Brexu-Cel Delivers Prolonged OS Benefit in Relapsed/Refractory MCL

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Andre H. Goy, MD, discusses how the ZUMA-18 trial data support the benefit of earlier-line use of brexucabtagene autoleucel in mantle cell lymphoma.

Andre Henri Goy, MD

Andre Henri Goy, MD

Brexucabtagene autoleucel (brexu-cel; Tecartus) continued to produce long-term survival benefits and an acceptable safety profile in patients with relapsed/refractory mantle cell lymphoma (MCL), including in heavily pretreated patient populations, according to Andre H. Goy, MD.

The phase 2 ZUMA-2 trial (NCT02601313) evaluated brexu-cel in patients with relapsed/refractory MCL (n = 68). At a median follow-up of 47.5 months (range, 37.9-68.3), brexu-cel elicited a median overall survival (OS) of 46.4 months (95% CI, 24.9-58.7) in the overall patient population.

The expanded-access ZUMA-18 trial (NCT04162756) explored brexu-cel in 2 patient cohorts. Cohort 1 consisted of patients with relapsed/refractory MCL who required access to brexu-cel before it was commercially available. Cohort 2 included patients with relapsed/refractory disease whose manufactured CAR T-cell product did not meet commercial release specifications. Findings from the primary analysis demonstrated that the median OS was not reached (95% CI, 10.4 months–not evaluable).

“[Brexu-cel] is a game changer in the context of MCL, and [these data] support the use of this [therapy] in the relapsed/refractory setting for patients who have no [other] options,” Goy said in an interview with OncLive® during the 2023 ASH Annual Meeting.

In the interview, Goy discussed key findings from ZUMA-18, updated OS data from ZUMA-2, and how the ZUMA-18 data point toward the increased benefit of using CAR T-cell therapy earlier in the MCL treatment course.

Goy is vice president and physician in chief of Oncology, as well as a senior administrator for the Care Transformation Service and a chairman and chief physician officer at John Theurer Cancer Center in Hackensack, New Jersey. He is also the Lydia Pfund Chair for Lymphoma and the academic chairman of Oncology at the Hackensack Meridian School of Medicine in New Jersey and a professor of medicine at Georgetown University in Washington, DC.

OncLive: What were the rationale for and design of the ZUMA-18 trial?

Goy: Patients with MCL [can] respond to induction therapy, but they all have a pattern of relapse, regardless of the situation. The standard of care has become BTK inhibitors, and once patients had progressed on chemotherapy, immunotherapy, anti-CD20 agents, and BTK inhibitors, the median OS, depending on the [treatment], was [approximately] 3 to 12 months. There was an unmet need there.

CAR T-cell therapy, [specifically] brexu-cel, an anti-CD19 agent, has been a game changer. [Brexu-cel] was FDA approved [for patients with relapsed/refractory MCL] based on the ZUMA-2 trial data, which showed an overall response rate [ORR] of 87%, a complete response [CR] rate of 62%, and impressive treatment durability in that setting. However, the trial was closed in early 2019.

To give patients expanded access to [brexu-cel], ZUMA-18 was born for the population of patients waiting [for brexu-cel] to become commercially available. By nature, many of these patients had not qualified for ZUMA-2 [because they] were sicker, older, and more difficult to treat. [ZUMA-18] was designed the same way [as ZUMA-2]. [Patients needed to have progressed on] at least 1 prior therapy—[either] an anti-CD20 agent, chemotherapy, or a BTK inhibitor. In reality, [most of the ZUMA-18 patient population had] received many more therapies than this. Allogeneic [stem cell] transplant and central nervous system involvement [were not allowed]. Bridging therapy with steroids or a BTK inhibitor was allowed [similar] to ZUMA-2; However, contrary to ZUMA-2, [patients could receive] chemotherapy or cell therapy to try to slow the disease in patients with more aggressive presentation. Patients underwent standard lymphodepletion, [then received] brexu-cel and were monitored with first imaging on day 28.

