Obe-Cel Approval Expands CAR T-Cell Therapy Options in Relapsed/Refractory ALL

With the November 2024 FDA approval of obecabtagene autoleucel (obe-cel; Aucatzyl) adding to the 2 other FDA-approved chimeric antigen receptor (CAR) T-cell agents in relapsed/refractory acute lymphoblastic leukemia (ALL), investigators are excited about the agent’s potential to offer a more manageable safety profile with similar efficacy to previously available options.^1-3 However, considerations regarding toxicity management, supportive care, and CAR T-cell access must be weighed appropriately when selecting a CAR T-cell agent for patients with relapsed/refractory ALL.

“The [FDA]-approved CAR T-cell therapies in their current iteration are autologous CAR T-cell products,” Lori Muffly, MD, explained. “In the case of ALL, the currently approved [agents] target CD19, which is expressed in nearly all of B-cell ALL, and there’s also a costimulatory domain that allows these CAR T cells to rapidly proliferate and expand. Tisagenlecleucel [tisa-cel; Kymriah] and brexucabtagene autoleucel [brexu-cel; Tecartus] have the same binder to CD19, whereas obe-cel has a different, more short-acting binder. Tisa-cel and obe-cel are also both 4-1BB costimulatory whereas brexu-cel is CD28 [costimulatory]. That’s important because the functional dynamics of CAR T-cell expansion and persistence are theoretically different based on costimulatory domain, with 4-1BB CARs being slower to peak and perhaps longer lasting than CD22, which tends to peak very quickly and expand very rapidly but then not persist quite as long.”

During an OncLive Peer Exchange, investigators in the field of hematologic oncology offered their perspective on the current and potential future standing of CAR T-cell therapies in the relapsed/refractory ALL treatment landscape. The panelists discussed updated data from the phase 1/2 ZUMA-3 trial (NCT02614066) and findings from the ongoing phase 1b/2 FELIX study (NCT04404660). They also highlighted CAR T adverse effect (AE) and supportive care considerations and examined CAR T-cell therapy access and availability issues.

Brexu-Cel Demonstrates Long-Term Survival Benefit, Obe-Cel Offers Glimpse Into the Future

During the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, investigators presented long-term survival outcomes from ZUMA-3, which supported the 2021 FDA approval of brexu-cel in relapsed/refractory B-cell precursor ALL. At the time of the approval, efficacy-evaluable patients (n = 54) achieved a complete response (CR) within 3 months at a rate of 52% (95% CI, 38%-66%), and the median duration of CR was not reached. CR/CR with incomplete count recovery (CRi) rate was the primary end point of the study; overall survival (OS) was a key secondary end point.^2,4

At a median follow-up for OS of 53.6 months (95% CI, 44.7-82.3), the median OS among all patients who received brexu-cel in phases 1 and 2 (n = 78) was 25.6 months (95% CI, 16.2-60.4). The 48-month OS rate among these patients was 40% (95% CI, 28%-52%).⁴

Notably, patients who received brexu-cel during phases 1 and 2 with a CR/CRi per independent review assessment (n = 57) achieved a median OS of 47.0 months (95% CI, 23.2-not estimable [NE]). Within this subgroup, patients who received no subsequent allogeneic stem cell transplantation (SCT; n = 43) achieved a median OS of 60.4 months (95% CI, 23.2-NE) and those who did receive subsequent allogeneic SCT experienced a median OS of 36.3 months (95% CI, 10.2-NE).

“It’s reassuring that we’re seeing a substantial [portion of] patients [who] are able to maintain remission beyond the 4-year mark,” Jae H. Park, MD, said.“Hopefully we will [perform] a more detailed analysis [about] the role of a transplant. As a field, [we need] better answers as to [why] some patients are able to maintain long-term remission after CAR T-cell therapy without subsequent transplant. We don’t understand well who these patients are, which makes it challenging to make the decision of [whether] to perform a transplant when a patient has a relapse in month 1 or 3.”

Additional findings from the ZUMA-3 update demonstrated that patients who received prior blinatumomab (Blincyto; n = 38) experienced a median OS of 15.9 months (95% CI, 8.3-26.0) compared with 60.4 months (95% CI, 18.6-NE) among patients who did not receive prior treatment with blinatumomab (n = 40). Patients who did (n = 17) and did not (n = 61) receive prior inotuzumab ozogamicin (Besponsa) experienced a median OS of 8.8 months (95% CI, 2.2-34.1) and 38.9 months (95% CI, 18.6-NE), respectively.

“Most of the patients I see have been exposed to blinatumomab in my region of the country; almost every [patient in this setting] receives blinatumomab at some point,” Muffly noted. “I typically use brexu-cel as the second of these therapeutic options. I also [prefer] brexu-cel for patients who have a history of central nervous system [CNS] involvement, because CAR T-cell therapy penetrates the CNS. One of the [remaining] questions is when to not use CAR T-cell therapy. Data are now accumulating in the adult ALL setting—we haven’t had these therapies as long as the pediatricians have—but [in my opinion] it’s very difficult to give our current CAR T-cell therapies in patients with a very high disease burden.”

