Long-term outcomes of the ZUMA-1 study assessing axicabtagene ciloleucel for the treatment of refractory B-cell lymphoma

Patients with refractory large B-cell lymphoma have a poor prognosis, with studies suggesting a median overall survival of just 6.3 months.¹ Chimeric antigen receptor (CAR) T-cell therapies that target CD19 are a potential option in the treatment of these refractory large B-cell lymphomas. The Lymphoma Hub has previously reported on the ZUMA-1 study (NCT02348216), having seen preliminary data presented at the 14th International Conference on Malignant Lymphoma (ICML) in Lugano, CH, (our report can be found here) and at the American Association for Cancer Research (AACR) Annual Meeting 2017, Washington DC, US, (read the Lymphoma Hub article here). In their recent Lancet Oncology publication, Frederick Locke, H. Lee Moffitt Cancer Center & Research Institute, Tampa, US, and team reported on the 2-year activity and safety results of this phase 1–2, single-arm, multicentre study.

Study design

Patients

• Aged ≥ 18 years
• Refractory B-cell lymphoma (including diffuse large B-cell lymphoma [DLBCL], primary mediastinal B-cell lymphoma, and transformed follicular lymphoma [FL]); defined as progressive/stable with most recent chemotherapy or progression/relapse within 1 year of autologous stem-cell transplantation (auto-SCT)
• Have received treatment containing anti-CD20 monoclonal antibody and an anthracycline chemotherapy regimen
• Those with transformed DLBCL should have had chemotherapy for FL and progressed to a chemorefractory state after transformation
• Exclusions included patients who had auto-SCT within 6 weeks of consenting to ZUMA-1; patients who had previously had allogeneic SCT (allo-SCT); patients who had previously received anti-CD19 or CAR T-cell therapy  

Procedures

• Leukapheresis: peripheral blood mononuclear cells for CAR T-cell production were obtained from eligible patients
• Conditioning chemotherapy: intravenous (IV) fludarabine (30 mg/m² body-surface area per day) plus cyclophosphamide (500 mg/m² body-surface area per day) on Days −5, −4, and −3
• Infusion: axicabtagene ciloleucel (axicel; KTE-C19) on Day 0 with target dose of 2 × 10⁶ CAR T cells per kg of body weight
• Bridging chemotherapy was not permitted between leukapheresis and conditioning chemotherapy
• Laboratory monitoring and safety assessments were continued until 24 months
• Response was assessed locally by PET (according to International Working Group Response Criteria²) at Month 1, every three months from Months 3–24, and as clinically indicated or per the institution’s standard-of-care after 2 years. Response was also assessed by an independent central review committee (IRC) during phase II

Outcomes

• Phase II primary endpoint: proportion of patients achieving an objective response per investigator assessment
• Secondary endpoints: overall response by IRC, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety

Results

• A total of 119 patients were enrolled, and 108 (phase I n = 7; phase II n = 101) were treated with axicel. Baseline characteristics of the patients are in Table 1
• Phase II patient follow-up was a median of 27.1 months (IQR, 25.7–28.8)
• Primary endpoint: 84 (83%) patients had an objective response by investigator assessment; 59 (58%) patients had a complete response (CR) and 25 (25%) patients had a partial response to axicel
• Concordance between the investigator and IRC assessments was 81% for objective response and 90% for CR
• Median DoR for phase II participants was 11.1 months (95% CI 4.2–not estimable)
  • Median DoR for participants with CRs was not reached (95% CI 12.9–not estimable).
• At final disease assessment, 39% patients had ongoing responses, with 37% patients having  ongoing CRs
• A total of 61/101 patients experienced disease progression or died during the study
• Median PFS was 5.9 months (95% CI 3.3–15.0)
• Median OS was not reached (95% CI 12.8–not estimable)
  • Estimated 24-month survival was 50.5% (95% CI 40.2–59.7)
• All 108 patients experienced adverse events (AEs), with 98% being Grade ≥3 (Table 2)
• There were 52/108 (48%) patients who experienced Grade ≥ 3 serious AEs
  • Since the 12-month analysis (data cut-off Aug 11, 2017), 4 patients developed new SAEs, none of which were considered to be related to axicel
• Grade ≥ 3 cytokine release syndrome (CRS) occurred in 12 (11%) patients and Grade ≥3 neurological events (NE) occurred in 35 (32%) patients; these events were manageable and largely reversible
  • Since the 12-month analysis, no new cases of CRS or NEs related to axicel have been reported
• There were 30 patients who experienced Grade ≥ 3 infections over the course of the study
• In total, 18/108 (17%) patients had Grade ≥ 3 cytopenias at 3 months or later, including 12 (11%) patients with neutropenia, eight (7%) with thrombocytopenia, and three (3%) with anemia. Two patients had Grade 3 cytopenias (one anaemia, one neutropenia)
• In total, 54/108 (50%) patients have died since study initiation (four patients in phase 1 and 50 in phase II); 50 patients died due to progressive disease

