Treatment with Obecabtagene Autoleucel Results in Durable Response Among Adults with Relapsed or Ref

In the phase Ib/II multicenter pivotal FELIX study, the autologous 41BB-ζ anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, obecabtagene autoleucel, demonstrated a high response rate in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), with side effects primarily observed in patients with a high bone marrow burden.

Additionally, obecabtagene autoleucel showed long-lasting responses, especially in patients with low-to-intermediate bone marrow burden, including those who did not receive consolidative allogeneic stem-cell transplantation. These findings were published by Dr. Claire Roddie from the Cancer Institute, University College London, and colleagues on November 27, 2024, in The New England Journal of Medicine.

Unlike tisagenlecleucel and brexucabtagene autoleucel, both of which use a high-affinity single-chain variable fragment (scFv) to target CD19, obecabtagene autoleucel utilizes a distinct scFv with intermediate affinity due to a fast off-rate. This difference is believed to reduce side effects and improve CAR T-cell engraftment and persistence.

Phase I trials of obecabtagene autoleucel in children and young adults with relapsed or refractory B-cell ALL showed a high response rate, durable persistence, and a low incidence of severe immune-related side effects.

Obecabtagene autoleucel was further evaluated in the phase I ALLCAR19 study involving adults aged 18 or older with relapsed or refractory B-cell ALL. Due to the increased risk of immune-related side effects in these adults, a bone marrow burden–guided split-dose regimen was applied. The therapy showed strong efficacy, with an 85% rate of measurable residual disease (MRD)-negative remission, and low incidences of grade 3 or higher cytokine release syndrome (CRS) (0%) and immune effector cell–associated neurotoxicity syndrome (ICANS) (15%). At a median follow-up of 43 months, 36% of patients remained in remission.

The FELIX study aimed to continue assessing the safety, efficacy, and scalability of obecabtagene autoleucel in adults with relapsed or refractory B-cell ALL. The main cohort 2A included patients with morphologic disease, while cohort 2B comprised patients with MRD. The primary endpoint was overall remission in cohort 2A, and secondary endpoints included event-free survival (EFS), overall survival (OS), and safety.

Of the 153 enrolled patients, 127 (83.0%) received at least one infusion of obecabtagene autoleucel and were evaluable. In cohort 2A, consisting of 94 patients with a median follow-up of 20.3 months, overall remission occurred in 77% (95% confidence interval [CI] 67 to 85), with 55% achieving complete remission (95% CI 45 to 66) and 21% achieving complete remission with incomplete hematologic recovery (95% CI 14 to 31). The prespecified null hypotheses for overall remission (≤40%) and complete remission (≤20%) were rejected (p < 0.001).

Among the 127 patients who received at least one infusion, with a median follow-up of 21.5 months, the median EFS was 11.9 months (95% CI 8.0 to 22.1), with estimated 6- and 12-month EFS rates of 65.4% and 49.5%, respectively. The median OS was 15.6 months (95% CI 12.9 to not evaluable), with estimated 6- and 12-month OS rates of 80.3% and 61.1%, respectively.

Patients with a low bone marrow burden (<5% blasts) or intermediate burden (5 to 75% blasts) before lymphodepletion showed better EFS than those with a high bone marrow burden (>75% blasts). This suggests that a low-to-intermediate bone marrow burden is optimal for CAR T-cell efficacy and toxicity, and that better tumor clearance prior to CAR T-cell therapy may improve outcomes. The study team also suggested that earlier-line consolidation with obecabtagene autoleucel, particularly for MRD-positive patients, warrants further investigation.

Grade 3 or higher CRS occurred in 2.4% of patients, and grade 3 or higher ICANS occurred in 7.1%. Severe ICANS after infusion were primarily observed in patients with a high bone marrow burden before lymphodepletion, suggesting that obecabtagene autoleucel may be safely administered in outpatient settings for patients with low bone marrow burden.

The authors noted that while blinatumomab and inotuzumab ozogamicin have been shown to increase response rates in relapsed or refractory B-cell ALL, consolidative allogeneic stem-cell transplantation is still necessary for durable responses. In comparison, although brexucabtagene autoleucel achieved a 71% overall remission rate, it was associated with a significantly higher incidence of grade 3 or higher CRS, grade 3 or higher ICANS, and vasopressor use compared to obecabtagene autoleucel.