Obecabtagene Autoleucel BLA for Relapsed/Refractory B-ALL Under FDA Review

FDA

The FDA has accepted for review the biologics license application (BLA) seeking the approval of obecabtagene autoleucel (obe-cel) in the treatment of adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).¹

The BLA is based on findings from the phase 2 FELIX study (NCT04404660). Topline data revealed that the CAR T-cell therapy elicited a complete response (CR) rate of 54.3% and a CR with incomplete count recovery (CRi) rate of 21.3% in infused patients (n = 94).² The overall remission rate in these patients was 76% (95% CI, 66%-84%; P < .0001). Moreover, most responders with evaluable samples (97%) had minimal residual disease (MRD) negativity at 10-4 level by flow cytometry.

Updated data from a pooled analysis of the study showed that in the overall population (n = 127), the CR/CRi rate was 78% (95% CI, 70%-85%).³ When broken down further, 74% of patients with morphologic disease (n = 98) achieved a CR/CRi and 95% of evaluable responders had MRD negativity. All patients without morphologic disease (n = 29) achieved MRD negativity.

Under the Prescription Drug User Fee Act, the regulatory agency will decide on the application by November 16, 2024.¹

“Acceptance of the BLA filing is an important milestone for Autolus and we look forward to continuing our collaboration with the FDA during the review cycle,” Christian Itin, PhD, chief executive officer of Autolus Therapeutics, plc, stated in a press release. “With the PDUFA date set for November, we remain focused on preparing for the potential launch of obe-cel.”

FELIX enrolled patients with relapsed or refractory adult B-ALL who were at least 18 years of age and who had at least 5% bone marrow blasts at screening if they were in cohort A, MRD positivity at screening if they were in cohort B, and isolated extramedullary disease at screening if they were in cohort C.^2,3

After screening, participants underwent leukapheresis and were given bridging therapy as obe-cel was manufactured. At day -6, preconditioning therapy was given with fludarabine at 30 mg/m2 and cyclophosphamide at 500 mg/m². The CAR T-cell therapy was administered via a split-dose infusion on days 1 and 10.

The split-dose schedule was tumor burden–adjusted to maximize the drug’s therapeutic index. In patients with bone marrow blasts up to 20% during the preconditioning stage, obe-cel was given at 100 x 10⁶ CAR T cells and, if any events of cytokine release syndrome (CRS) were below grade 2 and there were no cases of immune effector cell–associated neurotoxicity syndrome (ICANS), the product was administered again at a 310 x 10⁶ CAR T cells. In patients with bone marrow blasts that were greater than 20%, obe-cel was first given at 10 x 10⁶ CAR T cells, and following the same CRS/ICANS score, the therapy was then given at 400 x 10⁶ CAR T cells.

The primary end point of the study is CR/CRi rate by central assessment and secondary end points include duration of response (DOR), event-free survival (EFS), overall survival, MRD negativity rate, and safety.

At the time of the data cutoff date of September 13, 2023, a total of 153 patients had been enrolled in the study and 127 were infused with the CAR T-cell therapy. Of those patients, 107 were in cohort A, 13 were in cohort B, and 7 were in cohort C. Twenty-six patients discontinued because of death (n = 15), manufacturing related issues (n = 7), toxicity (n = 2), physician decision (n = 1), and disease progression (n = 1).

In the 127 patients who were infused with the product, the median age was 47 years (range, 20-81). Fifty-two percent of patients were male and 74% were White. Moreover, 28% of patients had Philadelphia chromosome–positive disease. At screening, the median percentage of bone marrow blasts was 36% (range, 0%-100%), and 23% of patients had extramedullary disease.

The median number of prior lines of treatment received was 2, with a range of 1 to 6 lines; 35% of patients received 3 or more prior lines. Just under half previously underwent allogeneic stem cell transplant (44%); 42%, 31%, and 17% of patients received blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), or both, respectively.

