Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide
alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN):
updated results from a randomised, controlled, open-label, phase 3 trial
Goldman, Jonathan W; CASPIAN investigators [Collaborative Organization]; Dvorkin, Mikhail; Chen, Yuanbin; Reinmuth, Niels; Hotta, Katsuyuki; Trukhin, Dmytro; Statsenko, Galina; Hochmair, Maximilian J; Özgüroğlu, Mustafa; Ji, Jun Ho; Garassino, Marina Chiara; Voitko, Oleksandr; Poltoratskiy, Artem; Ponce, Santiago; Verderame, Francesco; Havel, Libor; Bondarenko, Igor; Każarnowicz, Andrzej; Losonczy, György [Losonczy, György (Pulmonológia, kli...), author] Department of Pulmonology
(SU / FM / C); Conev, Nikolay V; Armstrong, Jon; Byrne, Natalie; Thiyagarajah, Piruntha; Jiang, Haiyi; Paz-Ares, Luis** ✉; Dvorkin, Mikhail [Collaborator]; Trukhin, Dmytro [Collaborator]; Statsenko, Galina [Collaborator]; Voitko, Nataliia [Collaborator]; Poltoratskiy, Artem [Collaborator]; Bondarenko, Igor [Collaborator]; Chen, Yuanbin [Collaborator]; Kazarnowicz, Andrzej [Collaborator]; Paz-Ares, Luis [Collaborator]; Özgüroglu, Mustafa [Collaborator]; Conev, Nikolay [Collaborator]; Hochmair, Maximilian [Collaborator]; Burghuber, Otto [Collaborator]; Havel, Libor [Collaborator]; Çiçin, Irfan [Collaborator]; Losonczy, György [Losonczy, György (Pulmonológia, kli...), Collaborator] Department
of Pulmonology (SU / FM / C); Moiseenko, Vladimir [Collaborator]; Erman, Mustafa [Collaborator]; Kowalski, Dariusz [Collaborator]; Wojtukiewicz, Marek [Collaborator]; Adamchuk, Hryhoriy [Collaborator]; Vasilyev, Alexander [Collaborator]; Shevnia, Serhii [Collaborator]; Valev, Spartak [Collaborator]; Reinmuth, Niels [Collaborator]; Ji, Jun Ho [Collaborator]; Insa Molla, Maria Amelia [Collaborator]; Ursol, Grygorii [Collaborator]; Chiang, Anne [Collaborator]; Hartl, Sylvia [Collaborator]; Horváth, Zsolt [Horváth, Zsolt (Onkológia), Collaborator] National Institute of Oncology; Pajkos, Gábor [Collaborator]; Verderame, Francesco [Collaborator]; Hotta, Katsuyuki [Collaborator]; Kim, Sang-We [Collaborator]; Smolin, Alexey [Collaborator]; Göksel, Tuncay [Collaborator]; Dakhil, Shaker [Collaborator]; Roubec, Jaromir [Collaborator]; Bogos, Krisztina [Bogos, Krisztina (Tüdőgyógyászat, K...), Collaborator]; Garassino, Marina Chiara [Collaborator]; Cornelissen, Robin [Collaborator]; Lee, Jong-Seok [Collaborator]; Garcia Campelo, Maria Rosario [Collaborator]; Lopez Brea, Marta [Collaborator]; Alacacioglu, Ahmet [Collaborator]; Casarini, Ignacio [Collaborator]; Ilieva, Rumyana [Collaborator]; Tonev, Ivan [Collaborator]; Somfay, Attila [Somfay, Attila (Tüdőgyógyászat), Collaborator] Department of Pulmonology