Obe-cel was evaluated for the treatment of adult patients with relapsed/refractory B-cell ALL in FELIX. Obe-cel is a novel anti-CD19 CAR T-cell agent with a fast off-rate that has shown the potential to improve T-cell persistence and lessen immune-mediated toxicities compared with currently available CAR T-cell therapies. The primary end point of the study is CR/CRi rate per independent response review committee; secondary end points include OS, event-free survival (EFS), duration of response, and safety.^5,6

At a median follow-up of 21.5 months (range, 8.6-41.4), findings from FELIX presented during the 2024 ASCO Annual Meeting and during the 2024 European Hematology Association Congress demonstrated that the CR/CRi rate among efficacy-evaluable patients (n = 99) was 78%. Among these patients, 40% were in ongoing remission without subsequent SCT or another therapy and 18% were negative for minimal residual disease (MRD) following SCT.

In the overall treated population (n = 127), the median EFS without censoring for SCT was 9.0 months (95% CI, 6.57-14.32), with a 12-month EFS rate of 44.0% (95% CI, 35.2%-52.5%). When censoring for SCT, these figures were 11.9 months (95% CI, 7.98-22.11) and 49.5% (95% CI, 39.6%-58.6%), respectively. All 18 patients who had SCT in remission were MRD negative, and 55.6% of these patients displayed ongoing CAR T persistence before SCT.

The median OS without censoring for SCT and with censoring for SCT was 15.6 months (95% CI, 12.91-NE) and 23.8 months (95% CI, 12.91-NE), respectively. The respective 12-month OS rates were 61.1% (95% CI, 52.0%-69.0%) and 63.7% (95% CI, 53.7%-72.0%).

“My conclusion [from this update] was that some responders can have a long-term remission without transplantation,” Elias Jabbour, MD, who presented the findings during the 2024 ASCO Annual Meeting, commented.

Additional findings showed that ongoing CAR T persistence correlated with long-term EFS in FELIX (HR, 2.7; 95% CI, 1.4-5.3). Patients who received obe-cel and had ongoing CAR T persistence at month 6 (n = 42) experienced a median EFS that was NE, with a 12-month EFS rate of 87.3% (95% CI, 72.0%-94.5%). Comparatively, patients who had a loss of persistence by month 6 (n = 18) displayed a median EFS of 15.1 months (95% CI, 8.11-NE), with a 12-month EFS rate of 59.3% (95% CI, 33.0%-78.1%).

“There was an interesting relationship with regard to CAR T-cell persistence and long-term EFS,” Gregory W. Roloff, MD, said. “There was a clear stratification of outcomes along the lines of loss of CAR T-[cell] persistence in patients at 6 months, or those who had ongoing persistence, and their ultimate outcomes.”

Prior safety data from FELIX showed that obe-cel therapy was generally well tolerated; any-grade cytokine-release syndrome (CRS) was reported in 69% of patients, with 2% experiencing grade 3 or higher CRS. Any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) was present in 23% of patients, with 7% experiencing grade 3 or higher ICANS. Notably, no grade 3 or higher CRS or ICANS were reported in patients with less than 5% bone marrow blasts at lymphodepletion.⁶

“[The safety profile] is the most striking difference with [obe-cel] vs brexu-cel,” Park said. “Why not use a safer product with the same efficacy? You could probably make that argument, [and] for high-burden patients, it’s an easy, no-brainer switch [from brexu-cel to obe-cel].”

Data from FELIX supported the November 2024 FDA approval of obe-cel for the treatment of adult patients with relapsed/refractory B-cell precursor ALL.3 FDA approval “It’s reasonable for all of us to [consider] reaching for [obe-cel] as the first CAR T-cell therapy that patients receive,” Roloff added.

Navigating CAR T–Related AE Management and Supportive Care

The panelists transitioned their conversation to AE management and supportive care considerations when using CAR T-cell therapies for the treatment of patients with relapsed/refractory ALL. In the July 2024 edition of their Clinical Practice Guidelines in Oncology for ALL, the National Comprehensive Cancer Network (NCCN) noted that severe CRS and/or neurologic toxicities may accompany CAR T-cell therapy and that these events should be managed according to the manufacturers’ Risk Evaluation and Mitigation Strategies program. The NCCN recommends tocilizumab (Actemra) to mitigate CRS and prefers the use of steroids for the treatment of tocilizumab-refractory CRS and/or other neurologic toxicities.⁷

“There’s variability in the way that we manage CRS and ICANS,” Roloff explained. “I will typically give a single dose of tocilizumab first, and if on the next vital check or next patient assessment the patient seems like they need continued therapy, I’m starting steroids with that second dose of tocilizumab.”

