Results from the phase II ZUMA-2 trial: CAR T therapy for MCL

Patients with mantle cell lymphoma (MCL), who relapse after first line therapy and salvage therapy have very poor prognosis with an overall survival (OS) of approximately 6-10 months if they progress after Bruton’s kinase inhibitor (BTKi) salvage therapy.¹ The potential of chimeric antigen receptor T-cell (CAR T) therapy has been seen in patients with aggressive relapsed or refractory (R/R) non-Hodgkin lymphomas (NHL), such as diffuse large B-cell lymphoma (DLBCL); however the role of CAR T therapy in indolent NHL, such as MCL, remains unclear but with promising preliminary data.²  

During the 61^st American Society of Hematology Annual (ASH) Meeting & Exposition, Michael Wang from The University of Texas, MD Anderson Cancer Center, Houston, US, presented an oral abstract (Abstract #754) on the interim results from the phase II ZUMA-2 trial which is investigating the efficacy and safety of KTE-X19, an autologous anti-CD19 CART product, in patients with R/R MCL.¹ This article is based on data presented at ASH and may supersede the data in the published abstract.

Since the Annual ASH Meeting & Exposition, the marketing authorization application for KTE-X19 has been fully validated by the European Medicines Agency (EMA). Read more here.

The Lymphoma Hub previously covered CAR T therapy as an educational theme. Read more here.

Study design¹

• Eligible patients with R/R MCL ≥ 18 years of age and:
  • Eastern Cooperative Oncology Group (ECOG) performance status 0–1
  • ≤ 5 prior therapies, including chemotherapy, an anti-CD20 antibody, and a BTKi
• Exclusion criteria included:
  • Prior allogeneic stem cell transplant
  • Prior CD19-targeted therapy
  • Prior CAR T therapy
  • Clinically significant infection
  • History of or current central nervous system (CNS) involvement by MCL or other CNS disorders
• Patients underwent leukapheresis and conditioning chemotherapy with 30 mg/m² intravenous (IV) injection of fludarabine and 500 mg/m² IV cyclophosphamide on Days -5 to -3
• Optional bridging therapy after leukapheresis but prior to infusion:
  • Dexamethasone: 20–40 mg or equivalent orally (PO) or IV daily for 1–4 days or,
  • Ibrutinib: 560 mg PO daily or,
  • Acalabrutinib: 100 mg PO twice daily
• KTE-X19 construct: anti-CD19 CAR with a CD3ζ activation domain and a CD28 signaling domain
• CAR T cell dose: 2×10⁶ KTE-X19 cells/kg in a single IV infusion on Day 0

• Primary endpoint: objective response rate (ORR) as assessed by an Independent Review Committee according to the Lugano classification (2014).³ Interim efficacy endpoints were investigator-assessed based on the revised International Working Group (IWG) response criteria for malignant lymphoma⁴
• Key secondary endpoints: duration of response (DoR), progression-free survival (PFS), OS, safety, and levels of circulating CAR T cells and cytokines

Key findings¹

Patients

• Enrolled/ leukapheresis: N= 74
  • n= 5 not treated (manufacturing failure n= 3 and death due to progressive disease [PD] n= 2)
• Conditioning Chemotherapy n= 69
  • n= 1 not treated (found ineligible)
• Received KTE-X19: n= 68
• Data cut-off: July 24, 2019
  • Primary analysis: n= 60 (per-protocol first 60 patients treated)
  • Safety analysis: n= 68 (all treated patients)

• KTE-X19 successfully manufactured for 71 patients (96%)
• Median time from leukapheresis to delivery of KTE-X19 to site: 16 days
• In total, 37% of patients (n= 25) received bridging therapy (21% ibrutinib, 18% dexamethasone, and 7% acalabrutinib)

For further details on dosing and patient characteristics see Table 1.

Table 1. Baseline patient characteristics

MIPI, MCL International Prognostic Index; MCL, mantle cell lymphoma
^aKi-67 data were available for n= 49 patients
^bExcludes bone marrow and splenic involvement
^cMorphology was unknown for n= 10 patients

Characteristic

N= 68

Median age (range), years

≥ 65 years, n (%)

65 (38–79)

39 (57)

Male, n (%)

57 (84)

Stage IV disease, n (%)

58 (85)

Intermediate/high risk MIPI, n (%)

38 (56)

Median number of prior lines (range)

≥ 3, n (%)

3 (1-5)

55 (81)

Ki-67 proliferation index ≥ 50%, n/n (%)^a

34/49 (69)

TP53 mutation, n/n (%)

6/36 (17)

Bone marrow involvement, n (%)^b

37 (54)

