Obecabtagene autoleucel (obe-cel) for Adult Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (R/R B-ALL) in the Open-Label, Multi-Center, Global, Single-Arm, Phase Ib/II FELIX Study: The Impact of Bridging Therapies on CAR T-Cell Expansion and Persistence

Background: Bridging therapies (BT) are often needed prior to CAR T-cell treatment for patients with adult R/R B-ALL to manage and reduce tumor burden prior to CAR T-cell infusion. However, the impact of BT such as steroids, chemotherapy, tyrosine kinase inhibitors (TKI), or monoclonal antibody-drug conjugates on the clinical efficacy of existing CAR T-cell therapies has not been fully characterized. Obe-cel is a CD19 autologous CAR T with a differentiated design to improve persistence and reduce toxicity (Roddie C, et al. J Clin Oncol 2021;39[30]:3352-63). Here, we report the impact of BT with and without inotuzumab ozogamicin (INO) on tumor burden at lymphodepletion (LD) and pharmacokinetics (PK), including CAR T expansion and persistence.

Methods: FELIX is a Phase Ib/II study evaluating the safety and efficacy of obe-cel in adult patients with R/R B-ALL. Eligible, consented patients aged ≥18 years with CD19+ R/R B-ALL were enrolled. Patients received BT (chemotherapy with or without INO or TKI, single-agent INO, single-agent TKI, steroids, or rituximab) per investigator decision; use of blinatumomab as a BT agent was not permitted. Patients then underwent LD (fludarabine, 4x30mg/m²; cyclophosphamide, 2x500mg/m²), followed by obe-cel tumor-burden guided infusions on Days 1 and 10, to a target dose of 410x10⁶ CAR T-cells. PK parameters were analyzed in peripheral blood, measured by droplet digital polymerase chain reaction, and included maximal expansion of transgene/CAR-positive T-cell levels post-infusion (C_max; copies/µg DNA), time to maximal expansion (T_max; days), exposure up to 28 days (area under the curve [AUC]_0-28d; days x copies/µg DNA), and persistence. In this analysis, we describe outcomes in patients who received BT with INO, BT without INO, or no BT (data cut-off date: 7 February 2024).

Results: In the FELIX study, 18/127 (14%) patients received BT with INO (with or without chemotherapy; median dose=1) and 100/127 (79%) received BT without INO, while 9/127 (7%) patients did not receive BT. Median bone marrow (BM) blast percentage at screening was numerically higher in patients who received BT with INO vs BT without INO vs no BT (82% vs 40% vs 20%, respectively). BT with INO led to an effective reduction in tumor burden at LD, with median BM blast percentages of 2% vs 52% vs 30% in patients who received BT with INO vs BT without INO vs no BT, respectively. Despite the substantial reduction in tumor burden at LD for the BT with INO group, CAR T expansion was high in all groups, increasing progressively from BT with INO, to BT without INO, and finally no BT: C_max geometric mean (copies/µg DNA; coefficient of variation [CV%]) 74,246 (210) vs 115,624 (280) vs 156,300 (83) and AUC_0-28d geometric mean (CV%) 625,122 (218) vs 1,214,474 (217) vs 1,316,749 (106), respectively. Median T_max (range) was similar for all groups at 13 days (8-55) vs 14 days (2-28) vs 14 days (10-28) for BT with INO, BT without INO, and no BT, respectively. The difference in expansion, however, is likely to be driven by the tumor burden rather than the type of BT specifically. CAR T-cell persistence was observed in all three groups, with the longest persistence beyond 24 months. At the current follow-up of median 21.5 months (range: 8.6-41.4), median event-free survival (95% confidence interval [CI]) was 22.1 months (4.1-not estimable [NE]) vs 9.0 months (6.0-15.0) vs NE, and median overall survival was 23.8 months (4.8-NE) vs 14.1 months (11.5-NE) vs NE, for BT with INO, BT without INO, and no BT, respectively. Rates of Grade ≥3 cytokine release syndrome/immune effector cell-associated neurotoxicity syndrome were 6%/11%, 2%/7%, and 0%/0% for BT with INO, BT without INO, and no BT, respectively.

Conclusions: BT with INO is effective in reducing disease burden prior to obe-cel infusion. No apparent differences in expansion and long-term persistence of obe-cel were observed based on any of the BT evaluated, suggesting that long-term persistence of obe-cel is possible irrespective of BT and independent of initial tumor burden at LD. Reduction in tumor burden at LD through BT with INO led to more favorable survival outcomes compared with BT without INO, while maintaining a tolerable safety profile. A limitation of this study is the small number of patients who received BT with INO. Further studies comparing BT with INO-containing therapies or chemotherapy are warranted.