Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial

Paz‐Ares, Luis; Dvorkin, Mikhail; Chen, Yuanbin; Reinmuth, Niels; Hotta, Katsuyuki; Trukhin, Dmytro; Statsenko, Galina; Hochmair, Maximilian; Özgüroǧlu, Mustafa; Ji, Jun Ho; Войтко, Олександр; Poltoratskiy, A.; Ponce, Santiago; Verderame, Francesco; Havel, Libor; Bondarenko, Igor; Każarnowicz, Andrzej; Losonczy, György; Conev, Nikolay; Armstrong, J.; Byrne, Natalie; Shire, Norah J.; Jiang, Haiyi; Goldman, Jonathan W.; Batagelj, Emilio; Casarini, Ignacio; Pastor, Anea Viviana; Sena, S.; Zarbá, Juan José; Burghuber, Otto Chris; Hartl, Sylvia; Lamprecht, Bernd; Studnicka, Michael; Schlittler, Luís Alberto; Oliveira, Fabrício Augusto Martinelli de; Calabrich, Aknar; Girotto, Gustavo; Reis, Peo Dos; Gorini, Carlos Fausto Nino; Marchi, Peo Rafael Martins De; Baldotto, Clarissa; Sette, Cláudia Vaz de Melo; Zukin, Mauro; Dudov, A.; Ilieva, Rumyana; Koynov, Krassimir; Krasteva, Rositsa; Tonev, I.; Valev, Spartak; Venkova, Violetka; Bi, Minghong; Chen, Chengshui; Chen, Yuan; Chen, Zhendong; Fang, Jian; Feng, Jifeng; Han, Ze‐Guang; Hu, Jie; Hu, Yi; Li, Wei; Liang, Zongan; Zou, Lin; Ma, Rui; Ma, Shenglin; Kang, Nan; Shu, Yongqian; Wang, Kai; Wang, Mengzhao; Wu, Gang; Yang, Nong; Yang, Zhijian; Zhang, Helong; Zhang, Wei; Zhao, Jun; Zhao, Yanqiu; Zhou, Caicun; Zhou, Jianying; Zhou, Xiangdong; Kolek, Vı́tězslav; Koubková, Leona; Roubec, Jaromı́r; Skřičková, Jana; Zemanová, Milada; Chouaïd, C.; Hilgers, Werner; Léna, H.; Moro-Sibilot, Denis; Robinet, G.; Souquet, Pierre-Jean; Alt, Jürgen August; Bischoff, Helge; Grohé, Christian; Laack, Eckart; Lang, Susanne M.; Panse, Jens; Schulz, Christian; Bogos, Krisztina; Csánky, Eszter; Fülöp, Anea; Horváth, Zsolt; Kósa, Judit; Laczó, Ibolya; Pajkos, Gábor; Pápai, Zsuzsanna; Székely, Zsolt Pápai; Sárosi, Veronika; Somfay, A; Ezer, Éva Somogyiné; Telekes, Anás; Bar, Jair; Gottfried, Maya; Heching, Norman; Kuch, Alona Zer; Bartolucci, R.; Bettini, Anna; Delmonte, Angelo; Garassino, Marina Chiara; Minelli, Mauro; Roila, Fausto; Atagi, Shinji; Azuma, Koichi; Goto, Hisatsugu; Goto, Kōichi; Hara, Yu; Hayashi, Hidetoshi; Hida, Toyoaki; Kanazawa, Kenya; Kanda, Shintaro; Kim, Young Hak; Kuyama, Shoichi; Maeda, Tadashi; Morise, Masahiro; Nakahara, Yasuharu; Nishio, Makoto; Nogami, Naoyuki; Okamoto, Isamu; Saito, Haruhiro; Shinoda, Masahiro; Umemura, Shigeki; Yoshida, Tatsuya; Claessens, Niels; Cornelissen, Robin; Heniks, Lizza; Hiltermann, Jeroen; Smit, Egbert F.; Brekel, Agnes Staal van den; Kowalski, Dariusz M.; Mańdziuk, Sławomir; Mróz, Robert; Wojtukiewicz, Marek Z.; Ciuleanu, Tudor-Eliade; Ganea, Doina; Ungureanu, Anei; Luft, Alexander; Моисеенко, В.; Сакаева, Д. Д.; Smolin, A.; Vasilyev, Alexander; Vladimirova, Lyubov; Anasina, Igor; Chovanec, Jozef; Demo, Pavol; Godal, Robert; Kasan, Peter; Streško, Marian; Urda, M.; Cho, Eun Kyung; Kim, Joo-Hang; Kim, Sang‐We; Lee, Gyeong‐Won; Lee, Jong-Seok; Lee, Ki Hyeong; Lee, Kyung Hee; Lee, Yun Gyoo; Molla, M.A. Insa; Gómez, M. Dómine; Mingorance, Juan Ignacio Delgado; Casado, D.; Brea, Marta López; Tarruella, M. Majem; Bueno, Teresa Morán; Mendivil, Alejano Navarro; Rodríguez, Luis Paz-Ares; Aix, Santiago Ponce; Campelo, M.R. García; Chang, Gee‐Chen; Chen, Yen‐Hsun; Chiu, Chao‐Hua; Hsia, Te‐Chun; Lee, Kang‐Yun; Li, Chien-Te; Wang, Chin‐Chou; Wei, Yufeng; Wu, Shang-Yin; Alacacıoğlu, Ahmet; Çiçin, İrfan; Demirkazık, Ahmet; Erman, Mustafa; Göksel, Tuncay; Adamchuk, Hryhoriy; Kolesnik, Oleksii; Kryzhanivska, Anna; Ostapenko, Yuriv; Shevnia, Serhii; Shparyk, Yaroslav; Ursol, Grygorii; Voitko, Nataliia; Vynnychenko, Ihor; Babu, Sunil; Chiang, Anne C.; Chua, Winston; Dakhil, Shaker R.; Dowlati, Afshin; Haque, Basir; Jamil, Rodney; Knoble, Jeanna; Lakhanpal, Shailena; Mi, Kailhong; Nikolinakos, Petros; Powell, Steven; Ross, Helen J.; Schaefer, Eric; Schneider, Jeffrey; Spahr, Joseph E.; Spigel, David R.; Stilwill, Joseph; Sumey, Christopher; Williamson, Michael

