Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial

Frederick L. Locke, Armin Ghobadi, Caron A. Jacobson, David B. Miklos, Lazaros J. Lekakis, Olalekan O. Oluwole, Yi Lin, Ira Braunschweig, Brian T. Hill, John M. Timmerman, Abhinav Deol, Patrick M. Reagan, Patrick Stiff, Ian W. Flinn, Umar Farooq, Andre Goy, Peter A. McSweeney, Javier Munoz, Tanya Siddiqi, Julio C. ChavezAlex F. Herrera, Nancy L. Bartlett, Jeffrey S. Wiezorek, Lynn Navale, Allen Xue, Yizhou Jiang, Adrian Bot, John M. Rossi, Jenny J. Kim, William Y. Go, Sattva S. Neelapu

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Background: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7–17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. Methods: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma—including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 10 6 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m 2 body-surface area) and cyclophosphamide (500 mg/m 2 body-surface area) on days −5, −4, and −3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Findings: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7–28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2–not estimable). The median overall survival was not reached (12·8–not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3–15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up. Interpretation: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma. Funding: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.

Original languageEnglish (US)
Pages (from-to)31-42
Number of pages12
JournalThe Lancet Oncology
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2019

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B-Cell Lymphoma
Safety
Body Surface Area
Disease-Free Survival
Survival
CD19 Antigens
Hemophagocytic Lymphohistiocytosis
Drug Therapy
Antigen Receptors
Lymphoma, Large B-Cell, Diffuse
Anthracyclines
Myelodysplastic Syndromes
Stem Cell Transplantation
Lymphoid Tissue
Israel
Therapeutics
Patient Safety
Cell- and Tissue-Based Therapy
Bacteremia
T-Cell Antigen Receptor

ASJC Scopus subject areas

  • Oncology

Cite this

Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1) : a single-arm, multicentre, phase 1–2 trial. / Locke, Frederick L.; Ghobadi, Armin; Jacobson, Caron A.; Miklos, David B.; Lekakis, Lazaros J.; Oluwole, Olalekan O.; Lin, Yi; Braunschweig, Ira; Hill, Brian T.; Timmerman, John M.; Deol, Abhinav; Reagan, Patrick M.; Stiff, Patrick; Flinn, Ian W.; Farooq, Umar; Goy, Andre; McSweeney, Peter A.; Munoz, Javier; Siddiqi, Tanya; Chavez, Julio C.; Herrera, Alex F.; Bartlett, Nancy L.; Wiezorek, Jeffrey S.; Navale, Lynn; Xue, Allen; Jiang, Yizhou; Bot, Adrian; Rossi, John M.; Kim, Jenny J.; Go, William Y.; Neelapu, Sattva S.

In: The Lancet Oncology, Vol. 20, No. 1, 01.01.2019, p. 31-42.

