1. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial
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Vassiliki Karantza, Shparyk Yaroslav, Sumrall Bradley, Javier Cortes, Iwata Hiroji, Kolesnik Oleksii, Ahn Jin Hee, Harbeck Nadia, Prausova Jana, Song Xinni, Berzoy Oleksandr, Mena Raul, Osaki Akihiko, Kahan Zsuzsanna, Simon Michael, Ozguroglu Mustafa, Chmielowska Ewa, Tsugawa Koichiro, Tsao Chao-Jung, Ozyilkan Ozgur, Nowecki Zbigniew, Fadeeva Natalia, Kaen Diego, Garcia Saenz Jose, Porter David, Ngan Kai Cheong Roger, Sherene Loi, Bermejo de las Heras Begona, Turner Nicholas, David W. Cescon, Hope S. Rugo, Oliff Ira, Kelly Catherine, Barrios Carlos, Cole Scott, Shevnya Sergii, Seock-Ah Im, Hoskins Kent, Komisarenko Hanna, Yavuz Sinan, Chaudhry Madhu, Sagara Yasuaki, Brust Leandro, Chan Steve, Gomez Villanueva Angel, Gallardo Carlos, Watanabe Junichiro, Ishikawa Takashi, Schleider Michael, Salas Claudio, Hardy-Bessard Anne-Claire, Erhan Gokmen, Adamchuk Hryhoriy, Beelen Karin, Holeckova Petra, Szczylik Cezary, Fujii Takaaki, Nakamura Seigo, Aruga Tomoyuki, Gokmen Erhan, Jing Zhao, Hiroji Iwata, Molinas Mandel Nil, Gogineni Keerthi, Im Seock-Ah, Zifang Guo, Loi Sherene, Costa Fabiano, Forstmeyer Dirk, Kosaka Yoshimasa, Gomez Diaz Alvaro, Ponomarova Olga, Wimberger Pauline, DAlessio Antonietta, Suzuki Eiji, Blohmer Jens-Uwe, Kowalwszyn Ruben, Molina Matias, Clingan Philip, Yamamoto Yutaka, Sabanathan Dhanusha, Gursel Aktan, Vynnychenko Ihor, Ferrario Cristiano, Schumann Raquel Von, Trukhin Dmytro, Arkosy Peter, Tseng Ling-Ming, Moore Susan, Gunduz Seyda, Stampleman Laura, de Freitas Junior Ruffo, Acevedo Alejandro, Lipatov Oleg, Niikura Naoki, Norikazu Masuda, Rusyn Andrii, Kral Zdenek, Crown John, Yamamoto Naohito, Jakobsen Erik, Blau Sibel, Bustam Anita, Zamora Adelantado Esther, Nanda Rita, Omene Coral, Arslan Cagatay, Kwong Ava, Teixeira Luis, Jensen Jeanette, Ito Yoshinori, Siegel Robert, Mastura Md Yusof, Nowakowska-Zajdel Ewa, Miyoshi Yasuo, Yu Joanne, Tuthill Mark, Mukhametshina Guzel, Matsumoto Koji, Gion Maria, Melichar Bohuslav, Desmoulins Isabelle, Moiseyenko Vladimir, Zurawski Bogdan, Carlos Gallardo, Lorincz Tamas, Cruz Jurado Josefina, Bondarenko Igor, Kaczerowsky Flores de Sousa Anna, Yamauchi Teruo, Loutfi Randa, Esther Holgado, Holgado Esther, Twelves Christopher, Streb Joanna, Tanabe Yuko, Tarnawski Rafal, Morales-Vasquez Flavia, Park Kwong Hwa, Csoszi Tibor, Meshcheryakov Andrey, Scalabrini Neto Antonio Orlando, Oleg Lipatov, Iwasa Tsutomu, Ricevuto Enrico, Tamura Kenji, Patson Brian, Liu Mei-Ching, Cinieri Saverio, Loibl Sibylle, Tjan-Heijnen Vivianne, Glavicic Vesna, Panwalkar Amit, Hargis Jeffrey, Kryzhanivska Anna, Yusof Mastura, O'Reilly Seamus, Rubovszky Gabor, Irvin William, Takahashi Masato, Ohtani Shoichiro, Peter Schmid, Carlos H. Barrios, Sanchez Cesar, Zbigniew Nowecki, Arkhipov Alexander, Chung Michael, Liu Chien-Ting, Mukai Hirofumi, Marco Torregroza Otero, Charpentier Danielle, Park-Simon Tjoung-Won, Lee Keun Seok, Leshchenko Iurii, Huang Chiun-Sheng, Tsai Michaela, Panella Timothy, Petrakova Katarina, MacPherson Iain, Schmid Peter, Baron-Hay Sally, Ursol Grygorii, Lacerda Domicio Carvalho, Cobb Patrick, Sanchez Jesus, Park Yeon Hee, Reyes Contreras Jessica, Fein Luis, Hegg Roberto, Diamond Jennifer, Huober Jens, Rugo Hope, Rybalova Irina, de la Cruz Merino Luis, Linnet Soren, Inoue Kenichi, Wheatley Duncan, Cescon David, Cicin Irfan, Gombos Andrea, Bonnefoi Herve, Nasonova Alla, Taylor Donatienne, Martinez Rodriguez Jorge, Valdes-Albini Frances, Juarez Ramiro Alejandro, Cortes Javier, Lu Janice, Silva Felipe, Lueftner Diana, Landherr Laszlo, Gomez Abuin Gonzalo, Yanez Eduardo, Rocha Roberto Odebrecht, Chow Louis, Otchenash Natalya, Radecka Barbara, Kolesnik Olena, Basaran Gul, Kurbacher Christian, Mahr Karoly, Goncalves Anthony, Begbie Stephen, Graham Janine, Fasching Peter, Varela Mirta, and Lissa Fernando Cezar Toniazzi
