Obe-Cel Approval Was a ‘Major Milestone’ for ALL Treatment

“This approval comes at a critical time and it’s a major milestone [for] patients with ALL,” Jabbour said.

The November 2024 FDA approval of obecabtagene autoleucel (obe-cel; Aucatzyl) for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) marks a significant addition to the paradigm as it is administered via split dosing thus reducing toxicities and allowing it to be given in an outpatient setting, according to Elias Jabbour, MD.¹

“This approval comes at a critical time and it’s a major milestone [for] patients with ALL,” Jabbour said in an interview with Oncology Nursing News’ sister publication, OncLive®. “Splitting the dose allows us to deliver a safe CAR T-cell therapy [with] minimal complications and [it is] effective in the long run. [Obe-cel is also] an outpatient therapy, which will have a major impact on society and our patient’s lives. It’s a very important accomplishment that will fill a major unmet need.”

Findings from the phase 1/2 FELIX trial (NCT04404660), which supported the regulatory decision, revealed that the overall complete remission (CR) rate was 63% (95% CI, 50%-75%) among efficacy-evaluable patients who received obe-cel (n = 65); the median duration of response was 14.1 months (95% CI, 95% CI, 6.2-not reached [NR]).^1,2 Additionally, 42% (95% CI, 29%-54%) of patients achieved CR within 3 months and the median duration of CR experienced within 3 months was 14.1 months (95% CI, 6.1-NR).1 Notably, obe-cel has boxed warnings for cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and T-cell malignancies.

In the interview, Jabbour, who is a professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, detailed considerations with obe-cel and how the agent is different from other CAR T-cell therapies.

OncLive: What is the significance of this approval?

Jabbour: In ALL, once a patient has relapsed the outcome is grim; you can [offer] the patient salvage [therapy] with whatever is available to us today, even immunotherapy, but most of these responses are short lived and [then we] offer transplant with all the complications that it can include. We’ve seen very good response rates so far with obe-cel [and] one of the advantages is [it elicits] deep responses.

In the [FELIX] trial, 40% of patients sustained remission without subsequent therapy, mainly [without] transplant, [at a median follow-up of 21.5 months]. What we’ve seen so far with the follow-up we have, and we have an update to be [presented at the 66th American Society of Hematology Annual Meeting & Exposition] coming [up in December 2024] in San Diego, is that patients who do respond have a plateau for survival; patients are maintaining remission without [needing] subsequent therapy. This plateau tells me that eventually this treatment can be curative in a way [where] patients will not need subsequent therapy—they will have a plateau, and no relapse will be seen. Of course, the follow-up [time] is too short, but that is major [news thus far].

What is important to note about obe-cel’s safety profile?

This treatment was given with a very acceptable and excellent safety profile. The complications we encounter with the available CAR T-cell [therapies] today are two-fold. One is CRS that we can manage by giving CAR T-[cell therapy to those with a] low tumor burden and the second is ICANS, which we see in approximately 30% of patients in the real-world setting, even though you cytoreduce the tumor first. In the FELIX trial, we saw a very good safety profile with obe-cel; 7% of patients [experienced grade 3 or higher] ICANS and only 3% [experienced grade 3 or higher] CRS. Treatment is well tolerated.

One other implication of this therapy is it can be given as outpatient therapy. So far with CAR T-cell therapy we’ve given 1 infusion. With obe-cel in the FELIX trial, we looked at the tumor burden before lymphodepletion [and] split the dose at day 1 and day 10, giving a high number of cells at the beginning [to patients with] a low tumor burden. When we split the dose, we gave a higher dose on day 1, [100 × 106 CAR T-cells], if a patient had a low tumor burden; we gave [10 × 106 CAR T-cells on day 1] to those with a high tumor burden above 20%.

What advice would you give to community clinicians about integrating obe-cel into practice?

CAR T-cell therapies were not very welcome in ALL because of the complications and the need for hospitalization for [approximately] 14 days. Today, we have a safer CAR T-cell therapy that will make managing complications much easier, if [there are] any, and outpatient [therapy is] more convenient for patients [as it can be given] wherever they are living. I still recommend communication between the patient, committee doctors, and experts in the field. Every patient with relapsed ALL should be considered for obe-cel because the responses [observed] with other options [have] limited, very short durations.

The best outcome seen with any CAR T-cell therapy, and obe-cel as well, is when you give the therapy in the low tumor burden [population]. When I see a patient in my practice with relapsed/refractory ALL, I will collect the patient’s [T-cells], [administer] bridging treatment, and then start lymphodepletion [therapy] and CAR T-cell infusion. When I do the [bridging therapy], I lower the tumor burden, and the outcome is better with a low tumor burden. When you look at the label, [dosing is tailored to disease burden].

How is obe-cel different from other approved CAR T-cell therapies for this patient population?

There are multiple differences, but the structure of obe-cel is [that it’s CAR has] a fast-off [kinetic so it has a] short binding time, and that is critical to have a safer profile with less CRS and ICANS [events]. The [costimulatory] domain is different, it’s 4-1BB, that leads to less of a peak of cells, but more persistence of the cells; we hope that the persistence will translate eventually into more durable responses and less need for transplantation as subsequent therapy. In the FELIX trial, we split the dose based on tumor burden, which is the only trial where such a thing [was done]. [This is] in contrast with other [approved] CAR T- cell therapies, where we give only 1 infusion. By splitting [doses], we were able to deliver a tailored treatment based on tumor burden and as such, a safer and effective therapy.

How will that translate into [data and practice] later on? I want to see a plateau. I want to have patients who receive CAR T-cell therapy [and] remain in remission without relapses. I want to see CAR T-cell therapy being frontline therapy on [its] own [with patients] not needing subsequent transplantation. What I’ve seen so far in the FELIX trial [is] that we have a plateau. We know that the follow-up is still short, but we’re seeing a plateau in patients who responded who had CAR T persistence at 6 months; they do not seem to have an event and that is a major advantage.

References

FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. November 8, 2024. Accessed November 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute

Aucatzyl. Prescribing information. Autolus Inc; 2024. Accessed November 22, 2024. https://www.fda.gov/media/183463/download?attachmen