In a phase Ib/II multicentre, pivotal registration FELIX study, an autologous 41BB-ζ anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, obecabtagene autoleucel, resulted in a high incidence of response among adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (ALL), with side effects mostly limited to patients with a high bone marrow burden.
Furthermore, obecabtagene autoleucel was associated with durable responses, particularly in patients with a low-to-intermediate bone marrow burden, including patients who did not receive consolidative allogeneic stem-cell transplantation. Findings were published by Dr. Claire Roddie of the Cancer Institute, University College London in London, UK, and colleagues on 27 November 2024 in The New England Journal of Medicine.
The authors wrote in the background that unlike tisagenlecleucel and brexucabtagene autoleucel, which both use the same high-affinity single-chain variable fragment (scFv) to recognise CD19, obecabtagene autoleucel uses a different scFv with intermediate affinity due to a fast binding off-rate, which is hypothesised to reduce side effects and improve CAR T-cell engraftment and persistence.
Phase I testing of obecabtagene autoleucel in children and young adults with relapsed or refractory B-cell ALL resulted in a high incidence of response, durable persistence, and a low incidence of severe immune-related side effects.
Obecabtagene autoleucel was subsequently tested in the phase I ALLCAR19 study involving adults 18 years of age or older with relapsed or refractory B-cell ALL. Given the increased susceptibility of adults with B-cell ALL to immune-related side effects, a bone marrow burden–guided split-dose regimen was used. Obecabtagene autoleucel showed high efficacy, with an incidence of measurable residual disease (MRD)-negative remission of 85% and a low incidence of grade 3 or higher cytokine release syndrome (CRS, 0%) and immune effector cell–associated neurotoxicity syndrome (ICANS, 15%); a total of 36% of the patients were in ongoing remission at a median follow-up of 43 months.
FELIX study was designed to continue the exploration of 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; patients in cohort 2B had MRD. The primary endpoint was overall remission (complete remission or complete remission with incomplete haematologic recovery) in cohort 2A. 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 comprised 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 complete remission in 55% (95% CI 45 to 66) and complete remission with incomplete haematologic recovery in 21% (95% CI 14 to 31). The prespecified null hypotheses of overall remission (≤40%) and complete remission (≤20%) were rejected (p < 0.001).
In the 127 patients who received at least one obecabtagene autoleucel infusion (median follow-up 21.5 months), the median EFS was 11.9 months (95% CI 8.0 to 22.1); estimated 6- and 12-month EFS was 65.4% and 49.5%, respectively. The median OS was 15.6 months (95% CI 12.9 to not evaluable); estimated 6- and 12 month OS was 80.3% and 61.1%, respectively.
Patients with a low bone marrow burden (<5% blasts) or intermediate bone marrow burden (5 to 75% blasts) before lymphodepletion had better EFS results than those with a high bone marrow burden (>75% blasts), which suggests that low-to intermediate bone marrow burden is optimal for CAR T-cell efficacy and toxicity and that optimised bridging therapy approaches toward better tumour clearance before CAR T-cell therapy may improve outcomes. Furthermore, obecabtagene autoleucel as earlier-line consolidation, particularly in the context of MRD, deserves further exploration according to the study team.
Grade 3 or higher CRS developed in 2.4% of the patients, and grade 3 or higher ICANS developed in 7.1% of the patients. Severe ICANS after obecabtagene autoleucel infusion was largely limited to patients with a high bone marrow burden before lymphodepletion, which suggests that obecabtagene autoleucel may be safely administered in an ambulatory setting in patients with a low bone marrow burden.
The authors commented that blinatumomab and inotuzumab ozogamicin have been shown to increase the likelihood of response in patients with relapsed or refractory B-cell ALL, but consolidation with allogeneic stem-cell transplantation is needed for durable response. Although the incidence of overall remission with brexucabtagene autoleucel was 71%, it was associated with a much higher incidence of grade 3 or higher CRS, grade 3 or higher ICANS, and vasopressor use as compared with obecabtagene autoleucel.
The study was funded by Autolus Therapeutics.
Reference
Roddie C, Sandhu KS, Tholouli E, et al. Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia. NEJM; Published online 2 November 2024. DOI: 10.1056/NEJMoa2406526