Obe-Cel Represents a Unique CAR T-Cell Therapy for Patients with Relapsed/Refractory ALL

Daniel J. DeAngelo, MD, PhD

The CAR T-cell agent obecabtagene autoleucel (obe-cel; Aucatzyl) is a notable recent addition to the acute lymphoblastic leukemia (ALL) treatment paradigm that produces a high incidence of durable responses with lower incidences of immune-related toxicities in patients with relapsed/refractory disease, according to Daniel J. DeAngelo, MD, PhD.

Obe-cel was approved by the FDA in November 2024 for the treatment of adult patients with relapsed/refractory B-cell precursor ALL based on findings from the phase 1/2 FELIX trial (NCT04404660) where the agent was given via split dosing.¹ The distinctive recommended dose of the drug per the FDA is 410 × 10⁶ CD19 CAR-positive viable T cells administered as a split dose infusion on day 1 and day 10 (± 2 days) based on bone marrow blast assessment with fludarabine and cyclophosphamide lymphodepleting chemotherapy preceding.

“[Following this approval], there are 2 big unanswered questions. First, in the relapsed/refractory setting is CAR T-cell therapy a standalone [therapy]? Second, can we move CAR T-cell agents to earlier lines of therapy either in the MRD-positive setting or even MRD-agnostic [setting] as a solution to try and shorten the duration, and therefore toxicity, of therapy?” DeAngelo said in an interview with OncLive^®. “Obe-cel lends itself to that, at least in comparison with the other 2 [FDA-approved] CAR T-cell agents brexucabtagene autoleucel [brexu-cel; Tecartus] and tisagenlecleucel [tisa-cel; Kymriah]. The FELIX study [showed] a profound reduction in terms of the cytokine release syndrome [CRS] and neurotoxicity rate. I’m expecting that these things will be investigated in the future.”

Notably, 2.4% of patients experienced grade 3 or higher CRS and 7.1% experienced grade 3 or higher immune effector cell-associated neurotoxicity syndrome in FELIX.² At a median follow-up of 20.3 months, updated data from FELIX published in the New England Journal of Medicine showed that patients in cohort 2A (n = 94), which enrolled those with morphologic disease, achieved an overall remission rate (ORR) of 77% (95% CI, 67%-85%). The complete remission (CR) rate was 55% (95% CI, 45%-66%) and the CR with incomplete hematologic recovery rate was 21% (95% CI, 14%-31%). Furthermore, patients experienced a median duration of response of 21.2 months (95% CI, 11.6-not evaluable).

In the interview, DeAngelo, who is the chief of the Division of Leukemia and an institute physician at Dana-Farber Cancer Institute as well as a professor of medicine at Harvard Medical School in Boston, Massachusetts, discussed details of the FELIX trial and the future of research with CAR T-cell agents in ALL.

OncLive: What was the design of the FELIX trial?

DeAngelo: FELIX was a study of adult patients with relapsed/refractory CD19-positive B-cell ALL. It included both patients who had Philadelphia [chromosome] negative as well as positive disease. CD19 is expressed in the vast majority of patients with ALL, and many of these patients [underwent] 1, 2, 3, or even more prior regimens.

FELIX [also] stratified patients based on disease burden prior to lymphodepleting chemotherapy. All patients received 2 doses of obe-cel and, importantly, they [received] the same total dose, but how the dose was split was based on disease burden. If the patient had a high disease burden going into lymphodepletion, then they would get a low dose [of obe-cel] followed by a higher dose. If they had a lower disease burden, then they got a slightly higher dose up front followed by the rest of the dose. Expansion occurred regardless of disease burden, but the outcome in terms of remission rate, durability of remission, event-free survival [EFS], and overall survival [OS] could be dictated based on the disease burden.

What makes obe-cel unique among other drugs in this agent class?

The construct is slightly different. It is a 4-1BB construct, but the receptor antibody that [it contains] has been mutagenized so that there is a fast-off [target effect]. The hit between the CAR T cell and its target is seconds to a minute vs [other CAR T-cell agents such as] brexu-cel or tisa-cel where the off-rate is a lot slower. Theoretically, this leads to decreased exhaustion of the T cells, which may help with prognosis and lower cytokine activation.

In FELIX, we saw markedly reduced [rates of] CRS and minimal neurologic toxicities or [cases of] immune effector cell-associated neurotoxicity syndrome. Patients tended to do much better, even [those] with high disease burden. Whether or not it was based on the construct or the study design [is unclear] but [these findings] led to the [FDA] approval of obe-cel in relapsed/refractory, CD19-positive ALL.

What were the key efficacy findings from FELIX?

[Data] from FELIX were recently published in the New England Journal of Medicine and the trial consisted of a total of 153 enrolled patients, with 127 receiving at least 1 infusion [of obe-cel]. Eighty-three percent of the patients that were enrolled on the study were able to receive at least 1 dose of obe-cel. At a median follow up of approximately 20 months, the ORR was 77% with a CR rate of 55%, [which is] remarkably high for a heavily pretreated, relapsed/refractory patient population. Importantly, the median EFS for these patients was approximately 12 months, and the EFS [rates] were 65.4% at 6 months and 49.5% at 12 months, with a median OS of 15.6 months.

[These are] remarkably excellent results and the durable remissions with obe-cel in [patients with] relapsed/refractory CD19-positive [disease] led to the FDA approval of this agent. We now have 3 CAR T-cell agents that are approved [by the FDA], which is a game changer for many of our patients.

What are the next steps in the investigation of CAR T-cell agents in hematologic malignancies?

In terms of analyzing CAR T-cell [agents], in my opinion [we need] to figure out how to use them best. One question is [whether] CAR T-cells [agents] are stand-alone therapy. Do we need to consolidate a patient who achieves a remission after CAR T-cell [therapy], regardless of the agent, with stem cell transplant [SCT]? To date, none of the [data from studies of] the agents have shown that adding SCT improves outcomes. Nevertheless, many of us, especially in patients who are transplant naive, will at least consider SCT for those patients.

The second [question] is when agents that work as well as these do in the relapsed/refractory setting, can you move them into earlier states of disease? For example, [could we] use CAR T-cell [agents] as standalone therapy for patients who are minimal residual disease [MRD] positive, [specifically in those with] persistent MRD post induction and consolidation? The current standard [of care] is to use a bispecific T-cell engager such as blinatumomab [Blincyto] and consolidating with transplant. [Could we] use CAR T-cell therapy, or even just CAR T-cell therapy in consolidation regardless of MRD status, to try to shorten the 2-to-3-year duration of chemotherapy?

References

1. FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. November 8, 2024. Accessed February 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute
2. Roddie C, Sandhu KS, Tholouli E, et al. Obecabtagene autoleucel in adults with B-cell acute lymphoblastic leukemia. N Engl J Med. 2024;391(23):2219-2230. doi:10.1056/NEJMoa2406526