ZUMA-18 had 2 cohorts. Cohort 1 [gave access to brexu-cel for patients who were] waiting until it became commercially available. Cohort 2 [enrolled] patients whose manufactured product did not meet [FDA standards for CAR T-cell therapy], which is viability of [at least] 80%. The [primary] end points were safety, investigator-defined CR and partial response, and survival.

What efficacy findings arose from the primary analysis of ZUMA-18?

Twenty-three patients [received brexu-cel] from July 2019 to July 2020. These patients were older, with a median age of 69.0 years vs 65 years [in ZUMA-2], and they had a higher ECOG performance status. Thirty-five percent of patients had an ECOG performance status of 1 in ZUMA-2 vs [57%] of those in ZUMA-18. [Patients in ZUMA-18] were more heavily pretreated, with a median of 4 prior therapies [range, 1-10].

Overall, [the ZUMA-18] population was older, sicker, and more heavily pretreated [than that of ZUMA-2]. The responses were still impressive, with an ORR of 87%, a CR rate of 57%, and a median duration of response of 15.1 months. The median OS has not been reached at 3 years of follow-up. This is important.

What safety findings have been observed in ZUMA-18?

There were no new safety signals. Cytokine release syndrome [CRS], by [the time the ZUMA-18 trial was conducted], was managed much more preemptively [than it had been in the past]. We saw only 4% [rate] of grade 3 [or higher] CRS. We saw some neurotoxicity, but no grade 5 [events]. Nine patients died [including 5 due to adverse effects]; 1 patient [died from] multi-organ failure with candidemia, just after [presenting with] CRS and the beginning [stages of] neurotoxicity.

Interestingly, the median OS [was impressive] in a population that was heavily pretreated, would not have qualified for a clinical trial, and had no [other treatment] options. None of these patients could have received another transplant, which would have been the only way to save them, [because] they were too old, they didn’t have time to find a donor, and [the risk of] graft-versus-host disease [was too high]. Many of these patients also had comorbidities. Finding the median OS has not been reached in this population [at 3 years] was remarkable.

What updated data have been read out for the ZUMA-2 trial?

During this presentation [at the 2023 ASH Annual Meeting], we also [discussed] updated ZUMA-2 long-term follow-up data at 4 years. The median OS at 4 years of follow-up for patients who achieved a CR was 58.7 months. That’s remarkable [considering that ZUMA-2 enrolled patients who had progressed on] prior chemotherapy, an anti-CD20 agent, and a BTK inhibitor, [for whom the] median OS [used to be] measured in months [rather than years].

How might the outcomes of the ZUMA-2 and ZUMA-18 trials impact the clinical management of patients with relapsed/refractory MCL?

Doing expanded-access trials matters because these [trials often enroll patients who have no other treatment] options. Secondly, despite [the ZUMA-18 population] being sicker, older, and more heavily pretreated [compared with the ZUMA-2 population], we still saw high response rates. [Although] the CR rate was only 57%, that was because expanded access trial [enrollment criteria] are not as tight as [those of] a regular trial. Several patients did not have repeat bone marrow [biopsies], and [thus their responses] could not be considered CRs, so the CR rate was potentially higher [than reported]. Despite these situations, [brexu-cel might be] less durable [in this population than in the ZUMA-2 population], but the median OS was impressive compared with [the median OS that is possible with the other treatments] that would have been available in that setting. To [provide] the full benefit of CAR T-cell therapy, it is better to refer patients earlier.

References

Goy A, Jacobson CA, Flinn IW, et al. Outcomes of patients with relapsed/refractory mantle cell lymphoma (R/R MCL) treated with brexucabtagene autoleucel (brexu-cel) in ZUMA-2 and ZUMA-18, an expanded access study. Blood. 2023;142(suppl 1):106. doi:10.1182/blood-2023-174273

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