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 R

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.