Background
Methods
Data sources
Study comparisons
Key study design features | TRANSCEND (liso-cel) | ZUMA-1 (axi-cel) |
---|---|---|
Phase | 1 | 1/2 |
Design | Single arm | Single arm |
Blinding | Open label | Open label |
Centers | Multicenter | Multicenter |
Country | United States | Multiple (Israel and United States) |
Bridging therapy | Allowed | Not allowed |
PET-positive disease after bridging therapy | Confirmed | NA |
LDC | Yes | Yes |
Regimen and dosage of LDC | FLU (30 mg/m2/day for 3 d) and CY (300 mg/m2/day for 3 d), completed 2–7 d before infusion | FLU (30 mg/m2) and CY (500 mg/m2) on the fifth, fourth, and third day before infusion |
CAR T cell regimen and dosage | DL1S: 50 × 106 CAR+ T cells (25 × 106 CD8+ CAR+ T cells and 25 × 106 CD4+ CAR+ T cells) DL1D: 50 × 106 CAR+ T cells DL2S: 100 × 106 CAR+ T cells (50 × 106 CD8+ CAR+ T cells and 50 × 106 CD4+ CAR+ T cells) DL3S: 150 × 106 CAR+ T cells (75 × 106 CD8+ CAR+ T cells and 75 × 106 CD4+ CAR+ T cells) | Single infused dose of 2 × 106 CAR T cells per kg of body weight, with a maximum permitted dose of 2 × 108 CAR T cells |
Key inclusion criteria | TRANSCEND (liso-cel) | ZUMA-1 (axi-cel) | Action taken in TRANSCEND IPD and rationale |
---|---|---|---|
NHL subtypes | DLBCL NOS, HGBCL, tFL, tiNHL, PMBCL, FL3B | DLBCL NOS,* HGBCL, PMBCL, tFL | Recategorized TRANSCEND to align with ZUMA-1 definition for DLBCL to retain TRANSCEND patients. Specifically, DLBCL NOS, HGBCL, and tiNHL from TRANSCEND were grouped together in “DLBCL” for comparison with “DLBCL” category in ZUMA-1 |
Age, years | ≥ 18 | ≥ 18 | None |
ECOG PS | ≤ 2† | ≤ 1 | None |
Prior lines of treatment | ≥ 2 | ≥ 2‡ | Redefined in TRANSCEND such that salvage chemotherapy and auto-HSCT were considered as 2 separate lines of therapy to align with ZUMA-1 definition |
Prior auto-HSCT | Allowed | Allowed, but not within 6 weeks of infusion | None |
Prior allo-HSCT | Allowed (not within 90 d of leukapheresis) | Not allowed | None |
Prior regimen required | Anthracycline and rituximab (or other CD20-targeted agents) | Anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and an anthracycline-containing chemotherapy regimen | None |
Response to prior therapy | R/R disease after ≥ 2 lines of prior therapy or after auto-HSCT | No response to first-line therapy (primary refractory disease) OR no response to second- or later-line of therapy OR refractory after auto-HSCT (disease progression or relapsed ≤ 12 mo of auto-HSCT) | |
