EMA Accepts MAA for Obecabtagene Autoleucel in R/R B-Cell Acute Lymphoblastic Leukemia

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The European Medicines Agency (EMA) has accepted a marketing authorization application (MAA) seeking the approval of obecabtagene autoleucel (obe-cel; formerly AUTO1) for use in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia (B-ALL).¹

The application is supported by findings from the phase 1b/2 FELIX study (NCT04404660). Data presented at the 2023 ASCO Annual Meeting showed that at a median follow-up of 9.5 months (range, 1.9-9.0), the CAR T-cell therapy elicited an overall response rate (ORR) of 76% (95% CI, 66%-84%; P < .0001) in evaluable patients (n = 94; this included a complete response (CR) rate of 54.3% and a CR with incomplete hematologic recovery (CRi) rate of 21.3%.² Moreover, the majority of responders (97%) achieved minimal residual disease (MRD) negativity at the 10^-4 level by flow cytometry.

Data from a pooled analysis of all 3 cohorts in the study were presented at the 2023 ASH Annual Meeting and showed that at a median follow-up of 11.0 months, obe-cel induced a CR/CRi rate of 77% in evaluable patients (n = 124).³ Of the 10 evaluable patients who had MRD at the time of screening, 9 experienced a CR/CRi and all achieved MRD-negative status. In the subset of patients with morphologic disease (n = 98), obe-cel led to a CR/CRi rate of 74% and achieved MRD negativity. All of those without morphologic disease (n = 29) were MRD negative following treatment with the CAR T-cell therapy.

“Along with the recent acceptance of the biologics license application [BLA] by the FDA, the acceptance of our European Union marketing application is an important milestone in expanding into the European market and delivering this potentially transformative therapy to B-ALL patients,” Christian Itin, PhD, chief executive officer of Autolus Therapeutics, plc., stated in a press release^.1 “We look forward to working with the EMA throughout the evaluation process of obe-cel, and thank the internal team at Autolus for their work on the submission and Nucleus site inspection.”

The open-label, multicenter FELIX study enrolled adult patients with relapsed/refractory B-ALL who had an ECOG performance status of 0 or 1. These patients were divided into the following 3 cohorts: those with morphological disease of at least 5% bone marrow (BM) blasts (cohort A), those in their second or later CR/CRi with measurable MRD (cohort B), and those with isolated extramedullary disease (cohort C).^2,3

If patients had Burkitt’s leukemia or lymphoma or chronic myeloid leukemia in lymphoid blast crisis, a history or presence of central nervous system (CNS) pathology determined to be clinically relevant or had CNS-3 or CNS-2 disease with neurological changes, they were excluded. Moreover, they could not have previously received CD19-targeted therapy with the exception of blinatumomab (Blincyto) or have experienced grade 3 or higher neurotoxicity after exposure to blinatumomab.

Patients received bridging therapy as needed. They also received lymphodepletion in the form of fludarabine (4 × 30 mg/m²) and cyclophosphamide (2 × 500 mg/m²). The target dose of CAR T cells was 410 × 10⁶ CAR T cells, which was split between day 1 and day 10 of treatment. Patients with 20% or less BM blasts 6 days before infusion were given 100 × 10⁶ cells at day 1 and 310 × 10⁶ cells at day 10. Those with less than 20% BM blasts received 10 × 106 cells on day 1 and 400 × 10⁶ cells on day 10. The day 10 dose was not given if grade 2 or higher cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity syndrome (ICANS) occurred.

CR/CRi served as the trial’s primary end point. Key secondary end points included event-free survival (EFS), overall survival, MRD negativity rate, safety, and duration of response.

In the total 127 patients who received obe-cel, the median age was 47 years (range, 20-81).³ Fifty-two percent of patients were male. The median number of prior therapies received was 2 and 35% of patients received 3 or more prior lines of treatment. Seventeen percent of patients received blinatumomab and inotuzumab ozogamicin (Besponsa), and just under half (44%) had previously undergone allogeneic stem cell transplant.

Additional efficacy data shared during the 2023 ASH Annual Meeting indicated that at a median follow-up of 16.6 months, the estimated EFS rate at 6 months was 65% (95% CI, 56%-73%); the 12-month EFS rate was 50% (95% CI, 39%-59%). Moreover, the median EFS with obe-cel was 11.7 months (95% CI, 7.2-not estimable). Of the 99 patients who responded to treatment, 17 went on to transplant during remission.

Leukemic burden was found to have an impact on EFS. In patients who had less than 5% BM blasts, the 6-month EFS rate was 83%. In those with BM blasts ranging from 5% to 75%, the EFS rate at 6 months was 72% and in those with greater than 75% BM blasts, this rate was 40%. The respective 12-month EFS rates were 65%, 55%, and 27%.

The safety profile of obe-cel was found to be favorable overall. Grade 3 or higher treatment-emergent adverse effects were experienced by 83% of patients, and included febrile neutropenia (24%), anemia (21%), neutropenia (21%), and decreased neutrophil count (20%).

Of all patients who received the CAR T-cell therapy, 69% experienced all-grade CRS, with grade 3 or higher events observed in 2% of patients. Any-grade ICANS occurred in 25% of patients, with 7% of events grade 3 or higher in severity.

When broken down further, 47% of those who had BM blasts of less than 5% experienced CRS; all of these events were grade 1 or 2. Grade 1/2 ICANS was reported in 85% of these patients. In those who had BM blasts within the range of 5% and 75%, 69% experienced any-grade CRS and 4% had a grade 3 or higher event. Any-grade ICANS occurred in 18% of these patients, and 6% of patients experienced a grade 3 or higher event. Lastly, in those with BM blasts that were greater than 75%, 88% and 3% of patients experienced grade 1/2 and grade 3 CRS events, respectively. Any-grade ICANS occurred in 43% of patients, with 15% of patients experiencing an event that was grade 3 or higher in severity.

In November 2023, a biologics license application seeking the approval of obe-cel for adult patient with relapsed/refractory B-ALL was submitted to the FDA.⁴ The Prescription Drug User Fee Act target action date is November 16, 2024.¹

References

1. Autolus Therapeutics announces acceptance of marketing authorization application (MAA) by the European Medicines Agency (EMA) for obecabtagene autoleucel (obe-cel) for patients with relapsed/refractory (r/r) adult B-cell acute lymphoblastic leukemia (B-ALL). News release. Autolus Therapeutics, plc. April 2, 2024. Accessed April 2, 2024. https://autolus.gcs-web.com/news-releases/news-release-details/autolus-therapeutics-announces-acceptance-marketing
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
4. Autolus Therapeutics submits biologics license application to US Food and Drug Administration for obecabtagene autoleucel (obe-cel) for patients with relapsed/refractory (r/r) adult B-cell acute lymphoblastic leukemia (ALL). News release. Autolus Therapeutics. November 27, 2023. Accessed April 2, 2024. https://autolus.gcs-web.com/news-releases/news-release-details/autolus-therapeutics-submits-biologics-license-application-us