Matching-Adjusted Indirect Comparison (MAIC) of Efficacy and Safety Outcomes for Lisocabtagene Maraleucel (liso-cel) Versus Axicabtagene Ciloleucel (axi-cel) and Tisagenlecleucel (tisa-cel) for the Treatment of Third-Line or Later (3L+) Relapsed or Refractory (R/R) Follicular Lymphoma (FL)
Bibliographic record
Abstract
Background: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product that was recently approved by the United States Food and Drug Administration for the treatment of patients with 3L+ R/R FL based on results from the TRANSCEND FL study (NCT04245839). Other CAR T cell therapies approved for 3L+ R/R FL include axi-cel and tisa-cel. Because of the lack of randomized prospective-controlled data, the comparative efficacy and safety of liso-cel versus axi-cel and liso-cel versus tisa-cel were assessed using MAICs. Methods: Individual patient data for liso-cel from TRANSCEND FL (N = 101 for treated efficacy set, N = 107 for treated set; data cutoff: 27 Jan 2023; median follow-up of 19.3 months) and aggregate data for axi-cel from ZUMA-5 (NCT03105336, N = 86 for updated analysis set, N = 124 for treated set; data cutoff: 14 Sep 2020; median follow-up of 24.4 months) and for tisa-cel from ELARA (NCT03568461, N = 94 for efficacy set, N = 97 for treated set; data cutoff: 29 Mar 2021; median follow-up of 16.85 months) were used for the MAICs. Efficacy outcomes included response (ORR and CR rate) and time-to-event (PFS and duration of response [DOR]) outcomes. Safety outcomes included cytokine release syndrome (CRS), neurological events (NE), infections, prolonged cytopenia, and use of corticosteroids or tocilizumab for CRS management. Given that TRANSCEND FL had a large proportion of patients with 3L+ R/R FL who received bridging therapy (N = 44 [41%]) versus ZUMA-5 (N = 4 [3%]), the primary analysis excluded liso-cel patients who received bridging therapy. Comparison with tisa-cel included all liso-cel patients, as the proportion of patients who received bridging therapy was similar (tisa-cel, N = 44 [47%]). Baseline characteristics and outcome measures in TRANSCEND FL were redefined to align with those reported in ZUMA-5 and ELARA. Data from TRANSCEND FL were weighted using a method-of-moments propensity score model to match the marginal distribution of clinical factors among patients from ZUMA-5 and ELARA, respectively. A panel of clinicians selected clinical factors separately for efficacy and safety endpoints. The key factors adjusted for included FL International Prognostic Index risk factor, bulky disease, age, prior lines of therapy, R/R status, progression of disease ≤ 24 months, ECOG PS, bridging therapy, prior ASCT, lymphoma present in bone marrow, sex, and histology subtype (grade 1, 2, or 3a). Response ratios (RR), hazard ratios (HR), and odds ratios (OR) with corresponding 95% CIs were used to compare response outcomes, time-to-event outcomes, and safety outcomes, respectively. Results: Compared with axi-cel, liso-cel demonstrated an improved CR rate (RR, 1.25; 95% CI, 1.09-1.45) and a comparable ORR (RR, 1.06; 95% CI, 1.00-1.12), PFS (HR, 1.14; 95% CI, 0.47-2.74), and DOR (HR, 1.26; 95% CI, 0.52-3.05). Liso-cel also exhibited a more favorable safety profile versus axi-cel, with lower odds of any-grade NEs (OR, 0.16; 95% CI, 0.06-0.45), any-grade infections (OR, 0.37; 95% CI, 0.14-0.93), and tocilizumab use for CRS management (OR, 0.30; 95% CI, 0.10-0.91). Trends of reduced odds of any-grade CRS (OR, 0.72; 95% CI, 0.31-1.69), grade ≥ 3 CRS (OR, 0.14; 95% CI, 0.02-1.23), corticosteroid use for CRS management (OR, 0.31; 95% CI, 0.06-1.57), grade ≥ 3 infections (OR, 0.67; 95% CI, 0.17-2.65), and prolonged cytopenia (OR, 0.52; 95% CI, 0.18-1.47) were observed in favor of liso-cel but were not statistically significant. Compared with tisa-cel, liso-cel demonstrated an improved CR rate (RR, 1.33; 95% CI, 1.06-1.68) and a comparable ORR (RR, 1.09; 95% CI, 0.95-1.25), PFS (HR, 0.62; 95% CI, 0.21-1.87), and DOR (HR, 0.47; 95% CI, 0.14-1.65). For safety outcomes, liso-cel showed a trend towards reduced odds of any-grade NEs (OR, 0.32; 95% CI, 0.10-1.02), grade ≥ 3 NEs (OR, 0.39; 95% CI, 0.06-2.48), any-grade infections (OR, 0.85; 95% CI, 0.25-2.87), and use of corticosteroids (OR, 0.94; 95% CI, 0.11-7.73) or tocilizumab (OR, 0.68; 95% CI, 0.19-2.41) for CRS management. Conclusions: After adjusting for intertrial differences, liso-cel showed a higher CR rate compared with axi-cel and tisa-cel, respectively, and comparable efficacy for ORR, PFS, and DOR. Liso-cel had a more favorable safety profile compared with axi-cel and a similar safety profile compared with tisa-cel, with a trend favoring liso-cel for reduced medication use in CRS management, any-grade infections, and NEs.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.013 | 0.027 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.004 | 0.010 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.012 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".