Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study - 29/06/21
, Ashish M Kamat, ProfMD b, Girish S Kulkarni, MD c, Edward M Uchio, ProfMD d, Joost L Boormans, MD e, Mathieu Roumiguié, MD f, Laurence E M Krieger, MD g, Eric A Singer, MD h, Dean F Bajorin, ProfMD i, Petros Grivas, MD j, Ho Kyung Seo, MD k, Hiroyuki Nishiyama, ProfMD l, Badrinath R Konety, ProfMD m, Haojie Li, PhD n, Kijoeng Nam, PhD n, Ekta Kapadia, MD n, Tara Frenkl, MD n, Ronald de Wit, ProfMD eSummary |
Background |
Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of bladder tumour followed by intravesical BCG immunotherapy. However, despite high initial responses rates, up to 50% of patients have recurrence or become BCG-unresponsive. PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study, we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasive bladder cancer.
Methods |
We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 years or older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumours, with an Eastern Cooperative Oncology Group performance status of 0–2, and who were ineligible for or declined radical cystectomy were enrolled. All enrolled patients were assigned to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression; unacceptable toxic effects; or withdrawal of consent. The primary endpoint was clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug. Patient follow-ups were done every 3 months for the first 2 years and every 6 months thereafter for up to 5 years. Efficacy was assessed in all patients who received at least one dose of the study drug and met BCG-unresponsive criteria. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing.
Findings |
Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186 patients did not meet inclusion criteria, and 47 patients were assigned to cohort B (patients with BCG-unresponsive high grade Ta or any grade T1 papillary disease without carcinoma in situ; results will be reported separately). 101 eligible patients were enrolled and assigned to receive pembrolizumab. All 101 patients received at least one dose of the study drug and were included in the safety analysis. Five patients had disease that did not meet the US Food and Drug Administration definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore not included in the efficacy analysis (n=96). Median follow-up was 36·4 months (IQR 32·0–40·7). 39 (41%; 95% CI 30·7–51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients; the most common were arthralgia (in two [2%] patients) and hyponatraemia (in three [3%] patients). Serious treatment-related adverse events occurred in eight (8%) patients. There were no deaths that were considered treatment related.
Interpretation |
Pembrolizumab monotherapy was tolerable and showed promising antitumour activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a a clinically active non-surgical treatment option in this difficult-to-treat population.
Funding |
Merck Sharp & Dohme.
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Vol 22 - N° 7
P. 919-930 - juillet 2021 Retour au numéro
Article précédent
- Is complete mesocolic excision superior to conventional colectomy for colon cancer?
- Danilo Miskovic, Reza Mirnezami
- 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
- Thomas Powles, Tibor Cs?szi, Mustafa Özgüro?lu, 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, KEYNOTE-361 Investigators, Diana Vera Cascallar, Mirta Varela, Mauricio Fernandez Lazzaro, Diego Lucas Kaen, Gabriela Gatica, David Hugo Flores, Agustin Falco, Matias Molina, Filip Van Aelst, Christof Vulsteke, 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, Yves Fradet, 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, Yohann Loriot, 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, Nobuaki Matsubara, 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, Alejo Rodriguez-Vida, Rafael Morales Barrera, 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, Seyda Gunduz, Mustafa Ozdogan, Alison Birtle, Thomas Powles, 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, Ronac Mamtani, 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, Ajjai Alva, Elizabeth Guancial, Chunkit Fung, Anthony Charles, Robert J Amato, Yull Arriaga, Isaac Bowman, Steven Ades, Robert Dreicer, Evan Yu, David I Quinn, Mark Fleming
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