TY - JOUR
T1 - Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN)
T2 - updated results from a randomised, controlled, open-label, phase 3 trial
AU - CASPIAN investigators
AU - Goldman, Jonathan W.
AU - Dvorkin, Mikhail
AU - Chen, Yuanbin
AU - Reinmuth, Niels
AU - Hotta, Katsuyuki
AU - Trukhin, Dmytro
AU - Statsenko, Galina
AU - Hochmair, Maximilian J.
AU - Özgüroğlu, Mustafa
AU - Ji, Jun Ho
AU - Garassino, Marina Chiara
AU - Voitko, Oleksandr
AU - Poltoratskiy, Artem
AU - Ponce, Santiago
AU - Verderame, Francesco
AU - Havel, Libor
AU - Bondarenko, Igor
AU - Każarnowicz, Andrzej
AU - Losonczy, György
AU - Conev, Nikolay V.
AU - Armstrong, Jon
AU - Byrne, Natalie
AU - Thiyagarajah, Piruntha
AU - Jiang, Haiyi
AU - Paz-Ares, Luis
AU - Voitko, Nataliia
AU - Kazarnowicz, Andrzej
AU - Özgüroglu, Mustafa
AU - Conev, Nikolay
AU - Hochmair, Maximilian
AU - Burghuber, Otto
AU - Çiçin, Irfan
AU - Moiseenko, Vladimir
AU - Erman, Mustafa
AU - Kowalski, Dariusz
AU - Wojtukiewicz, Marek
AU - Adamchuk, Hryhoriy
AU - Vasilyev, Alexander
AU - Shevnia, Serhii
AU - Valev, Spartak
AU - Insa Molla, Maria Amelia
AU - Ursol, Grygorii
AU - Chiang, Anne
AU - Hartl, Sylvia
AU - Wu, Shang Yin
AU - Lin, Sheng Hao
AU - Lee, Kang Yun
AU - Chang, Huang Chih
AU - Wang, Chin Chou
AU - Li, Wei
AU - Chiu, Chao-Hua
N1 - Funding Information:
JWG has received grants and personal fees from AstraZeneca during the conduct of the study; and grants and personal fees from Genentech outside the submitted work. YC has received personal fees from AstraZeneca, Genentech, Bristol Myers Squibb (BMS), Merck, Novartis, Takeda, Eli Lilly, Guardant Health, Pfizer, and Array Biopharma; and grants from AstraZeneca, Ipsen, Roche, and BMS, all outside the submitted work. NR has received personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim, Hoffmann La-Roche, BMS, and Pfizer; non-financial support from AbbVie; and personal fees from Merck Sharp and Dohme (MSD) and Takeda, all outside the submitted work. KH has received grants and personal fees from AstraZeneca during the conduct of the study; grants and personal fees from Lilly, AstraZeneca, BMS, MSD, and Chugai outside the submitted work; personal fees from Pfizer, Ono, Nipponkayaku, Taiho, Boehringer Ingelheim, Novartis, Daiichi-Sankyo, and Kyorin outside the submitted work; and grants from Astellas outside the submitted work. MÖ has participated in advisory boards for Janssen, Sanofi, and Astellas; has received honoraria from Novartis, Roche, Janssen, Sanofi, and Astellas; and has been reimbursed for travel, accommodation, or expenses from BMS and Janssen, all outside the submitted work. MCG has received grants and personal fees from Eli Lilly, Otsuka Pharmaceutical, AstraZeneca, Novartis, BMS, Roche, Pfizer, Celgene, Incyte, Bayer, MSD, GlaxoSmithKline, Spectrum Pharmaceuticals, and Blueprint Medicines; personal fees from Boehringer Ingelheim, Inivata, Takeda, Sanofi, Seattle Genetics, Daiichi-Sankyo, and Janssen; grants from Tiziana Life Sciences, Clovis, Merck Serono, United Therapeutics, Merck, Turning Point Therapeutics, Ipsen, and Exelisis; and non-financial support from MSD, Pfizer, and Eli Lilly, all outside the submitted work. SP has received grants from Roche and MSD; and lecture fees from Roche, BMS, AstraZeneca, and Pfizer, all outside the submitted work. FV has received grants from AstraZeneca during the conduct of this study. JA, PT, and HJ are full-time employees of and own stock in AstraZeneca. NB is a contractor for and owns stock in AstraZeneca. LP-A reports leadership with Genomica and Altum Sequencing; has been reimbursed for travel, accommodation, or expenses from Roche, AstraZeneca, AstraZeneca Spain, MSD, BMS, Lilly, and Pfizer; has received honoraria from Roche/Genentech, Lilly, Pfizer, Boehringer Ingelheim, BMS, MSD, AstraZeneca, Merck Serono, PharmaMar, Novartis, Celgene, Sysmex, Bayer, Amgen, Blueprint Medicines, and Incyte; and fees (immediate family member) from Novartis, Ipsen, Pfizer, Servier, Sanofi, Roche, Amgen, and Merck, all outside the submitted work. All other authors declare no competing interests.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85097833126&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(20)30539-8
DO - 10.1016/S1470-2045(20)30539-8
M3 - Article
C2 - 33285097
AN - SCOPUS:85097833126
SN - 1470-2045
VL - 22
SP - 51
EP - 65
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 1
ER -