Lisocabtagene Maraleucel in RelapsedRefractory RR Large BCell Lymphomas Abramson JS Palomba ML Gordon LI Lunning M Wang M Arnason J Mehta A Purev E Maloney DG Andreadis ID: 811599
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Slide1
Pivotal Safety and Efficacy Results From TRANSCEND NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel in Relapsed/Refractory (R/R) Large B-Cell Lymphomas
Abramson JS, Palomba ML, Gordon LI, Lunning M, Wang M, Arnason J, Mehta A, Purev E, Maloney DG, Andreadis C, Sehgal A, Solomon SR, Ghosh N, Albertson T, Garcia J, Kostic A, Li D, Kim Y, Siddiqi T
Abstract 241
Slide2CAR T-Cell Therapy for Treatment of R/R Large B-Cell Lymphomas
Historically, patients with R/R LBCL in whom second-line therapy failed had no curative options, with fewer than 50% of patients achieving responses to subsequent standard treatments[a,b] Outcomes are worse in patients with chemotherapy-refractory disease, with CR rates to conventional treatment of 7% and a median OS of 6 months[c]Characteristics such as older age, CNS involvement,
[
d.e
] and comorbidities[f] further portend adverse outcomes but have not been rigorously studied in other clinical trials of novel therapiesAvailable anti-CD19 CAR T-cell therapies have shown high response rates and durable remissions in patients with R/R LBCL[g-i]
CAR = chimeric antigen receptor; CNS = central nervous system; CR = complete response; LBCL = large B-cell lymphoma; OS = overall survival; R/R = relapsed/refractory.a. Van Den Neste E, et al. Bone Marrow Transplant. 2016;51:51-57; b. González-Barca E, et al. Bone Marrow Transplant. 2019 Sept 20. [Epub ahead of print]; c. Crump M, et al. Blood. 2017;130:1800-1808; d. Thanarajasingam G, et al. Br J Haematol. 2018;183:149-152; e. El-Galaly TC, et al. Eur J Cancer. 2018;93:57-68; f. Pfreundschuh M, et al. Blood. 2010;116:5103-5310; g. Neelapu SS, et al. N Engl J Med. 2017;377:2531–2544; h. Schuster SJ, et al. N Engl J Med. 2019;380:45-56; i. Abramson JS, et al. ASCO 2018. Abstract 7505.
Abramson JS, et al. ASH 2019. Abstract 241.
Slide3CD8+ and CD4+ CAR+ T-cell components are administered separately at equal target doses of CD8+ and CD4+ CAR+ T cells
CRS = cytokine release syndrome.
a. Turtle CJ, et al.
Sci Transl Med
. 2016;8:355ra116
; b. DeAngelo DJ, et al. SITC 2017. Abstract P217; c. Neelapu SS, et al. N Engl J Med. 2017;377:2531-2544.Dose and ratio of CD8+ and CD4+ CAR+ T cells may influence the incidence and severity of CRS and neurological events[a-c]The defined composition of lisocabtagene maraleucel results in: Consistent administered CD8+ and CD4+ CAR+ T-cell doseLow variability in the CD8+/CD4+ ratio
Leukapheresis Material
CD8+ T cells
CD4+ T cells
Immunomagnetic selection for CD8+ and CD4+ T cells
Activation and lentiviral transduction
Sequential infusion
CD8+
CAR+ T cells
CD4+
CAR+ T cells
in vitro
expansion
Formulation
Drug product
CD8+
component
CD4+
component
Lisocabtagene
Maraleucel
CD19-Directed, Defined Composition, 4-1BB CAR T-Cell Product
Abramson JS, et al. ASH 2019. Abstract 241.
Slide4a
DL1 was also tested as a 2-dose regimen, with a second dose of lisocabtagene maraleucel given 14 days after the first dose. ALC = absolute lymphocyte count; ANC = absolute neutrophil count;
CrCl
= creatinine clearance; CY = cyclophosphamide; DL = dose level; DLBCL = diffuse large B-cell lymphoma; ECOG PS = Eastern Cooperative Oncology Group performance status; FL = follicular lymphoma; FL3B = follicular lymphoma grade 3B; FLU = fludarabine; HGBCL = high-grade B-cell lymphoma; HSCT = hematopoietic stem cell transplantation; IRC = independent review committee; LVEF = left ventricular ejection fraction; MZL = marginal zone lymphoma; NOS = not otherwise specified; ORR = objective response rate; PET = positron emission tomography; PFS = progression-free survival; PK = pharmacokinetics; PMBCL = primary mediastinal large B-cell lymphoma.