doi:10.1016/s0140-6736(19)32222-6

Cited by 1,499 publications

(1,484 citation statements)

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“…In the last year, two randomised, controlled Phase 3 trials showed that adding atezolizumab (IMpower-133 study) or durvalumab (CASPIAN study), two antibodies directed against PD-L1, to standard first-line chemotherapy led to a statistically significant improvement in terms of OS in patients with ED-SCLC, although this benefit would not be considered clinically significant. 23,24 In second-line setting, different clinical studies are investigating the efficacy of several new agents, either alone or combined to standard chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Phase 2 study of NAB-paclitaxel in SensiTivE and refractory relapsed small cell lung cancer (SCLC) (NABSTER TRIAL)

et al. 2020

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Background Despite sensitivity to first-line chemotherapy, most small-cell lung cancer (SCLC) patients relapse. In this setting, topotecan demonstrated modest activity with significant toxicity. Paclitaxel was also active. This study was designed to evaluate activity and safety of nab-paclitaxel in relapsed SCLC. Methods In this multicentre prospective Phase 2 trial, patients with refractory or sensitive SCLC progressed to first-line platinum-based chemotherapy received nab-paclitaxel 100 mg/smq on days 1, 8, 15 every 4 weeks up to six cycles, progressive disease or intolerable toxicity. Primary endpoint was investigator-assessed objective tumour response. Secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Results Of the 68 patients treated, partial response was 8% in the refractory cohort and 14% in the sensitive cohort. Most common toxicities of any grade were fatigue (54%), anaemia (38%), neutropenia (29%), leukopenia (26%) and diarrhoea (21%). Median PFS was similar in both refractory (1.8 months) and sensitive cohorts (1.9 months), while median OS was longer in sensitive one (6.6 versus 3.6 months). Conclusions Although nab-paclitaxel has shown some modest anti-tumour activity in relapsed SCLC, associated with a favourable toxicity profile, the primary end-point of the study was not met. Clinical Trial registration Clinical Trial registration number is ClinicalTrials.gov Identifier: NCT03219762.