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Oncology ,double blind procedure ,pharmacist ,CD274 protein, human ,hazard ratio ,0302 clinical medicine ,middle aged ,Antineoplastic Combined Chemotherapy Protocols ,cancer survival ,comparative study ,education.field_of_study ,progression free survival ,adult ,drug effect ,gemcitabine ,clinical trial ,General Medicine ,nausea ,anemia ,Progression-Free Survival ,priority journal ,immunological antineoplastic agent ,thyroiditis ,pembrolizumab ,metastatic breast cancer ,neoadjuvant chemotherapy ,medicine.medical_specialty ,Antineoplastic Agents ,intention to treat analysis ,Article ,skin manifestation ,03 medical and health sciences ,Breast cancer ,cancer combination chemotherapy ,neutropenia ,Humans ,Progression-free survival ,human ,education ,protein expression ,cancer immunotherapy ,treatment response ,Interim analysis ,medicine.disease ,major clinical study ,tumor recurrence ,Carboplatin ,programmed death 1 ligand 1 ,drug efficacy ,multicenter study ,chemistry ,monoclonal antibody ,randomized controlled trial ,fatigue ,drug tolerability ,cancer patient ,age distribution ,drug safety ,colitis ,clinical outcome ,Triple Negative Breast Neoplasms ,Pembrolizumab ,030204 cardiovascular system & hematology ,B7-H1 Antigen ,Placebos ,chemistry.chemical_compound ,paclitaxel ,Antineoplastic Agents, Immunological ,Outcome Assessment, Health Care ,030212 general & internal medicine ,antineoplastic agent ,cancer adjuvant therapy ,Eastern Cooperative Oncology Group performance status ,female ,carboplatin ,sodium chloride ,immunohistochemistry ,medicine.drug ,interactive voice response system ,alanine aminotransferase ,overall survival ,Population ,Antibodies, Monoclonal, Humanized ,Double-Blind Method ,Internal medicine ,medicine ,follow up ,hyperthyroidism ,pneumonia ,controlled study ,Taxane ,phase 3 clinical trial ,business.industry ,hypertransaminasemia ,alopecia ,Gemcitabine ,human tissue ,cancer recurrence ,functional status assessment ,triple negative breast cancer ,placebo ,inoperable cancer ,pathology ,hypothyroidism ,Neoplasm Recurrence, Local ,business ,metabolism ,Follow-Up Studies - Abstract
Background: Pembrolizumab monotherapy showed durable antitumour activity and manageable safety in patients with metastatic triple-negative breast cancer. We aimed to examine whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy in patients with metastatic triple-negative breast cancer. Methods: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine–carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ?1 or, Breast Cancer Research Foundation, BCRF; Pfizer; AstraZeneca; Merck; Roche; Samsung; Merck Sharp and Dohme, MSD; Eisai, JC reports personal fees and research funding paid to his institution from Roche, AstraZeneca, Merck Sharp & Dohme, and Eisai; personal fees from Celgene, Cellestia, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, GlaxoSmithKline, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Kyowa Kirin, Novartis, Pfizer, Samsung Bioepis; research funding paid to his institution from Ariad Pharmaceuticals, Bayer Healthcare, F Hoffman-La Roche, Guardanth Health, Piqur Therapeutics, Puma C, and Queen Mary University of London, outside the submitted work. In addition, JC has a MedSIR patent pending. DWC reports research support from Merck during the conduct of the study; research support paid to his institution from Merck, Pfizer, and GlaxoSmithKline; personal fees from Merck, Roche–Genentech, AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Puma, Agenda, Exact Sciences, and Dynamo Therapeutics, outside the submitted work. In addition, DWC has a Biomarkers of TTK inhibitors patent pending. HSR reports funding for sponsored studies paid to the University of California San Francisco from Pfizer, Novartis, Lilly, Roche–Genentech, Macrogenics, OBI, Merck, Eisai, Immunomedics, Daiichi Sankyo, Seattle Genetics, and Odonate; travel support for educational meetings from Daiichi Sankyo, Mylan, Pfizer, Merck, AstraZeneca, Novartis, and