TRANSCEND NHL 001 (NCT02631044)
Pivotal Phase 1, Multicenter, Seamless Design StudyDL1 DL2DL3Dose Finding, n=60a100 × 106 CAR+ T cellsDose Confirmation, n=126Dose Expansion, n=83
50 × 10
6
CAR+ T cells
DL1
100 × 10
6
CAR+ T cells
DL2
150 × 10
6
CAR+ T cells
DL3
Patient Eligibility
LBCL after ≥2 lines of therapy
DLBCL NOS (de novo)
DLBCL NOS
(transformed from FL, CLL,
MZL, or other)
HGBCL (double/triple hit)
PMBCL
FL3B
Prior HSCT allowed (auto/
allo
)
ECOG PS of 0-2
Patients with secondary CNS lymphoma were eligible
CrCl
> 30 mL/min/1.73 m2
LVEF ≥ 40%No lower threshold for ALC, ANC, platelets, or hemoglobin
Lymphodepletion
FLU 30 mg/m
2
and CY 300 mg/m2
× 3 days
Lisocabtagene
maraleucel manufacturing
Enrollment and
leukapheresis
PET-positive
disease reconfirmed
Lisocabtagene
maraleucel
2-7 days after FLU/CY
Bridging
therapy allowed
Follow-Up
On-study:
24 months
Long-term:
up to 15 years after last
lisocabtagene
maraleucel
treatment
End Points
Primary
Adverse events, ORR by IRC
Secondary
CR rate by IRC, duration of response, PFS, OS, PK
Screen
Abramson JS, et al. ASH 2019. Abstract 241.
Slide5Patient Flow Diagram
aLisocabtagene maraleucel is composed of a target dose of CD8+ and CD4+ CAR+ T cells, each of which was required to meet quality specifications. Nonconforming product refers to product that did not meet the specifications of
lisocabtagene
maraleucel (eg, one of the CD8 or CD4 cell components did not meet one of the requirements to be considered for lisocabtagene
maraleucel).LDC = lymphodepleting chemotherapy.Reasons for not receiving CAR+ T cells (n = 50)Death (n = 33)Other (n = 9)Disease-related complications (n = 6) Product could not be manufactured (n = 2)Received nonconforming producta (n = 25)Received lisocabtagene maraleucel – LBCL treated set(N = 269)
Reasons for exclusions (n = 13)
No PET-positive disease per IRC assessment
before
lisocabtagene
maraleucel
administration
(n = 4)
No PET scan after bridging therapy and before
lisocabtagene
maraleucel
administration (n = 6)Other (n = 3)
Underwent Leukapheresis
(N = 344)
Received LDC and CAR+ T cells
(N = 294)
LBCL efficacy set (N=256)
Dose level 1, n = 51 Dose level 2, n = 177
Dose level 3, n = 41
Dose level 1, n = 46 Dose level 2, n = 169Dose level 3, n = 41
Abramson JS, et al. ASH 2019. Abstract 241.
Slide6Baseline Characteristics
89% of patients had high-risk features known to portend a shortened OSHGBCL/double/triple hit lymphomaECOG PS of 2Primary refractory diseaseRefractory to second-line or later therapyNo prior ASCTNever achieved CR
a
Patients with DLBCL transformed from indolent lymphomas with
MYC and BCL2
or BCL6 rearrangements are not included as HGBCL. bPatients with LDC SPD ≥ 50 cm2 or LDH ≥ 500 U/L (N = 269). cThe status was chemotherapy-refractory if the patient achieved SD or PD to last chemotherapy-containing regimen or relapsed < 12 months after autologous HSCT; otherwise the status was chemotherapy-sensitive.ASCT, allogeneic stem cell transplantation; NHL, non-Hodgkin lymphoma; SPD, sum of product of diameter.CharacteristicAll lisocabtagne maraleucel–Treated Patients (N = 269) Median age
(range), years
≥ 65, n (%)
≥ 75, n (%)
63 (18
to
86)
112 (42)
27 (10)
NHL
subtypes, n (%)
DLBCL NOS
137 (51)
Transformed from FL / other indolent lymphomas
60 (22) / 18 (7)
HGBCL
a
/ PMBCL / FL3B
36 (13) / 15 (6) / 3 (1)
Secondary CNS lymphoma, n (%)
7 (3)
ECOG PS of 0-1 / 2 at screening, n (%)
265 (99) / 4 (1)
High disease burden,
b
n (%)
103 (38)
Creatinine clearance > 30 mL/min to
< 60 mL/min, n (%)
51 (19)
LVEF ≥ 40% to < 50%, n (%)
13 (5)
Prior systemic therapies, median (range)
3 (1
to
8)
≥ 4 prior therapies, n (%)
71 (26)
Received prior HSCT, n (%)
Autologous / allogeneic HSCT
94 (35)
90 (33) / 9 (3)
Chemotherapy-refractory,
c
n (%)
181 (67)
Never achieved CR with prior therapy, n (%)
119 (44)
Received bridging therapy, n (%)
159 (59)
Abramson JS, et al. ASH 2019. Abstract 241.