R/R to last therapy | Refractory: best response to last therapy as progressive disease, stable disease, or PR Relapsed: best response to last therapy as CR | Refractory: best response to last therapy§ as progressive disease or stable disease Relapsed: best response to last therapy§ of PR or CR | Redefined in TRANSCEND to align with ZUMA-1 definition. Specifically, in TRANSCEND, % refractory to last therapy was rederived to include progressive disease and stable disease, whereas % relapse was rederived to include PR and CR |
Absolute lymphocyte count | No minimum requirement¶ | ≥ 100/μL | Redefined in TRANSCEND to align with ZUMA-1 definition |
Absolute neutrophil count | No minimum requirement¶ | ≥ 1000/μL | None |
Platelet count | No minimum requirement¶ | ≥ 75,000/μL | None |
Hemoglobin | No minimum requirement¶ | Not reported | None |
Alanine aminotransferase | ≤ 5 × ULN | ≤ 2.5 × ULN | None |
Total bilirubin | < 2.0 mg/dL | ≤ 1.5 mg/dL | None |
Serum creatinine | ≤ 1.5 × ULN | Not reported | None |
CrCl | > 30 mL/min/1.73 m2 (Cockcroft-Gault) | ≥ 60 mL/min (Cockcroft-Gault) | Redefined in TRANSCEND to align with ZUMA-1 definition |
Dyspnea | Grade ≤ 1 by NCI CTCAE | Not clinically significant | None |
Oxygen saturation | ≥ 92% on room air | > 92% on room air | None |
LVEF | ≥ 40% | ≥ 50% | Redefined in TRANSCEND to align with ZUMA-1 definition |
Active CNS involvement | Secondary CNS involvement allowed | Not allowed | None |
History of another primary malignancy | Not allowed unless another primary malignancy has been in remission for ≥ 2 y | Not allowed unless disease free for ≥ 3 y | None |
Infections | Uncontrolled systemic fungal, bacterial, viral, or other infection despite appropriate antibiotics or other treatment at the time of leukapheresis or liso-cel administration | Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management | None |
Cardiovascular conditions or clinically significant cardiac disease | Within 6 mo of screening/enrollment | Within 12 mo of enrollment | None |
Study designs
Patient characteristics
Clinical factor | OS | ||||||
---|---|---|---|---|---|---|---|
ZUMA-1 (axi-cel) phase 2 mITT set | TRANSCEND (liso-cel) LBCL efficacy set | ||||||
Before MAIC (naïve) | After MAIC (SA1) | After MAIC (SA2) | |||||
N/ESS | N = 101 | N = 256 | ESS = 152.6 | ESS = 98.9 | |||
Stat | Stat | SMD | Stat | SMD | Stat | SMD | |
Age, years, mean (SD) | 56.3 (12.0) | 60.3 (13.3) | 0.308 | 56.3 (12.0) | 0.000 | 56.3 (12.0) | 0.000 |
Male sex, % | 67.3 | 66.0 | 0.027 | 68.3 | 0.020 | 67.3 | 0.000 |
