Obe-Cel Demonstrates Durable, Safe Responses in Relapsed/Refractory B-ALL

With a median time of 21 days from cell collection to infusion, as well as low rates of high-grade cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) observed in the phase 2 FELIX trial (NCT04404660), the CD19-directed CAR T-cell therapy obecabtagene autoleucel (obe-cel; AUTO1) could represent a novel treatment option for adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), according to Claire Roddie, MD.

Data from the trial presented at the 2023 ASCO Annual Meeting showed that among patients with relapsed/refractory B-ALL infused with obe-cel (n = 94) experienced a complete response (CR) rate of 53.4% and a CR with incomplete count recovery (CRi) rate of 21.3%, translating to a CR/CRi rate of 76% (95% CI, 66%-84%; P < .0001). Additionally, 97% of evaluable responders were minimal residual disease (MRD) negative at a 10-4 sensitivity. At a median follow-up of 9.5 months, 61% of responders remained in remission.

Any-grade CRS was reported in 75.5% of patients; however, 3.2% of patients experienced grade 3 or higher CRS. Additionally, 25.5% of patients experienced any-grade ICANS, and 7.4% had grade 3 or higher ICANS.

“We've been testing this novel CAR [T-cell therapy] in adult ALL to see whether we can make this therapy more effective and more tolerable, and improve the persistence of these CAR T cells in the peripheral blood in the patients for long periods of time,” Roddie said.

In an interview with OncLive^®, Roddie, a consultant hematologist at the University College London Hospital, expanded on the rationale for investigating obe-cel in patients with relapsed/refractory B-ALL, detailed the key topline findings from FELIX, and provided insights on unmet needs that remain for this patient population.

OncLive: What was the rationale of launching the FELIX trial of obe-cel in patients with relapsed/refractory B-ALL?

Roddie: Relapsed/refractory ALL is a very challenging clinical condition. As it stands, there haven't been any sort of curative therapies in this setting. CD19 CAR T-cell therapy has been transformative in the leukemia setting, particularly in pediatrics. In adults, it's been more challenging. Part of the reason for that is CD19-[directed] CAR T-cell therapies have been conventionally and traditionally associated with high levels of immune toxicity, which has meant it's been more difficult to give to frailer and older patients. That is where an obe-cel comes in.

What differentiates obe-cel from other CD19-directed CAR T-cell therapies?

Obe-cel has a unique CD19 CAR T-cell binder. It is unique because it binds to CD19 on the leukemia cell in a different way [compared with] all the other binders that are being used for CAR T-cell [therapies in] clinical trials, meaning it comes off target more quickly. That equates to the CAR T cells secreting less cytokines per interaction with targets than a conventional CAR T cell, and that can lead to less in the way of immunotoxicity with this particular construct.

Because it's coming off target more quickly than other CAR T cells, it means that the CAR T cell isn't getting exhausted, and as a consequence of that, it means that those CAR T cells can exist in the bloodstream and persist in the patient for long periods of time.

Could you highlight the methodologies used in FELIX? What patients were evaluated?

The FELIX study has recruited patients with macroscopic ALL, meaning more than 5% blasts in the bone marrow. These were patients who relapsed after other therapies. To date, we've managed to recruit and infuse 94 patients on this study with obe-cel. Obe-cel is an autologous CAR, meaning it is made from patient T cells, and it's delivered in a conventional way following lymphodepleting chemotherapy with fludarabine and cyclophosphamide.

We have a couple of safety features that we built into this study. We orchestrated a split-dose administration of the CAR with 1 dose on day 1 and a subsequent dose on day 10. The purpose of that was to allow for the second dose to be avoided or delayed if there was immune toxicity. The second feature was that we titrated the initial dose of the CAR T cells to the burden of leukemia disease in the bone marrow. If a patient had a lot of disease, they got a smaller dose of CAR T cells up-front, and if they had a lesser amount of disease, they got more CAR T cells up-front.

We've infused 94 patients and so far, 94% of the infused patients have received both of the doses of the CAR T cells both on day 1 and day 10 to a total of 410 x 10⁶ CAR T cells. The median duration of follow up we've got on that patient population is 9.5 months.