Slide7TEAEsa in ≥ 25% of Patients
aA TEAE was defined as an adverse event that started any time from initiation of lisocabtagene
maraleucel
administration through and including 90 days following the final cycle of lisocabtagene
maraleucel. Any AE that occurred after the initiation of another anticancer treatment or lisocabtagene maraleucel retreatment was not considered a lisocabtagene maraleucel TEAE.DLT, dose-limiting toxicity; NE, neurologic event; TEAE, treatment-emergent adverse event.Grade 5 TEAEs occurred in 7 patients (3%)Considered related to lisocabtagene maraleucel (n = 4): diffuse alveolar damage (DLT), pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathyConsidered unrelated to lisocabtagene maraleucel (n = 3): fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathyNo grade 5 CRS or NE occurred
All
Lisocabtagene Maraleucel–Treated Patients
(N=269)
Any Grade
Grade ≥ 3
Any
TEAEs,
a
n (%)
267 (99)
213 (79)
Neutropenia
169 (63)
161 (60)
Anemia
129 (48)
101 (38)
Fatigue
119 (44)
4 (1)
CRS
113 (42)
6 (2)
Nausea
90 (33)
4 (1)
Thrombocytopenia
84 (31)
72 (27)
Headache
80 (30)
3 (1)
Decreased appetite
76 (28)
7 (3)
Diarrhea
71 (26)
1 (< 1)
Abramson JS, et al. ASH 2019. Abstract 241.
Slide8Patient Incidence and Management of CRS and NE
aCRS was graded according to the Lee criteria (Lee DW, et al. Blood. 2014;124:188-195).
b
NEs were based on investigator assessment and graded per
National Cancer Institute Common Terminology Criteria for Adverse Events v4.03.
cDuring initial hosptial admission following lisocabtagene maraleucel administration. ICU, intensive care unit; toci, tocilizumab.All Lisocabtagene Maraleucel–Treated Patients (N = 269)CRSa Any grade, n (%)
113 (42)
Grade 3, n (%)
4 (1)
Grade 4, n (%)
2 (1)
Time to onset, median (range), days
5 (1
to
14)
Time to resolution, median (range), days
5 (1
to
17)
NE
b
Any grade, n (%)
80 (30)
Grade 3, n (%)
23 (9)
Grade 4, n (%)
4 (1)
Time to onset, median (range), days
9 (1
to
66)
Time to resolution, median (range), days
11 (1
to
86)
CRS or NE, n (%)
127 (47)
ICU
admissions
,
c
n (%)
19 (7)
For CRS and/or NE
12 (4)
Other reasons
7 (3)
CRS and NE were reversible
1 patient had an unresolved NE (grade 1 tremor) at data cutoff
8 patients had ongoing CRS/NE at time of death from
other reasons
13%
0.4%
3%
3% of patients received vasopressors for CRS or NE
2 patients received other anti-inflammatory/
anticytokine
agents
8%
10%
2%
13%
8%
7%
CRS
NE
CRS ± NE
Patients, %
Treatment for CRS and NE
Abramson JS, et al. ASH 2019. Abstract 241.
Slide9Other TEAEs of Special Interest
Patient Incidence
All
Lisocabtagene
Maraleucel–Treated Patients (N = 269)Prolonged grade ≥ 3 cytopenias,a n (%)100 (37)Grade ≥ 3 infections,b n (%)33 (12)
Bacterial
11 (4)
Viral
4 (1)
Fungal
2 (1)
Pathogen unspecified
22 (8)
Infusion-related reactions, n (%)
3 (1)
Grade ≥ 3
0
Tumor lysis syndrome, n (%)
2 (1)
Grade ≥ 3
2 (1)
Hypogammaglobulinemia, n (%)
37 (14)
Grade ≥3
0
a
Prolonged cytopenias were based on laboratory assessments of neutropenia, thrombocytopenia, or anemia not resolved at study day 29.
b
Infection includes grade 3 or higher TEAEs from Infections and Infestations system organ classification as shown by AE high level group term. Patients could have ≥ 1 pathogen present.
