1. Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN)
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Jonathan W Goldman, Mikhail Dvorkin, Yuanbin Chen, Niels Reinmuth, Katsuyuki Hotta, Dmytro Trukhin, Galina Statsenko, Maximilian J Hochmair, Mustafa Özgüroğlu, Jun Ho Ji, Marina Chiara Garassino, Oleksandr Voitko, Artem Poltoratskiy, Santiago Ponce, Francesco Verderame, Libor Havel, Igor Bondarenko, Andrzej Każarnowicz, György Losonczy, Nikolay V Conev, Jon Armstrong, Natalie Byrne, Piruntha Thiyagarajah, Haiyi Jiang, Luis Paz-Ares, Nataliia Voitko, Andrzej Kazarnowicz, Mustafa Özgüroglu, Nikolay Conev, Maximilian Hochmair, Otto Burghuber, Irfan Çiçin, Vladimir Moiseenko, Mustafa Erman, Dariusz Kowalski, Marek Wojtukiewicz, Hryhoriy Adamchuk, Alexander Vasilyev, Serhii Shevnia, Spartak Valev, Maria Amelia Insa Molla, Grygorii Ursol, Anne Chiang, Sylvia Hartl, Zsolt Horváth, Gábor Pajkos, Sang-We Kim, Alexey Smolin, Tuncay Göksel, Shaker Dakhil, Jaromir Roubec, Krisztina Bogos, Robin Cornelissen, Jong-Seok Lee, Maria Rosario Garcia Campelo, Marta Lopez Brea, Ahmet Alacacioglu, Ignacio Casarini, Rumyana Ilieva, Ivan Tonev, Attila Somfay, Jair Bar, Alona Zer Kuch, Mauro Minelli, Roberta Bartolucci, Fausto Roila, Haruhiro Saito, Koichi Azuma, Gyeong-Won Lee, Alexander Luft, Michal Urda, Juan Ignacio Delgado Mingorance, Margarita Majem Tarruella, David Spigel, Krassimir Koynov, Milada Zemanova, Jens Panse, Christian Schulz, Zsolt Pápai Székely, Veronika Sárosi, Angelo Delmonte, Anna Cecilia Bettini, Makoto Nishio, Isamu Okamoto, Lizza Hendriks, Slawomir Mandziuk, Yun Gyoo Lee, Lyubov Vladimirova, Dolores Isla Casado, Manuel Domine Gomez, Alejandro Navarro Mendivil, Teresa Morán Bueno, Shang-Yin Wu, Jeanna Knoble, Jana Skrickova, Violetka Venkova, Werner Hilgers, Eckart Laack, Helge Bischoff, Andrea Fülöp, Ibolya Laczó, Judit Kósa, András Telekes, Tatsuya Yoshida, Shintaro Kanda, Toyoaki Hida, Hidetoshi Hayashi, Tadashi Maeda, Tetsuji Kawamura, Yasuharu Nakahara, Niels Claessens, Ki Hyeong Lee, Chao-Hua Chiu, Sheng-Hao Lin, Chien-Te Li, Ahmet Demirkazik, Eric Schaefer, Petros Nikolinakos, Jeffrey Schneider, Sunil Babu, Bernd Lamprecht, Michael Studnicka, Carlos Fausto Nino Gorini, Juraj Kultan, Vitezslav Kolek, Pierre-Jean Souquet, Denis Moro-Sibilot, Maya Gottfried, Egbert Smit, Kyung Hee Lee, Peter Kasan, Jozef Chovanec, Olexandr Goloborodko, Oleksii Kolesnik, Yuriy Ostapenko, Shailendra Lakhanpal, Basir Haque, Winston Chua, Joseph Stilwill, Susana Noemi Sena, Gustavo Colagiovanni Girotto, Pedro Rafael Martins De Marchi, Fabricio Augusto Martinelli de Oliveira, Pedro Dos Reis, Rositsa Krasteva, Yanqiu Zhao, Chengshui Chen, Leona Koubkova, Gilles Robinet, Christos Chouaid, Christian Grohe, Jürgen Alt, Eszter Csánky, Éva Somogyiné Ezer, Norman Isaac Heching, Young Hak Kim, Shinji Aatagi, Shoichi Kuyama, Daijiro Harada, Naoyuki Nogami, Hiroshi Nokihara, Hisatsugu Goto, Agnes Staal van den Brekel, Eun Kyung Cho, Joo-Hang Kim, Doina Ganea, Tudor Ciuleanu, Ekaterina Popova, Dina Sakaeva, Marian Stresko, Pavol Demo, Robert Godal, Yu-Feng Wei, Yen-Hsun Chen, Te-Chun Hsia, Kang-Yun Lee, Huang-Chih Chang, Chin-Chou Wang, Afshin Dowlati, Christopher Sumey, Steven Powell, Jonathan Goldman, Juan Jose Zarba, Emilio Batagelj, Andrea Viviana Pastor, Mauro Zukin, Clarissa Serodio da Rocha Baldotto, Luis Alberto Schlittler, Aknar Calabrich, Claudia Sette, Asen Dudov, Caicun Zhou, Hervé Lena, Susanne Lang, Zsuzsanna Pápai, Koichi Goto, Shigeki Umemura, Kenya Kanazawa, Yu Hara, Masahiro Shinoda, Masahiro Morise, Jeroen Hiltermann, Robert Mróz, Andrei Ungureanu, Igor Andrasina, Gee-Chen Chang, Ihor Vynnychenko, Yaroslav Shparyk, Anna Kryzhanivska, Helen Ross, Kailhong Mi, Rodney Jamil, Michael Williamson, Joseph Spahr, Zhigang Han, Mengzhao Wang, Zhixiong Yang, Jie Hu, Wei Li, Jun Zhao, Jifeng Feng, Shenglin Ma, Xiangdong Zhou, Zongan Liang, Yi Hu, Yuan Chen, Minghong Bi, Yongqian Shu, Kejun Nan, Jianying Zhou, Wei Zhang, Rui Ma, Nong Yang, Zhong Lin, Gang Wu, Jian Fang, Helong Zhang, Kai Wang, Zhendong Chen, Pulmonary Medicine, and Department of Technology and Operations Management