Research output: Contribution to journalArticle

Locke, FL, Ghobadi, A, Jacobson, CA, Miklos, DB, Lekakis, LJ, Oluwole, OO, Lin, Y, Braunschweig, I, Hill, BT, Timmerman, JM, Deol, A, Reagan, PM, Stiff, P, Flinn, IW, Farooq, U, Goy, A, McSweeney, PA, Munoz, J, Siddiqi, T, Chavez, JC, Herrera, AF, Bartlett, NL, Wiezorek, JS, Navale, L, Xue, A, Jiang, Y, Bot, A, Rossi, JM, Kim, JJ, Go, WY & Neelapu, SS 2019, 'Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial', The Lancet Oncology, vol. 20, no. 1, pp. 31-42. https://doi.org/10.1016/S1470-2045(18)30864-7
Locke, Frederick L. ; Ghobadi, Armin ; Jacobson, Caron A. ; Miklos, David B. ; Lekakis, Lazaros J. ; Oluwole, Olalekan O. ; Lin, Yi ; Braunschweig, Ira ; Hill, Brian T. ; Timmerman, John M. ; Deol, Abhinav ; Reagan, Patrick M. ; Stiff, Patrick ; Flinn, Ian W. ; Farooq, Umar ; Goy, Andre ; McSweeney, Peter A. ; Munoz, Javier ; Siddiqi, Tanya ; Chavez, Julio C. ; Herrera, Alex F. ; Bartlett, Nancy L. ; Wiezorek, Jeffrey S. ; Navale, Lynn ; Xue, Allen ; Jiang, Yizhou ; Bot, Adrian ; Rossi, John M. ; Kim, Jenny J. ; Go, William Y. ; Neelapu, Sattva S. / Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1) : a single-arm, multicentre, phase 1–2 trial. In: The Lancet Oncology. 2019 ; Vol. 20, No. 1. pp. 31-42.
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abstract = "Background: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7–17·3), 89 (82{\%}) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58{\%}) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. Methods: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma—including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 10 6 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m 2 body-surface area) and cyclophosphamide (500 mg/m 2 body-surface area) on days −5, −4, and −3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Findings: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7–28·8), 84 (83{\%}) had an objective response, and 59 (58{\%}) had a complete response. The median duration of response was 11·1 months (4·2–not estimable). The median overall survival was not reached (12·8–not estimable), and the median progression-free survival was 5·9 months (95{\%} CI 3·3–15·0). 52 (48{\%}) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11{\%}) patients, and grade 3 or worse neurological events in 35 (32{\%}). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up. Interpretation: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma. Funding: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.",
author = "Locke, {Frederick L.} and Armin Ghobadi and Jacobson, {Caron A.} and Miklos, {David B.} and Lekakis, {Lazaros J.} and Oluwole, {Olalekan O.} and Yi Lin and Ira Braunschweig and Hill, {Brian T.} and Timmerman, {John M.} and Abhinav Deol and Reagan, {Patrick M.} and Patrick Stiff and Flinn, {Ian W.} and Umar Farooq and Andre Goy and McSweeney, {Peter A.} and Javier Munoz and Tanya Siddiqi and Chavez, {Julio C.} and Herrera, {Alex F.} and Bartlett, {Nancy L.} and Wiezorek, {Jeffrey S.} and Lynn Navale and Allen Xue and Yizhou Jiang and Adrian Bot and Rossi, {John M.} and Kim, {Jenny J.} and Go, {William Y.} and Neelapu, {Sattva S.}",
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TY - JOUR

T1 - Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1)

T2 - a single-arm, multicentre, phase 1–2 trial

AU - Locke, Frederick L.

AU - Ghobadi, Armin

AU - Jacobson, Caron A.

AU - Miklos, David B.

AU - Lekakis, Lazaros J.

AU - Oluwole, Olalekan O.

AU - Lin, Yi

AU - Braunschweig, Ira

AU - Hill, Brian T.

AU - Timmerman, John M.

AU - Deol, Abhinav

AU - Reagan, Patrick M.

AU - Stiff, Patrick

AU - Flinn, Ian W.

AU - Farooq, Umar

AU - Goy, Andre

AU - McSweeney, Peter A.

AU - Munoz, Javier

AU - Siddiqi, Tanya

AU - Chavez, Julio C.

AU - Herrera, Alex F.

AU - Bartlett, Nancy L.

AU - Wiezorek, Jeffrey S.

AU - Navale, Lynn

AU - Xue, Allen

AU - Jiang, Yizhou

AU - Bot, Adrian

AU - Rossi, John M.

AU - Kim, Jenny J.

AU - Go, William Y.

AU - Neelapu, Sattva S.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7–17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. Methods: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma—including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 10 6 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m 2 body-surface area) and cyclophosphamide (500 mg/m 2 body-surface area) on days −5, −4, and −3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Findings: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7–28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2–not estimable). The median overall survival was not reached (12·8–not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3–15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up. Interpretation: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma. Funding: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.

AB - Background: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7–17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. Methods: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma—including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 10 6 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m 2 body-surface area) and cyclophosphamide (500 mg/m 2 body-surface area) on days −5, −4, and −3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Findings: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7–28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2–not estimable). The median overall survival was not reached (12·8–not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3–15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up. Interpretation: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma. Funding: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.

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