IgG, immunoglobin G
Laboratory-based hypogammaglobulinemia (IgG < 500 mg/dL) was present in 49% (127 of 258 patients) at baseline, 58% (136 of 236 patients) at study day 29, and 61% (68 of 112 patients) at study day 365
Intravenous immunoglobulin was administered to 57 patients (21%) over the entire follow-up of the study
Abramson JS, et al. ASH 2019. Abstract 241.
Slide10Response and Durability by IRC Assessment
CI, confidence interval; DOR, duration of response; NR, not reached; PR, partial response.
Efficacy-Evaluable Patients
(N = 256)
ORR (95% CI)
73% (67 to 78)CR rate (95% CI)53% (47 to 59) Time to first CR or PR, median (range), months1.0 (0.7 to 8.9)
DOR at 6 months (95% CI), %
60.4 (52.6
to
67.3)
DOR at 12 months (95% CI), %
54.7 (46.7
to
62.0)
Median Follow-Up (95% CI): 12.0 (11.2, 16.7) Months
25
136
106
91
79
48
43
1
1
0
23
50
4
2
2
2
2
0
110
186
93
25
23
1
0
81
50
45
1
CR
PR
Total
Probability of Continued Response (%)
Median (95% CI): 1.9 (1.1, 2.1) months
Median (95% CI): NR (8.6‒NR) months
Median (95% CI): NR (NR‒NR) months
Censored
0
20
40
60
80
100
Months
0
3
9
21
18
24
27
30
12
15
6
Total
PR
CR
Efficacy among patients who received nonconforming product (n = 25) was similar to those who received lisocabtagene maraleucel
Abramson JS, et al. ASH 2019. Abstract 241.
Slide11OR Rate (95% CI)
0
10
20
30
40
50
60
70
80
90
100
Subgroup
Evaluable Patients, n
Overall
256
Age
≥65 years
108
<65 years
148
Subtype
DLBCL NOS
131
tFL
57
Transformed
iNHL
18
PMBCL
14
HGBCL
33
Bridging therapy
Yes
150
No
106
High disease
burden
a
Yes
99
No
149
HSCT
Yes
87
No
169
Comorbidities
b
Yes
60
No
196
Secondary CNS lymphoma
Yes
6
No
250
ORR and CR by Patient and Clinical Characteristics
a
Patients with
LDC SPD ≥ 50 cm
2
or LDH ≥ 500 U/L
.
b
Patients with CrCl > 30 mg/min but < 60 mg/min or with LVEF ≥ 40% to < 50%.
iNHL, indolent non-Hodgkin lymphoma.
0
10
20
30
40
50
60
70
80
90
100
CR Rate (95% CI)
Abramson JS, et al. ASH 2019. Abstract 241.
Slide12PFS and OS by Objective Response
6-month PFS (95% CI), %
All patients
51.4 (44.6
,
57.7)Patients with BOR of CR76.1 (67.9, 82.4)12-month PFS (95% CI), %All patients44.1 (37.3, 50.7)Patients with BOR of CR
65.1 (56.1,
72.7)
6-month OS (95% CI), %
All patients
74.7 (68.9,
79.6)
Patients with BOR of CR
94.1 (88.6,
97.0)
12-month OS (95% CI), %
All patients
57.9 (51.3,
63.8)
Patients with BOR of CR
85.5 (78.2,
90.5)
OS Median Follow-up (95% CI): 17.6 (13.5, 18.0) Months
PFS Median Follow-up (95% CI): 12.3 (12.0, 17.5) Months
136
135
128
113
94
68
48
36
26
16
13
8
5
1
0
50
45
33
20
8
3
3
0
70
41
27
14
7
3
1
1
1
1
1
1
1
0
256
221
188
147
109
74
52
37
27
17
14
9
6
1
0
0
3
6
9
12
15
30
33
36
39
42
45
0
20
40
60
80
100
Probability of OS, %
CR
PR
SD/PD
Total
Censored
18
24
21
27
Median (95% CI): 9.0 (6.0, 10.4) months
Median (95% CI): 21.1 (13.3, NR) months
Median (95% CI): NR (NR, NR) months
Median (95% CI): 5.1 (2.9, 6.5) months
CR
Total
SD/PD
PR
Months
Total
Progression-Free Probability, %
0
3
9
21
18
24
27
30
12
15
6
Months
31
136
116
98
85
63
45
14
1
0
23
50
14
2
2
2
2
2
0
70
3
0
133
256
100
33
23
1
0
87
65
47
14
CR
PR
SD/PD
Total
Median (95% CI): 2.8 (2.1, 3.0) months
Median (95% CI): 6.8 (3.3, 14.1) months
Median (95% CI): NR (NR, NR) months
Censored
0
20
40
60
80
100
Median (95% CI): 1.1 (1.0, 1.6) months
CR
PR
SD/PD
BOR, best objective response; PD, progressive disease; SD, stable disease.