IPI score, %* | |||||||
0–2 | 54.5 | 58.6 | 0.162 | 54.5 | 0.000 | 54.5 | 0.000 |
3–4 | 45.5 | 39.8 | 45.5 | 45.5 | |||
5 | 0.0 | 0.8 | 0.0 | 0.0 | |||
Missing | 0.0 | 0.8 | 0.0 | 0.0 | |||
ECOG PS at screening, % | |||||||
0 | 41.6 | 40.6 | 0.178 | 37.9 | 0.075 | 41.6 | 0.000 |
1 | 58.4 | 57.8 | 62.1 | 58.4 | |||
2 | 0.0 | 1.6 | 0.0 | 0.0 | |||
Disease stage, % | |||||||
I or II | 14.9 | 27.0 | 0.304 | 23.5 | 0.219 | 14.9 | 0.000 |
III or IV | 85.1 | 72.3 | 76.5 | 85.1 | |||
Missing | 0.0 | 0.8 | 0.0 | 0.0 | |||
Tumor burden based on SPD before LDC, cm2, mean (SD)† | 50.4
(43.7) | 43.7 (48.1) | 0.142 | 50.4 (43.8) | 0.000 | 50.4 (43.9) | 0.000 |
Secondary CNS disease at time of treatment, % | |||||||
No | 100.0 | 97.7 | 0.219 | 100.0 | 0.000 | 100.0 | 0.000 |
Yes | 0.0 | 2.3 | 0.0 | 0.0 | |||
Extranodal disease, % | |||||||
No | 30.7 | 46.9 | 0.344 | 42.9 | 0.255 | 30.7 | 0.000 |
Yes | 69.3 | 52.3 | 57.1 | 69.3 | |||
Missing | 0.0 | 0.8 | 0.0 | 0.0 | |||
Bulky disease, % | |||||||
No | 83.2 | 87.9 | 0.155 | 83.2 | 0.000 | 83.2 | 0.000 |
Yes | 16.8 | 11.3 | 16.8 | 16.8 | |||
Missing | 0.0 | 0.8 | 0.0 | 0.0 | |||
Disease histology, % | |||||||
DLBCL‡ | 76.2 | 71.1 | 0.242 | 76.3 | 0.000 | 76.3 | 0.000 |
DLBCL tFL | 15.8 | 22.3 | 15.8 | 15.8 | |||
PMBCL | 7.9 | 5.5 | 7.9 | 7.9 | |||
FL3B | 0.0 | 1.2 | 0.0 | 0.0 | |||
No. of lines of prior therapy, %§ | |||||||
1 | 3.0 | 0.8 | 0.179 | 0.2 | 0.228 | 3.0 | 0.000 |
2 | 27.7 | 25.0 | 25.9 | 27.7 | |||
≥ 3 | 69.3 | 73.8 | 73.9 | 69.3 | |||
Missing | 0.0 | 0.4 | 0.0 | 0.0 | |||
Prior allo-HSCT, % | 0.0 | 2.7 | 0.237 | 0.0 | 0.000 | 0.0 | 0.000 |
Prior auto-HSCT, % | 24.8 | 33.2 | 0.186 | 31.4 | 0.148 | 24.8 | 0.000 |
Bridging therapy, % | |||||||
No | 100.0 | 41.4 | 1.682 | 35.0 | 1.925 | 35.9 | 1.889 |
Yes | 0.0 | 58.6 | 65.0 | 64.1 | |||
R/R to last therapy, %¶ | |||||||
Relapsed | 20.8 | 35.9 | 0.359 | 20.8 | 0.000 | 20.8 | 0.000 |
Refractory | 79.2 | 61.7 | 79.2 | 79.2 | |||
Missing | 0.0 | 2.3 | 0.0 | 0.0 | |||
CrCl before LDC, %# | |||||||
< 60 mL/min | 0.0 | 19.1 | 0.688 | 13.4 | 0.557 | 0.0 | 0.000 |
≥ 60 mL/min | 100.0 | 80.9 | 86.8 | 100.0 | |||
LVEF at screening, %# | |||||||
< 50% | 0.0 | 5.1 | 0.327 | 4.3 | 0.300 | 0.0 | 0.000 |
≥ 50% | 100.0 | 94.9 | 95.7 | 100.0 | |||
Pre-leukapheresis ALC (109/L), %# | |||||||
< 0.1 | 0.0 | 0.4 | 0.091 | 0.2 | 0.067 | 0.0 | 0.000 |
≥ 0.1 | 100.0 | 94.1 | 94.2 | 100.0 | |||
Missing | 0.0 | 5.5 | 5.6 | 0.0 | |||
Statistics, % | |||||||