Macrogenics; and consulting fees from Samsung and Puma, outside the submitted work. S-AI reports grants from AstraZeneca, Eisai, Pfizer, Roche, and Daewoong; an advisory role for AstraZeneca, Amgen, Eisai, Hanmi, Novartis, Lily, MedPacto, Pfizer, and Roche; and travel expenses for presentation from Novartis, outside the submitted work. CG reports Advisory Board fees from Merck Sharp & Dohme and Roche; and speaker's bureau fees from Bristol Myers Squibb and AstraZeneca, outside the submitted work. CHB reports grants and fees from Merck Sharp & Dohme for clinical research consulting during the conduct of the study; consulting–advisory role fees from Boehringer Ingelheim, GlaxoSmithKline, and Bayer; consulting–advisory role fees and grants for clinical research from Novartis, Pfizer, Roche–Genentech, Eisai, Merck Sharp & Dohme, and AstraZeneca; grants for clinical research from Abbvie, Amgen, Astellas Pharma, Bristol Myers Squibb, Celgene, Covance, Lilly, Medication, Merck Serono, and PharmaMar; grants for academic research projects from CPO, Pontificia Universidade Católica do Rio Grande do Sul, Latin American Cooperative Oncology Group, Grupo Brasileiro Estudos Câncer Mama, and Instituto Nacional de Câncer-Brazil, outside the submitted work. HI reports a grant from Merck Sharp & Dohme during the conduct of the study; honoraria and consulting fees from Novartis, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, Eisai, and Chugai; and a grant from Chugai, outside the submitted work. NM reports honoraria and research funding paid to his institution from Chugai, AstraZeneca, Pfizer, Eli-Lilly, Eisai, Takeda, Kyowa-Kirin, Merck Sharp & Dohme, Novartis, and Daiichi Sankyo, outside the submitted work. EG reports non-financial support from Merck Sharp & Dohme during the conduct of the study; honoraria, consulting–advisory fees and meeting support from Novartis, Roche, Bristol Myers Squibb, and Pfizer; and honoraria from AstraZeneca and Astellas, outside the submitted work. SL reports research funding or consulting fees paid to her institution from Bristol Myers Squibb, Roche–Genentech, Puma Biotechnology, Pfizer, Seattle Genetics, Novartis, Merck Sharp & Dohme, Eli Lilly, Aduro Biotech, GI Therapeutics, AstraZeneca, and GlaxoSmithKline; and non-remunerated consultancy for Bristol Myers Squibb, Roche–Genentech, Pfizer, Seattle Genetics, Novartis, Merck Sharp & Dohme, and AstraZeneca, outside the submitted work. In addition, SL is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. ZG, JZ, GA, and VK are employees of Merck Sharp & Dohme and own stock or stock options in Merck. PS reports consultancy fees from Pfizer, AstraZeneca, Novartis, Roche, Merck Sharp & Dohme, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma; consultancy fees to his spouse from Genentech and Roche; and grants or funding to his institution from Roche, Genentech, Oncogenex, Novartis, Astellas, and AstraZeneca, outside the submitted work. All other authors declare no competing interests., The authors thank the patients, their families and caregivers for participating in this trial, all of the investigators and site personnel, and the following employees of Merck Sharp & Dohme: Wilbur Pan, Deborah Card, Eleanor Readinger, Shana Hamm, Roger Maxwell, and Krystal Bourdon, for collection of data, supervision of research, provision of study materials or patients or administrative or logistical support; Aline Galvao, for collection of data, supervision of research, administrative or logistical support, and review of imaging data related to the primary end point; Donna Letizia, for collection of data and imaging expertise; Jennifer Kimmel, for study management; Mercedes Bustamante, for data collection and management; Xuan Zhou and Madhusudhan Reddy Papasani, for statistical expertise; Christine McCrary Sisk, for medical writing and editorial assistance; and Joseph C Naggar and Michele McColgan, for administrative or logistical support.
- Published
- 2020