Abramson JS, et al. ASH 2019. Abstract 241.
Slide13PFS by Subgroup
a
Comorbidities
were defined as
CrCl
> 30 60 mL/min but < 60 mL/min or LVEF ≥ 40 to < 50%.
HR, hazard ratio; LVEF, left ventricular ejection fraction;
tiNHL
, transformed from indolent NHL
Progression-Free Probability, %
0
3
9
21
18
24
27
30
12
15
6
16
106
67
50
45
33
21
6
1
0
11
0
20
40
60
80
100
150
66
50
42
32
26
17
12
8
0
Bridging Therapy
0
20
40
60
80
100
Months
Progression-Free Probability, %
0
3
6
9
21
24
27
30
18
15
12
NR (11.8, NR)
3.0 (2.8, 6.3)
5.0 (2.9, NR)
NR (2.8, NR)
2.9 (1.3, NR)
PMBCL
tFL
HGBCL
DLBCL, NOS
tiNHL
Median PFS (95% CI), months
N
N
Censored
Censored
No Bridging Therapy
Median PFS (95% CI), months
14.1 (3.7, NR)
5.0 (3.0 , 10.0)
33
20
13
13
10
9
6
4
2
0
57
41
34
27
17
15
12
9
7
0
14
7
7
7
5
0
18
7
5
3
3
1
1
1
1
0
131
56
40
36
29
21
13
8
4
1
0
HR (95% CI):
1.3 (0.9, 1.9)
P
= .13
Abramson JS, et al. ASH 2019. Abstract 241.
Months
Progression-free Probability (%)
0
3
9
21
18
24
27
30
12
15
6
Months
0
20
40
60
80
100
Censored
60
15
23
9
4
0
196
65
85
38
21
1
0
Comorbidities
a
No
Comorbidities
a
3.0 (2.5, 10.0)
9.5 (4.6, NR)
Median (95% CI), months
N
HR (95% CI):
1.5 (1.0, 2.2)
P
=.03
Slide14Cellular Kinetics
CAR+ T cells showed long-term persistence at 1 year in 53% of patients (n=37/70) The kinetics of CD4+ and CD8+ CAR+ T cell expansion were similar
a
CAR
+ cells were detected by an EGFR transgene.
bLower limit of detection was 10−1 cells/mL.AUC0–28d, area under the concentration–time curve from 0 to 28 days; Cmax, maximum plasma concentration; EGFRt, epidermal growth factor receptor transgene; IQR, interquartile range; qPCR, quantitative polymerase chain reaction; Tmax, time to maximum expansion.PK Analysis Set (qPCR) (N = 267)T
max
, median (IQR)
11 (10
to
14)
C
max
, median
23,726.2 copies/µg
AUC
0‒28d
, median
203,809.9 day*copies/µg
CAR+ T Cells (CD3+, CD8+, and CD4+) by
Flow
a,b
CD19+ B cells
Study Day
1
4
8
1
1
15
22
29
60
90
180
270
365
CD3+/CD4+/CD8+ EGFRt+ or
CD19+ B-Cell (Cells/µL), Median (IQR)
CD3+ CAR+
CD4+ CAR+
CD8+ CAR+
10
-3
10
-2
10
-1
10
0
10
1
10
2
Quantitative PCR (qPCR) strongly correlated with PK by flow cytometry
Abramson JS, et al. ASH 2019. Abstract 241.
Slide15Conclusions
TRANSCEND NHL 001 is the largest clinical study reported to date of CD19-directed CAR T cells in patients with R/R aggressive LBCLTreatment with lisocabtagene maraleucel resulted in a rapid, high rate of durable CR and low incidence of severe CRS and NE Clinically meaningful activity was observed across patient subgroups, including uncommon LBCL histologic subtypes and those with high-risk prognostic characteristicsThe low incidence of severe CRS and NE and their late onset support lisocabtagene maraleucel
treatment in the outpatient setting
Abramson JS, et al. ASH 2019. Abstract 241.