Additional data from the pooled analysis presented at the 2023 ASH Annual Meeting indicated that obe-cel induced high CR/CRi rates across all subgroups.³

At a median follow-up of 16.6 months (range, 3.7-36.6), the median EFS was 11.7 months (95% CI, 7.2-not evaluable [NE]) in all treated patients; the 6- and 12-month EFS rates were 65% (95% CI, 56%-73%) and 50% (95% CI, 39%-59%), respectively. Seventeen percent of responders went on to transplant while in remission.

Those who had bone marrow blasts of less than 5% before lymphodepletion (n = 36) experienced a median EFS that was NE; in this group, the 6-month and 12-month EFS rates were 83% (95% CI, 65%-92%) and 65% (95% CI, 44%-80%), respectively. In those with bone marrow blasts of at least 5% up to 75% (n = 51), the median EFS was 15.0 months (95% CI, 6.6-NE) with 6- and 12-month EFS rates of 72% (95% CI, 57%-82%) and 55% (95% CI, 38%-69%), respectively. In those with bone marrow blasts greater than 75% (n = 40), the median EFS was 4.5 months (95% CI, 1.5-9.0); the 6-month EFS rate was 40% (95% CI, 23%-56%) and the 12-month EFS rate was 27% (95% CI, 12%-44%).

Regarding safety, there were low rates of grade 3 or higher CRS and/or ICANS reported. In all patients, 69% of patients experienced grade 1 or 2 CRS and 2% experienced CRS that was grade 3 or greater. In this population, grade 1 or 2 ICANS occurred in 23% of patients and 7% experienced events that were grade 3 or greater.

In the subgroup of patients with bone marrow blasts of less than 5%, 47% of patients experienced grade 1 or 2 CRS and 8% experienced grade 1 or 2 ICANS; no patients experienced grade 3 or higher events. In the group with bone marrow blasts of at least 5% but no greater than 75%, 69% experienced grade 1 or 2 CRS and 18% experienced grade 1 or 2 ICANS; 4% and 6% of patients experienced grade 3 or higher CRS and ICANS, respectively. Lastly, in the group who had bone marrow blasts of greater than 75%, grade 1 or 2 CRS and ICANS were reported in 88% and 43% of patients, respectively; these effects were grade 3 or higher for 3% and 15% of patients, respectively.

Other common treatment-emergent adverse effects experienced by 20% or more of patients who received obe-cel included pyrexia (any grade, 29%; grade ≥3, 2%), nausea (26%; 2%), diarrhea (25%; 2%), febrile neutropenia (24%; 24%), anemia (24%; 21%), headache (24%; 0%), neutropenia (23%; 21%), hypotension (22%; 5%), hypokalemia (21%; 6%), and decreased neutrophil count (20%; 20%).

References

1. Autolus Therapeutics announces acceptance of biologics license application for obecabtagene autoleucel (obe-cel) as a potential treatment for relapsed/refractory adult B-cell acute lymphoblastic leukemia (ALL). News release. January 22, 2024. Accessed January 23, 2024. https://autolus.gcs-web.com/news-releases/news-release-details/autolus-therapeutics-announces-acceptance-biologics-license
2. Roddie C, Sandhu KS, Tholouli E, et al. Safety and efficacy of obecabtagene autoleucel (obe-cel, AUTO1), a fast-off rate CD19 CAR, in relapsed/refractory adult B-cell acute lymphoblastic leukemia (r/r B-ALL): Top line results of the pivotal FELIX study. J Clin Oncol. 2023;41(suppl 16):7000. doi:10.1200/JCO.2023.41.16_suppl.7000
3. Roddie C, Sandhu KS, Tholouli E, et al. Obecabtagene autoleucel (obe-cel, AUTO1) for relapsed/refractory adult B-cell acute lymphoblastic leukemia (R/R B-ALL): pooled analysis of the ongoing FELIX phase Ib/II study. Blood. 2023;142(suppl_1):222. doi:10.1182/blood-2023-179454