Factors with SMD < 0.2 | NA | 44.4 | NA | 66.7 | NA | 94.4 | NA |
Factors with SMD < 0.1 | NA | 11.1 | NA | 61.1 | NA | 94.4 | NA |
Definitions of outcome measures
Statistical analysis
Results
Clinical factors before and after matching and adjusting
Efficacy outcomes
Response rates
ZUMA-1 (axi-cel) | TRANSCEND (liso-cel) | Liso-cel versus axi-cel | ||||
---|---|---|---|---|---|---|
N (%) | Response rate, % | N/ESS | Response rate, % | OR (95% CI) | P | |
ORR | ||||||
Naïve comparison | 101 | 74.3 | 256 | 72.7 | 0.92 (0.54–1.55) | 0.753 |
Initial analysis | 42.1 | 80.1 | 1.40 (0.56–3.49) | 0.476 | ||
Sensitivity analysis 1 | 150.3 | 71.2 | 0.85 (0.48–1.52) | 0.591 | ||
Sensitivity analysis 2 | 98.9 | 70.9 | 0.84 (0.45–1.58) | 0.596 | ||
CRR | ||||||
Naïve comparison | 101 | 54.5 | 256 | 53.1 | 0.95 (0.60–1.50) | 0.815 |
Initial analysis | 39.6 | 59.2 | 1.21 (0.56–2.64) | 0.630 | ||
Sensitivity analysis 1 | 169.1 | 48.2 | 0.78 (0.47–1.27) | 0.318 | ||
Sensitivity analysis 2 | 98.9 | 49.5 | 0.82 (0.47–1.43) | 0.483 |
Survival outcomes
ZUMA-1 (axi-cel) | TRANSCEND (liso-cel) | Liso-cel versus axi-cel | ||||
---|---|---|---|---|---|---|
N (%) | Median (95% CI), mo | N/ESS | Median (95% CI), mo | HR (95% CI) | P | |
PFS | ||||||
Naïve comparison | 101 | 5.8 (3.4–15.0)* | 256 | 4.1 (3.0–6.0) | 1.20 (0.90–1.59) | 0.219 |
Initial analysis | 40.0 | 6.3 (3.0–NR) | 0.95 (0.58–1.57) | 0.847 | ||
Sensitivity analysis 1 | 151.4 | 3.5 (3.0–5.9) | 1.30 (0.96–1.77) | 0.095 | ||
Sensitivity analysis 2 | 98.9 | 5.0 (3.0–9.2) | 1.16 (0.81–1.66) | 0.408 | ||
OS | ||||||
Naïve comparison | 101 | NR (12.8–NR)* | 256 | 21.1 (13.3–NR) | 1.13 (0.81–1.58) | 0.457 |
Initial analysis | 38.3 | NR (11.6–NR) | 0.81 (0.44–1.49) | 0.506 | ||
Sensitivity analysis 1 | 152.6 | 19.9 (12.1–NR) | 1.15 (0.80–1.65) | 0.454 | ||
Sensitivity analysis 2 | 98.9 | 21.1 (14.4–NR) | 1.04 (0.70–1.56) | 0.838 |
Safety outcomes
Safety outcome, scenario | ZUMA-1 (axi-cel) phase 1/2 safety analysis set | TRANSCEND (liso-cel) LBCL-treated set | Liso-cel versus axi-cel | |||
---|---|---|---|---|---|---|
N | Event rate, % | N/ESS | Event rate, % | OR (95% CI) | P | |
CRS, per Lee 2014 criteria | ||||||
All grade | ||||||
Naïve | 108 | 92.6 | 269 | 42.0 | 0.06 (0.03–0.12) | < 0.001 |
Initial | 63.0 | 26.6 | 0.03 (0.01–0.07) | < 0.001 | ||
Sensitivity | 209.9 | 42.9 | 0.06 (0.03–0.13) | < 0.001 | ||
Grade ≥ 3 | ||||||
Naïve | 108 | 11.1 | 269 | 2.2 | 0.18 (0.07–0.50) | 0.001 |
Initial | 63.0 | 1.0 | 0.08 (0.01–0.67) | 0.019 | ||
