: Inglês

10.1016/s1470-2045(22)00487-9

1474-5488

Thomas Powles, Piotr Tomczak, Se Hoon Park, Balaji Venugopal, Thomas Ferguson, Stefan N. Symeonides, Jaroslav Hájek, Howard Gurney, Yen‐Hwa Chang, Jae‐Lyun Lee, Naveed Sarwar, Antoine Thiery-Vuillemin, Marine Gross‐Goupil, Mauricio Mahave, Naomi B. Haas, Piotr Sawrycki, Joseph E. Burgents, Lei Xu, Kentaro Imai, David I. Quinn, Toni K. Choueiri, Piotr Tomczak, Toni K. Choueiri, Se Hoon Park, Balaji Venugopal, Thomas Ferguson, Jaroslav Hájek, Tzu-Ping Lin, Stefan N. Symeonides, Jae‐Lyun Lee, Piotr Sawrycki, Naomi B. Haas, Howard Gurney, Mauricio Mahave, Naveed Sarwar, Antoine Thiery-Vuillemin, Marine Gross‐Goupil, Christine Chevreau, John M. Burke, Gurjyot K. Doshi, Bohuslav Melichar, Delphine Topart, Stéphane Oudard, Evgeniy Kopyltsov, H. Hammers, David I. Quinn, Ajjai Alva, Juliana de Menezes, Adriano Goncalves e Silva, Eric Winquist, Alketa Hamzaj, Giuseppe Procopio, Boguslawa Karaszewska, Ewa M. Nowakowska-Zajdel, B. Yа. Alekseev, Rustem Gafanov, А. А. Измайлов, Andrey Semenov, S. G. Afanasyev, O. N. Lipatov, T.B. Powles, Sandy Srinivas, David F. McDermott, Samith T. Kochuparambil, Ian D. Davis, Katriina Peltola, Roberto Sabbatini, Jinsoo Chung, М. I. Shkolnik, В. Б. Матвеев, P. Gajate Borau, Steven McCune, Thomas E. Hutson, Alejandro Dri, Silvio Correia Sales, Carrie Yeung, Carmen Marcela Alcala Castro, Peter J. Boström, Brigitte Laguerre, Consuelo Buttigliero, Ugo De Giorgi, Eugeniy A. Fomin, Yousef Zakharia, Clara Hwang, Eric A. Singer, Jeffrey T. Yorio, David Waterhouse, Rubén Dario Kowalyszyn, Margarita Sonia Alfie, Eduardo Yañez Ruiz, Tomáš Büchler, Krista Kankaanranta, G. Ferretti, Go Kimura, Kazuo Nishimura, Naoya Masumori, Satoshi Tamada, Haruaki Kato, Hiroshi Kitamura, Iwona Danielewicz, Joanna Wojcik-Tomaszewska, Nuria Sala Gonzalez, Kun‐Yuan Chiu, Michael B. Atkins, Elisabeth I. Heath, Gustavo Adolfo Rojas-Uribe, Manuel Enrique Gonzalez Fernandez, Susan Feyerabend, Sandro Pignata, Kazuyuki Numakura, Bozena Cybulska Stopa, Р. А. Зуков, Miguel Á. Climent Durán, Pablo Jose Maroto Rey, Á. Montesa Pino, Chao‐Hsiang Chang, Salil Vengalil, Tom Waddell, Patrick Cobb, Ralph J. Hauke, D. Mark Anderson, John Sarantopoulos, Theodore Stewart Gourdin, Tian Zhang, Gautam Jayram, Luis Fein, Carole A. Harris, Patricia Medeiros Milhomem Beato, Francisco Flores, Angela Estay, Juan Andres Rubiano, Jens Bedke, Stefan Hauser, Andreas Neisius, Jonas Busch, Satoshi Anai, Hiroyuki Tsunemori, Dariusz Sawka, Bożena Sikora-Kupis, José Ángel Arranz, Ignacio Delgado, Chung‐Hsin Chen, Elizabeth A. Gunderson, Scott S. Tykodi, Alan J. Koletsky, Kevin Chen, Manish Agrawal, Diego Kaen, Juan Pablo Sade, Marcelo Tatangelo, Francis Parnis, Fernando Maciel Barbosa, Genevieve Faucher, Nayyer Iqbal, Danièle Marceau, Jean-Benoit Paradis, Nawar Hanna, Alejandro Acevedo, Carolina Ibáñez, Luis J. Villanueva-Rivera, Pedro Pablo Galaz, Isabel Cristina Durango, Ray Manneh Kopp, Zdeněk Král, Petra Holečková, Heikki Hakkarainen, Hanna Ronkainen, Sophie Abadie‐Lacourtoisie, Sophie Tartas, Peter J. Goebell, Marc‐Oliver Grimm, Thomas Hoefner, Manfred P. Wirth, Andrej Panic, Wolfgang Schultze-Seemann, Akira Yokomizo, Ryuichi Mizuno, Hirotsugu Uemura, Masatoshi Eto, Masao Tsujihata, Yoshihisa Matsukawa, Yoji Murakami, Miso Kim, Paul Hamberg, Malgorzata Marczewska-Skrodzka, Szczylik Cezary, Alison C. Humphreys, Peter Jiang, Birendra Kumar, Gary Lu, Arpita Desai, José A. Karam, George P. Keogh, Mark T. Fleming, Juan José Zarbá, Viviana E. Leiva, Guillermo Ariel Mendez, S.J. Harris, Stephen J. Brown, João Neif Antonio, Rita de Cassia Costamilan, Roberto Odebrecht Rocha, David Q.B. Muniz, Leandro Brust, Aly‐Khan A. Lalani, Jeffrey Graham, Michael A. Levesque, F. Orlandi, Rostislav Kotasek, Jean L. Deville, Delphine Borchiellini, Axel S. Merseburger, Michael Rink, Frederik C. Roos, Ray McDermott, Masafumi Oyama, Yoshiaki Yamamoto, Yoshihiko Tomita, Yuji Miura, Naomasa Ioritani, Hans M. Westgeest, Tomasz Kubiatowski, Wiesław Bal, Regina Gironés Sarrió, Julie Rowe, Debra M. Prow, Francis M. Senecal, Neda Hashemi‐Sadraei, Scott Cole, Stephan D. Kendall, Donald Richards, Ian D. Schnadig, Mukul Kumar Gupta,

Bladder and Urothelial Cancer Treatments

The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints.In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334.Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7-36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50-0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3-4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab.Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy.Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.