Extranodal disease, n (%)

38 (56)

MCL morphology, n (%)^c:

Classical

Pleiomorphic Pleomorphic

Blastoid

 

40 (59)

4 (6)

17 (25)

Efficacy

• ORR was consistent across subgroups and the response rates are shown in Table 2

Table 2. Response rates to KTE-X19 infusion of 60 evaluable patients

CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease

 

Efficacy-evaluable patients
(N= 60)

Median follow-up (range)

     Patients with ≥ 24 months follow-up, n (%)

12.3 (7–32.3) months

28 (47)

ORR

93 (95% CI, 84–98)

CR (%)

67(95% CI, 53–78)

PR (%)

27

SD (%)

3

PD (%)

3

Median time to initial response (range)

1 (0.8–3.1) months

Median time to CR (range)

3 (0.9–9.3) months

Patients converting from PR/SD to CR, n (%)

PR to CR

SD to CR

24 (40)

21 (35)

3 (5)

• Robust expansion of anti-CD19 CAR T cells in blood was associated with objective response (p= 0.0036) and measurable residual disease (MRD; p= 0.027) assessment at week four by next-generation sequencing
• Median time to peak anti-CD19 CAR T cells after infusion: 15 days (range, 8–31)
• In patients with evaluable samples, anti-CD19 CAR T cells were detectable in 6/10 patients at 24 months
• Median DoR has not been reached yet after a median follow-up of 12.3 months
• Up to the cut-off date, 57% of all patients and 78% of patients in CR remain in remission
• From the first 28 patients that were treated, after a median follow-up of 27 months, 43% remain in remission without additional therapy
• Median PFS and OS have not been reached with 12.3 months of follow-up
  • 12-month PFS rate: 61% (95% CI, 45–74)
  • 12-month OS rate: 83% (95% CI, 71–91)

Safety

• The most frequent treatment-emergent adverse events (TEAEs) of any grade were pyrexia (94%), neutropenia (87%), thrombocytopenia (74%), anemia (68%), and hypotension (51%)
• Grade ≥ 3 TEAEs are shown in Table 3
• Grade five adverse events (AEs) occurred in two patients (3%):
  • Organizing pneumonia on Day 37 considered related to conditioning chemotherapy
  • Staphylococcus bacteremia on Day 134 was considered to be related to conditioning chemotherapy and KTE-X19
• Cytokine release syndrome (CRS) occurred in 62 patients (91%), with Grade ≥ 3 CRS occurring in 10 patients (15%)
• No patients experienced Grade five CRS
• For CRS management:
  • Tocilizumab was used in 59% of patients (n= 40)
  • Corticosteroids were used in 22% of patients (n= 15)
• Median time to CRS onset was two (range, 1–13) days with a median duration of 11 days
• All CRS events were successfully resolved
• Neurological events (NE) occurred in 43 patients (63%), with Grade ≥ 3 NE occurring in 21 patients (31%)
• No patients experienced Grade five NE
• One patient experienced Grade four cerebral edema which was fully resolved
• For NE management:
  • Tocilizumab was used in 26% of patients (n= 18)
  • Corticosteroids were used in 38% of patients (n= 26)
• Median time to NE onset was seven (range, 1-32) days with a median duration of 12 days
• At data cut-off, NE had resolved in 86% of patients
• Patients with the most robust CAR T cell expansion were at higher risk of experiencing a more severe CRS event (Grade ≥ 3 vs Grade 0-2; p= 0.016) and NE (p< 0.0001)

Table 3. Grade ≥ 3 treatment-emergent AEs following KTE-X19 infusion

AE, adverse events

AE, n (%)

Grade three

Grade four

Grade five

Any AE

11 (16)

52 (76)

2 (3)

Neutropenia

11 (16)

47 (69)

0

Thrombocytopenia

11 (16)

24 (35)

0

Anemia

34 (50)

0

0

Hypophosphatemia

15 (22)

0

0

Hypotension

13 (19)

2 (3)

0

Pyrexia

9 (13)

0

0

Hypoxia

 8 (12)

6 (9) 

0 

Conclusions

The interim results of the phase II ZUMA-2 trial indicate that infusion of KTE-X19 CAR T cells leads to high and durable response rates in patients with R/R MCL, with an ORR of 93% and a CR rate of 67%. Of the 28 initial patients, 43% of them are still in remission more than two years later. No new safety concerns were observed, all CRS AEs were successfully resolved, and no deaths occurred due to CRS or NE. These promising results bring CAR T therapy one step closer to the clinical reality of patients with R/R MCL, who present a major unmet medical need.