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Male ,medicine.medical_specialty ,Durvalumab ,Lung Neoplasms ,Time Factors ,endocrine system diseases ,Population ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,Sudden death ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,030212 general & internal medicine ,Progression-free survival ,education ,Aged ,Etoposide ,Neoplasm Staging ,education.field_of_study ,Performance status ,business.industry ,Antibodies, Monoclonal ,Middle Aged ,medicine.disease ,Small Cell Lung Carcinoma ,Progression-Free Survival ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,Cisplatin ,business ,Tremelimumab ,Febrile neutropenia ,medicine.drug - Abstract
Background: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum–etoposide) showed a significant improvement in overall survival versus platinum–etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide alone. Methods: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum–etoposide, durvalumab plus platinum–etoposide, or platinum–etoposide alone. In all groups, patients received etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL/min or cisplatin 75–80 mg/m2 on day 1 of each cycle. Patients in the platinum–etoposide group received up to six cycles of platinum–etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum–etoposide versus platinum–etoposide and for durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. Findings: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum–etoposide, 268 to durvalumab plus platinum–etoposide, and 269 to platinum–etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3–27·9). Durvalumab plus tremelimumab plus platinum–etoposide was not associated with a significant improvement in overall survival versus platinum–etoposide (hazard ratio [HR] 0·82 [95% CI 0·68–1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6–12·0) versus 10·5 months (9·3–11·2). Durvalumab plus platinum–etoposide showed sustained improvement in overall survival versus platinum–etoposide (HR 0·75 [95% CI 0·62–0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3–14·7) versus 10·5 months (9·3–11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum–etoposide group, and 88 [33%] of 266 patients in the platinum–etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 85 (32%) in the durvalumab plus platinum–etoposide group, and 97 (36%) in the platinum–etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum–etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum–etoposide group (pancytopenia and thrombocytopenia [n=1 each]). Interpretation: First-line durvalumab plus platinum–etoposide showed sustained overall survival improvement versus platinum–etoposide but the addition of tremelimumab to durvalumab plus platinum–etoposide did not significantly improve outcomes versus platinum–etoposide. These results support the use of durvalumab plus platinum–etoposide as a new standard of care for the first-line treatment of ES-SCLC. Funding: AstraZeneca.
- Published
- 2021
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