“Fever is usually the first sign [of CRS or ICANS],” Park added. “Brexu-cel is mostly performed as an inpatient [therapy], but if it were to be outpatient, we ask patients to measure their temperature routinely. If patients get that first fever, we usually give tocilizumab and steroids together if the patient is receiving brexu-cel.”

The NCCN guidelines also recommend that antiseizure medications be considered for prophylactic use during the first month after CAR T-cell therapy infusion. They also noted that growth factor therapy, prophylactic antimicrobial therapy, and intravenous immunoglobulin can be considered to combat the severe neutropenia, T-cell depletion, and B-cell aplasia that can occur with CAR T-cell therapy in ALL.

Muffly noted that in her practice she continues treatment with acyclovir (Sitavig) during prophylaxis as would be done during a bone marrow transplant. She also advocated for prophylaxis for continued Pneumocystis jirovecii pneumonia and antibiotic prophylaxis for patients with neutropenia.

“We also have to keep in mind that every patient is not able to stay at the center [for toxicity monitoring],” Park said. “As patients are [return for treatment], I’ve struggled with [factors such as] the frequency [with which] I’m going to tell them to check IgG levels, what to do with [this information], and what to do [in terms of] growth factors. These are important factors because they may lead to late toxicities and late complications. Short-term toxicities [may be improved with obe-cel vs brexu-cel] because there is less CRS and ICANS. But as these T cells persist longer, we may see more B-cell aplasia and cytopenia. We don’t know [for sure], but we have to keep that in mind and keep monitoring these patients.”

Taking Steps to Address CAR T Access and Availability Issues

The panelists concluded their talk by discussing barriers to CAR T-cell therapy access. CAR T-cell agents often entail a long manufacturing period with a vein-to-vein time of several weeks and a high production cost that can limit their use in patients with disease that necessitates a faster response. Additionally, CAR T-cell therapies usually need to be administered in an inpatient setting at a large academic medical center, creating geographic, financial, and referral barriers for patients.⁸

“One of the main logistical limitations [of CAR T-cell therapies] is time,” Evandro D. Bezerra, MD, said. “Referral to our CAR T doctor and insurance approval is usually at least a week, then with apheresis and manufacturing it can be 3 to 4 weeks from the diagnosis of relapsed [disease] to the ability to start lymphodepletion. Having the disease under control during that time so that the patient can receive CAR T-cell therapy is a major challenge.”

Most young adult patients with ALL are not receiving their primary treatment for the disease at centers that can deliver CAR T-cell treatments, according to Muffly. Thus, a multipronged approach must be employed to educate patients and offer them solutions to access CAR T-cell therapies, she said. Roloff added that access to lodging for patients receiving CAR T-cell therapies can be pivotal to allow for closer monitoring. Muffly also highlighted that the addition of obe-cel to the CAR T treatment arsenal could eventually offer patients a more feasible outpatient option due to its lessened toxicity profile compared with brexu-cel.

“An easy thought would be, ‘Why don’t we set up CAR T centers all over the place?’” Muffly said. “[But data have shown] that if you treat [patients with] ALL in less experienced centers, they don’t do as well. The solution is not to just create more CAR T-cell centers at random or try to cover the scope of the country [with them]. These are extremely specialized therapies, and this patient population is so specialized. Some of that [expansion] is good, but that as a broadscale answer is not a good thing for patients with ALL.”

References

1. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA. Updated September 7, 2017. Accessed October 11, 2024. bit.ly/3U9YSvB
2. FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. October 1, 2021. Accessed October 11, 2024. bit.ly/4eWFSIW
3. FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. November 8, 2024. Accessed November 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute
4. Oluwole OO, Ghobadi A, Cassaday RD, et al. Long-term survival outcomes of patients (pts) with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) treated with brexucabtagene autoleucel (brexu-cel) in ZUMA-3. J Clin Oncol. 2024;42(suppl 16):6531. doi:10.1200/JCO.2024.42.16_suppl.6531
5. Jabbour E, Tholouli E, Sandhu KS, et al. Obecabtagene autoleucel (obe-cel, AUTO1) in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL): overall survival (OS), event-free survival (EFS) and the potential impact of chimeric antigen receptor (CAR)-T cell persistency and consolidative stem cell transplantation (SCT) in the open-label, single-arm FELIX phase Ib/II study. J Clin Oncol. 2024;42(suppl 16):6504. doi:10.1200/JCO.2024.42.16_suppl.6504
6. Autolus Therapeutics. Developing next generation programmed T cell therapies. September 2024. Accessed October 11, 2024. bit.ly/3XXCiaw
7. NCCN. Clinical Practice Guidelines in Oncology. Acute lymphoblastic leukemia, version 2.2024. Accessed October 11, 2024. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf
8. Gajra A, Zalenski A, Sannareddy A, Jeune-Smith Y, Kapinos K, Kansagra A. Barriers to chimeric antigen receptor T-cell (CAR-T) therapies in clinical practice. Pharmaceut Med. 2022;36(3):163-171. doi:10.1007/s40290-022-00428-w