(SZTE / ASZMS); Bar, Jair [Collaborator]; Zer Kuch, Alona [Collaborator]; Minelli, Mauro [Collaborator]; Bartolucci, Roberta [Collaborator]; Roila, Fausto [Collaborator]; Saito, Haruhiro [Collaborator]; Azuma, Koichi [Collaborator]; Lee, Gyeong-Won [Collaborator]; Luft, Alexander [Collaborator]; Urda, Michal [Collaborator]; Delgado Mingorance, Juan Ignacio [Collaborator]; Majem Tarruella, Margarita [Collaborator]; Spigel, David [Collaborator]; Koynov, Krassimir [Collaborator]; Zemanova, Milada [Collaborator]; Panse, Jens [Collaborator]; Schulz, Christian [Collaborator]; Pápai Székely, Zsolt [Collaborator]; Sárosi, Veronika [Collaborator]; Delmonte, Angelo [Collaborator]; Bettini, Anna Cecilia [Collaborator]; Nishio, Makoto [Collaborator]; Okamoto, Isamu [Collaborator]; Hendriks, Lizza [Collaborator]; Mandziuk, Slawomir [Collaborator]; Lee, Yun Gyoo [Collaborator]; Vladimirova, Lyubov [Collaborator]; Isla Casado, Dolores [Collaborator]; Domine Gomez, Manuel [Collaborator]; Navarro Mendivil, Alejandro [Collaborator]; Morán Bueno, Teresa [Collaborator]; Wu, Shang-Yin [Collaborator]; Knoble, Jeanna [Collaborator]; Skrickova, Jana [Collaborator]; Venkova, Violetka [Collaborator]; Hilgers, Werner [Collaborator]; Laack, Eckart [Collaborator]; Bischoff, Helge [Collaborator]; Fülöp, Andrea [Collaborator]; Laczó, Ibolya [Collaborator]; Kósa, Judit [Collaborator]; Telekes, András [Telekes, András (onkológia), Collaborator]; Yoshida, Tatsuya [Collaborator]; Kanda, Shintaro [Collaborator]; Hida, Toyoaki [Collaborator]; Hayashi, Hidetoshi [Collaborator]; Maeda, Tadashi [Collaborator]; Kawamura, Tetsuji [Collaborator]; Nakahara, Yasuharu [Collaborator]; Claessens, Niels [Collaborator]; Lee, Ki Hyeong [Collaborator]; Chiu, Chao-Hua [Collaborator]; Lin, Sheng-Hao [Collaborator]; Li, Chien-Te [Collaborator]; Demirkazik, Ahmet [Collaborator]; Schaefer, Eric [Collaborator]; Nikolinakos, Petros [Collaborator]; Schneider, Jeffrey [Collaborator]; Babu, Sunil [Collaborator]; Lamprecht, Bernd [Collaborator]; Studnicka, Michael [Collaborator]; Fausto Nino Gorini, Carlos [Collaborator]; Kultan, Juraj [Collaborator]; Kolek, Vitezslav [Collaborator]; Souquet, Pierre-Jean [Collaborator]; Moro-Sibilot, Denis [Collaborator]; Gottfried, Maya [Collaborator]; Smit, Egbert [Collaborator]; Lee, Kyung Hee [Collaborator]; Kasan, Peter [Collaborator]; Chovanec, Jozef [Collaborator]; Goloborodko, Olexandr [Collaborator]; Kolesnik, Oleksii [Collaborator]; Ostapenko, Yuriy [Collaborator]; Lakhanpal, Shailendra [Collaborator]; Haque, Basir [Collaborator]; Chua, Winston [Collaborator]; Stilwill, Joseph [Collaborator]; Sena, Susana Noemi [Collaborator]; Girotto, Gustavo Colagiovanni [Collaborator]; De Marchi, Pedro Rafael Martins [Collaborator]; Martinelli de Oliveira, Fabricio Augusto [Collaborator]; Dos Reis, Pedro [Collaborator]; Krasteva, Rositsa [Collaborator]; Zhao, Yanqiu [Collaborator]; Chen, Chengshui [Collaborator]; Koubkova, Leona [Collaborator]; Robinet, Gilles [Collaborator]; Chouaid, Christos [Collaborator]; Grohe, Christian [Collaborator]; Alt, Jürgen [Collaborator]; Csánky, Eszter [Collaborator]; Somogyiné Ezer, Éva [Somogyiné Ezer, Éva (Onkológia), Collaborator]; Heching, Norman Isaac [Collaborator]; Kim, Young Hak [Collaborator]; Aatagi, Shinji [Collaborator]; Kuyama, Shoichi [Collaborator]; Harada, Daijiro [Collaborator]; Nogami, Naoyuki [Collaborator]; Nokihara, Hiroshi [Collaborator]; Goto, Hisatsugu [Collaborator]; Staal van den Brekel, Agnes [Collaborator]; Cho, Eun Kyung [Collaborator]; Kim, Joo-Hang [Collaborator]; Ganea, Doina [Collaborator]; Ciuleanu, Tudor [Collaborator]; Popova, Ekaterina [Collaborator]; Sakaeva, Dina [Collaborator]; Stresko, Marian [Collaborator]; Demo, Pavol [Collaborator]; Godal, Robert [Collaborator]; Wei, Yu-Feng [Collaborator]; Chen, Yen-Hsun [Collaborator]; Hsia, Te-Chun [Collaborator]; Lee, Kang-Yun [Collaborator]; Chang, Huang-Chih [Collaborator]; Wang, Chin-Chou [Collaborator]; Dowlati, Afshin [Collaborator]; Sumey, Christopher [Collaborator]; Powell, Steven [Collaborator]; Goldman, Jonathan [Collaborator]; Zarba, Juan Jose [Collaborator]; Batagelj, Emilio [Collaborator]; Pastor, Andrea Viviana [Collaborator]; Zukin, Mauro [Collaborator]; Baldotto, Clarissa Serodio da Rocha [Collaborator]; Schlittler, Luis Alberto [Collaborator]; Calabrich, Aknar [Collaborator]; Sette, Claudia [Collaborator]; Dudov, Asen [Collaborator]; Zhou, Caicun [Collaborator]; Lena, Hervé [Collaborator]; Lang, Susanne [Collaborator]; Pápai, Zsuzsanna [Collaborator]; Goto, Koichi [Collaborator]; Umemura, Shigeki [Collaborator]; Kanazawa, Kenya [Collaborator]; Hara, Yu [Collaborator]; Shinoda, Masahiro [Collaborator]; Morise, Masahiro [Collaborator]; Hiltermann, Jeroen [Collaborator]; Mróz, Robert [Collaborator]; Ungureanu, Andrei [Collaborator]; Andrasina, Igor [Collaborator]; Chang, Gee-Chen [Collaborator]; Vynnychenko, Ihor [Collaborator]; Shparyk, Yaroslav [Collaborator]; Kryzhanivska, Anna [Collaborator]; Ross, Helen [Collaborator]; Mi, Kailhong [Collaborator]; Jamil, Rodney [Collaborator]; Williamson, Michael [Collaborator]; Spahr, Joseph [Collaborator]; Han, Zhigang [Collaborator]; Wang, Mengzhao [Collaborator]; Yang, Zhixiong [Collaborator]; Hu, Jie [Collaborator]; Li, Wei [Collaborator]; Zhao, Jun [Collaborator]; Feng, Jifeng [Collaborator]; Ma, Shenglin [Collaborator]; Zhou, Xiangdong [Collaborator]; Liang, Zongan [Collaborator]; Hu, Yi [Collaborator]; Chen, Yuan [Collaborator]; Bi, Minghong [Collaborator]; Shu, Yongqian [Collaborator]; Nan, Kejun [Collaborator]; Zhou, Jianying [Collaborator]; Zhang, Wei [Collaborator]; Ma, Rui [Collaborator]; Yang, Nong [Collaborator]; Lin, Zhong [Collaborator]; Wu, Gang [Collaborator]; Fang, Jian [Collaborator]; Zhang, Helong [Collaborator]; Wang, Kai [Collaborator]; Chen, Zhendong [Collaborator]
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.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.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]).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.AstraZeneca.