Sensitivity | 209.9 | 2.0 | 0.16 (0.06–0.47) | 0.001 | ||
NE, study-specific | ||||||
All grade | ||||||
Naïve | 108 | 66.7 | 269 | 29.7 | 0.21 (0.13–0.34) | < 0.001 |
Initial | 63.0 | 24.6 | 0.16 (0.08–0.33) | < 0.001 | ||
Sensitivity | 209.9 | 29.8 | 0.21 (0.13–0.35) | < 0.001 | ||
Grade ≥ 3 | ||||||
Naïve | 108 | 32.4 | 269 | 10.0 | 0.23 (0.13–0.41) | < 0.001 |
Initial | 63.0 | 2.5 | 0.05 (0.02–0.15) | < 0.001 | ||
Sensitivity | 209.9 | 8.7 | 0.20 (0.11–0.37) | < 0.001 | ||
NE of encephalopathy, group term | ||||||
All grade | ||||||
Naïve | 108 | 37.0 | 269 | 21.2 | 0.46 (0.28–0.75) | 0.002 |
Initial | 63.0 | 19.8 | 0.42 (0.19–0.91) | 0.028 | ||
Sensitivity | 209.9 | 20.4 | 0.44 (0.26–0.73) | 0.002 | ||
Grade ≥ 3 | ||||||
Naïve | 108 | 23.1 | 269 | 6.7 | 0.24 (0.12–0.46) | < 0.001 |
Initial | 63.0 | 1.5 | 0.05 (0.01–0.18) | < 0.001 | ||
Sensitivity | 209.9 | 5.6 | 0.20 (0.09–0.41) | < 0.001 | ||
NE of aphasia, group term | ||||||
All grade | ||||||
Naïve | 108 | 17.6 | 269 | 9.7 | 0.50 (0.26–0.95) | 0.034 |
Initial | 63.0 | 7.2 | 0.36 (0.13–1.00) | 0.049 | ||
Sensitivity | 209.9 | 9.7 | 0.51 (0.26–1.00) | 0.049 | ||
Grade ≥ 3 | ||||||
Naïve | 108 | 7.4 | 269 | 1.9 | 0.24 (0.08–0.74) | 0.014 |
Initial* | – | – | – | – | ||
Sensitivity | 209.9 | 1.5 | 0.19 (0.06–0.61) | 0.005 | ||
Infections, any pathogens, per infections and infestations SOC | ||||||
Grade ≥ 3 | ||||||
Naïve | 108 | 26.0 | 269 | 12.3 | 0.40 (0.23–0.70) | 0.001 |
Initial | 63.0 | 6.3 | 0.19 (0.07–0.49) | 0.001 | ||
Sensitivity | 209.9 | 11.2 | 0.36 (0.20–0.65) | 0.001 | ||
Prolonged anemia, reported as AE | ||||||
Grade ≥ 3 | ||||||
Naïve | 108 | 10.2 | 269 | 5.9 | 0.56 (0.25–1.24) | 0.153 |
Initial | 63.0 | 0.4 | 0.04 (0.00–0.32) | 0.002 | ||
Sensitivity | 209.9 | 4.9 | 0.46 (0.20–1.05) | 0.064 | ||
Prolonged neutropenia, reported as AE | ||||||
Grade ≥ 3 | ||||||
Naïve | 108 | 25.9 | 269 | 14.1 | 0.47 (0.27–0.82) | 0.007 |
Initial | 63.0 | 13.6 | 0.45 (0.19–1.07) | 0.072 | ||
Sensitivity | 209.9 | 15.3 | 0.52 (0.29–0.91) | 0.022 | ||
Prolonged thrombocytopenia, reported as AE | ||||||
Grade ≥ 3 | ||||||
Naïve | 108 | 24.1 | 269 | 17.5 | 0.67 (0.39–1.15) | 0.143 |
Initial | 63.0 | 6.9 | 0.23 (0.10–0.57) | 0.001 | ||
Sensitivity | 209.9 | 16.3 | 0.61 (0.35–1.08) | 0.090 | ||
Hypogammaglobulinemia,† group term | ||||||
All grade | ||||||
Naïve | 108 | 16.0 | 269 | 13.8 | 0.84 (0.45–1.56) | 0.575 |
Initial | 63.0 | 6.6 | 0.37 (0.14–0.97) | 0.043 | ||
Sensitivity | 209.9 | 11.9 | 0.71 (0.37–1.37) | 0.311 |