TY - JOUR
T1 - Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1)
T2 - a phase 1b/2 open-label study
AU - Berdeja, Jesus G.
AU - Madduri, Deepu
AU - Usmani, Saad Z.
AU - Jakubowiak, Andrzej
AU - Agha, Mounzer
AU - Cohen, Adam D.
AU - Stewart, A. Keith
AU - Hari, Parameswaran
AU - Htut, Myo
AU - Lesokhin, Alexander
AU - Deol, Abhinav
AU - Munshi, Nikhil C.
AU - O'Donnell, Elizabeth
AU - Avigan, David
AU - Singh, Indrajeet
AU - Zudaire, Enrique
AU - Yeh, Tzu Min
AU - Allred, Alicia J.
AU - Olyslager, Yunsi
AU - Banerjee, Arnob
AU - Jackson, Carolyn C.
AU - Goldberg, Jenna D.
AU - Schecter, Jordan M.
AU - Deraedt, William
AU - Zhuang, Sen Hong
AU - Infante, Jeffrey
AU - Geng, Dong
AU - Wu, Xiaoling
AU - Carrasco-Alfonso, Marlene J.
AU - Akram, Muhammad
AU - Hossain, Farah
AU - Rizvi, Syed
AU - Fan, Frank
AU - Lin, Yi
AU - Martin, Thomas
AU - Jagannath, Sundar
N1 - Funding Information:
This study was funded by Janssen Research and Development and Legend Biotech. We thank the patients who volunteered to participate in the study, their families and caregivers, the physicians and nurses who cared for the patients and supported this clinical trial, staff members at the 16 study sites in the USA who enrolled patients, and staff members involved in data collection and analysis. Medical writing support was provided by Jaya Kolipaka and Joanna Bloom of Eloquent Scientific Solutions, and funded by Janssen Global Services.
Funding Information:
This study was funded by Janssen Research and Development and Legend Biotech. We thank the patients who volunteered to participate in the study, their families and caregivers, the physicians and nurses who cared for the patients and supported this clinical trial, staff members at the 16 study sites in the USA who enrolled patients, and staff members involved in data collection and analysis. Medical writing support was provided by Jaya Kolipaka and Joanna Bloom of Eloquent Scientific Solutions, and funded by Janssen Global Services.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/7/24
Y1 - 2021/7/24
N2 - Background: CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis. Methods: This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR-positive viable T cells per kg) was administered 5–7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207. Findings: Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 106 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6–15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2–99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9–1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9–not estimable), neither was progression-free survival (16·8–not estimable). The 12-month progression-free rate was 77% (95% CI 66·0–84·3) and overall survival rate was 89% (80·2–93·5). Haematological adverse events were common; grade 3–4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5–8) and median duration of 4·0 days (IQR 3–6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events. Interpretation: A single cilta-cel infusion at the target dose of 0·75 × 106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions. Funding: Janssen Research & Development and Legend Biotech.
AB - Background: CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis. Methods: This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR-positive viable T cells per kg) was administered 5–7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207. Findings: Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 106 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6–15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2–99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9–1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9–not estimable), neither was progression-free survival (16·8–not estimable). The 12-month progression-free rate was 77% (95% CI 66·0–84·3) and overall survival rate was 89% (80·2–93·5). Haematological adverse events were common; grade 3–4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5–8) and median duration of 4·0 days (IQR 3–6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events. Interpretation: A single cilta-cel infusion at the target dose of 0·75 × 106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions. Funding: Janssen Research & Development and Legend Biotech.
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U2 - 10.1016/S0140-6736(21)00933-8
DO - 10.1016/S0140-6736(21)00933-8
M3 - Article
C2 - 34175021
AN - SCOPUS:85111003312
SN - 0140-6736
VL - 398
SP - 314
EP - 324
JO - The Lancet
JF - The Lancet
IS - 10297
ER -