At the 12-month analysis, there were four AE-related deaths, including two that were attributable to axicel. There have been no new axicel-related deaths since then

Table 1. Baseline characteristics of included patients¹

Data are presented as n (%) unless otherwise stated. IQR, interquartile range; ECOG PS, Eastern Cooperative Oncology Group performance status
	Phase I (n = 7)	Phase II (n = 101)
Median age, years (IQR)	59 (34–69)	58 (51–64)
Sex Female Male	2 (29%) 5 (71%)	33 (33%) 68 (67%)
ECOG PS 0 1	4 (57%) 3 (43%)	42 (42%) 59 (58%)
Disease stage I or II III or IV	3 (43%) 4 (57%)	15 (15%) 86 (85%)
Neutropenia Any grade Grade ≥ 3	2 (29%) 1 (14%)	16 (16%) 3 (3%)
Thrombocytopenia Any grade Grade ≥ 3	3 (43%) 0	34 (34%) 4 (4%)
Anemia Any grade Grade ≥ 3	5 (71%) 1 (14%)	95 (94%) 2 (2%)
Previous therapies Median (IQR) 1 2 ≥ 3	3 (3–4) 0 1 (14%) 6 (86%)	3 (2–4) 3 (3%) 28 (28%) 70 (69%)
History of primary refractory disease	1 (14%)	26 (26%)
History of resistance to two consecutive lines	1 (14%)	54 (53%)

 

Table 2. The most common treatment-emergent AEs of any grade (≥ 40%)¹

Data are presented as n (%). *Includes five patients who had progression of their disease; this was recorded as AE AE, adverse event
		Worst grade
	Any grade	1	2	3	4	5
Any	108 (100%)	0	2 (2%)	28 (26%)	69 (64%)	9 (8%)*
Pyrexia	94 (87%)	17 (16%)	62 (57%)	15 (14%)	0	0
Anemia	73 (68%)	4 (4%)	20 (19%)	46 (43%)	3 (3%)	0
Hypotension	63 (58%)	19 (18%)	29 (27%)	14 (13%)	1 (1%)	0
Nausea	63 (58%)	42 (39%)	21 (19%)	0	0	0
Fatigue	57 (53%)	32 (30%)	22 (20%)	3 (3%)	0	0
Decreased appetite	55 (51%)	37 (34%)	16 (15%)	2 (2%)	0	0
Headache	50 (46%)	40 (37%)	9 (8%)	1 (1%)	0	0
Diarrhea	48 (44%)	33 (31%)	10 (9%)	5 (5%)	0	0
Neutropenia	48 (44%)	1 (1%)	5 (5%)	10 (9%)	32 (30%)	0
Hypoalbuminemia	43 (40%)	17 (16%)	25 (23%)	1 (1%)	0	0
Hypocalcemia	43 (40%)	20 (19%)	16 (15%)	7 (6%)	0	0
Tachycardia	43 (40%)	38 (35%)	3 (3%)	2 (2%)	0	0

 Conclusion

Frederick Locke and team conclude that this represents the longest follow-up of an anti-CD19 CAR T-cell therapy study. The results demonstrate that a substantial proportion of patients with refractory large B-cell lymphoma treated with axicel achieve durable responses with manageable long-term safety.

In terms of limitations of the study, the team discuss the need for further studies to assess axicel in other large B-cell lymphoma settings, the effect on quality of life, the effect of prolonged cytopenias, and mechanisms of relapse, as these were not included in ZUMA-1.