In this patient cohort, we had relapsed patients. We know that this is a difficult patient population to treat. We had a particularly high disease burden cohort, with lots of patients with extensive marrow infiltration, circulating blasts in the peripheral blood, and [19.1%] of our patients had extramedullary disease. This confers a particularly poor prognosis in ALL. We recognized that this patient cohort is a very challenging cohort [to treat].

With that in mind, we were heartened to see some of the early results on this study because we're making autologous CAR T cells using the patients’ cells, and we were able to have products released for 94% of those patients who [underwent] leukapheresis. This is a good outcome considering that you have got challenging starting materials with a lot of leukemia on board for many of these patients.

The [median] vein to release time for [obe-cel] was 21 days. It's important because these were patients with rapidly progressive disease who can't tolerate long periods of time without therapy. Therefore, getting that product to that patient quickly is key.

What efficacy results were shared at the 2023 ASCO Annual Meeting on the use of obe-cel in patients with B-ALL?

In terms of responses, thinking about this patient population, we saw good responses here. Seventy-six percent of our patients achieved CR/CRi. When you deep dive into that, you can see that the majority of those responses were deep and profound, with 97% achieving MRD negativity. Early responses at day 28 were excellent.

If you look at those patients and follow them up, 61% of those responses were ongoing at a median of 9.5 months. That's heartening to us. It reminds us of the [previous] phase 1 ALLCAR19 trial [NCT02935257] we did [with obe-cel], and we're seeing a similar profile emerging.

What was found regarding safety and pharmacokinetics?

The most important thing to emphasize is the toxicity profile. These were frailer, older patients, and they may not tolerate the immune toxicities associated with conventional CAR T-cell therapy. Here with this novel CD19 binder, it has a different cytokine secretion profile. As a consequence, we saw minimal CRS in this patient group. Only [3.2%] experienced grade 3 [or higher] CRS, and only [7.4%] with grade 3 [or higher] ICANS. This was limited toxicity in what would potentially be a high-risk patient group.

We saw beautiful, early expansion within that first 28 days, getting the CAR T cells to over 100,000 copies/µg of genomic DNA. That's an extremely impressive early-level expansion, and it's not seen to this extent with other products. What's even more encouraging to us is the fact that this plateaus over time. Looking at 6 months, 9 months, and 12 months after the infusion for the patients that have reached those time points, we see that the level of CAR T cells in the blood has stabilized out at about 1,000 copies/µg of genomic DNA.

What are the next steps for investigating obe-cel in patients with relapsed/refractory B-ALL?

These outcomes hearten us to think that what we're seeing in the phase 2 is going to replicate the impactful results we saw in the phase 1 [study]. The CAR that we're giving is effective, and it's safe. It seems to have that nice persistence profile that we saw on the phase 1 study. Moreover, it's deliverable. The manufacture process is robust, it's reproducible, and even in patients with lots of disease, you're able to get a CAR T-cell product.

It is still early, but we are going to follow these patients up. We will probably have updated data come at the end of this year, potentially at the 2023 ASH Annual Meeting, and beyond at the 2024 ASCO Annual Meeting. Hopefully, we'll begin to talk a bit about the event-free survival, overall survival, and other long-term measures of good outcome for patients.

What unmet needs still remain in this space to be addressed?

One aspect that is important is the feasibility of delivery of CAR T cells to patients who are in frank relapse. It is such an aggressive condition and a debilitating condition. Whenever a patient presents with active, proliferative, high-burden disease, they are really debilitated, and their performance status falls off. It's difficult to collect T cells and manufacture a product from them. It's difficult to administer the product to the patients because they are sometimes so ill and have lots of complications with infection.

Therefore, the speedier the CAR T cell manufacture process, the more optimized the apheresis process is to get that product to the patient. The shorter that we can make that period from the point of diagnosis of relapse to the point of administration of CAR T cells is going to be key because that will improve our intention to treat.

Even on the FELIX study, there were a few patients who didn't get to CAR T-cell infusion. Predominantly, this was because of progressive disease and death from progressive disease; by the time these patients come to CAR T, they've exhausted all of their conventional treatment options. [The disease] can sometimes be very hard to control. That is a big priority for the field right now, trying to streamline, shrink, and optimize the manufacture and delivery process so that patients can reach treatment as swiftly as possible.

Reference

Roddie C, Sandhou 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.