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Section: Discussionmentioning

confidence: 99%

Phase 2 study of NAB-paclitaxel in SensiTivE and refractory relapsed small cell lung cancer (SCLC) (NABSTER TRIAL)

et al. 2020

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“…The phase III CASPIAN trial evaluated durvalumab plus etoposide and cis/carboplatin in first-line ES-SCLC demonstrating a statistically significant improvement in mOS: 13.0 vs 10.3 months, HR 0.73 (95% CI 0.59-0.91; p = 0.0047) for durvalumab. The combination of durvalumab with either cisplatin or carboplatin-etoposide could stand as a new treatment option in first-line for ES-SCLC (I, A) [21].…”

Section: Combined Chemotherapy and Immunotherapymentioning

confidence: 99%

SEOM clinical guidelines for the treatment of small-cell lung cancer (SCLC) (2019)

et al. 2020

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Small-cell lung cancer (SCLC) accounts for 15% of lung cancers. Only one-third of patients are diagnosed at limited stage. The median survival remains to be around 15-20 months without significative changes in the strategies of treatment for many years. In stage I and IIA, the standard treatment is the surgery followed by adjuvant therapy with platinum-etoposide. In stage IIB-IIIC, the recommended treatment is early concurrent chemotherapy with platinum-etoposide plus thoracic radiotherapy followed by prophylactic cranial irradiation in patients without progression. However, in the extensive stage, significant advances have been observed adding immunotherapy to platinum-etoposide chemotherapy to obtain a significant increase in overall survival, constituting the new recommended standard of care. In the second-line treatment, topotecan remains as the standard treatment. Reinduction with platinum-etoposide is the recommended regimen in patients with sensitive relapse (≥ 3 months) and new drugs such as lurbinectedin and immunotherapy are new treatment options. New biomarkers and new clinical trials designed according to the new classification of SCLC subtypes defined by distinct gene expression profiles are necessary.

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“…However, there is still limited evidence of the efficacy of immune checkpoint inhibition in many types of NENs, while it proved effective in other difficult-to-treat NENs, such as SCLC and MCC [20,22,23,37].…”

Section: Immunotherapy In Human Cancers and Rationale In Nensmentioning

confidence: 99%

“…In the phase III CASPIAN trial, patients with untreated SCLC were assigned to received durvalumab, an IgG1 kappa anti-PD-L1 monoclonal human antibody, plus platinum-etoposide or durvalumab plus tremelimumab (an IgG2 anti-CTLA-4 fully human monoclonal antibody) plus platinum-etoposide followed by durvalumab as maintenance, until disease progression or unacceptable toxicity, or chemotherapy alone [23]. The primary endpoint was overall survival in the intention-to-treat population.…”

Section: Sclc First Line and Maintenancementioning

confidence: 99%

“…While studies of immune checkpoint inhibitors in monotherapy have often proven inferior to standard chemotherapy, the most recent studies show that a combination strategy is more effective in leading to a survival advantage in SCLC [22,23]. Several trials are ongoing in SCLC investigating immunotherapy in combination either with chemotherapy or with other immune checkpoint inhibitors, in order to achieve a synergistic effect.…”

Section: Pulmonary High-grade Nensmentioning

confidence: 99%

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Landscape and Future Perspectives of Immunotherapy in Neuroendocrine Neoplasia

Maggio

Manuzzi

Ricci

et al. 2020

Cancers

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Background: Neuroendocrine neoplasms are rare entities consisting of a heterogeneous group of tumors that can originate from neuroendocrine cells present in the whole body. Their different behavior, metastatic potential, and prognosis are highly variable, depending on site of origin, grade of differentiation, and proliferative index. The aim of our work is to summarize the current knowledge of immunotherapy in different neuroendocrine neoplasms and its implication in clinical practice. Results: Several studies evaluated the efficacy and safety of immunotherapy in neuroendocrine neoplasms, in any setting of treatment, alone or in combination. Studies led to approval in neuroendocrine neoplasia of the lung, in combination with chemotherapy as first-line treatment or as a single-agent in a third-line setting, and Merkel cell carcinoma as a single agent. Results in other settings have been disappointing so far. Conclusions: Immunotherapy seems a valid treatment option for high grade, poorly differentiated neoplasms. Future trials should explore the combination of immunotherapy with other agents, such as anti-angiogenic or other immunotherapy agents, in order to evaluate potential efficacy in low and intermediate grades, well differentiated tumors.

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Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial

Cited by 1,499 publications

References 20 publications

Phase 2 study of NAB-paclitaxel in SensiTivE and refractory relapsed small cell lung cancer (SCLC) (NABSTER TRIAL)

Phase 2 study of NAB-paclitaxel in SensiTivE and refractory relapsed small cell lung cancer (SCLC) (NABSTER TRIAL)

SEOM clinical guidelines for the treatment of small-cell lung cancer (SCLC) (2019)

Landscape and Future Perspectives of Immunotherapy in Neuroendocrine Neoplasia

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