Phase 3 ZUMA-3 Study of Brexu-cel Elicits Survival Benefit in Relapsed/Refractory B-cell ALL
Regardless of prior therapies, brexucabtagene autoleucel showed a survival benefit in patients with relapsed/refractory B-cell acute lymphoblastic leukemia, according to subgroup analyses of the phase 3 ZUMA-3 trial.
Bijal Shah, MD
Findings from subgroup analyses of the phase 3 ZUMA-3 trial (NCT02614066) revealed that treatment with brexucabtagene autoleucel (brexu-cel; Tecartus) generated a survival benefit in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), regardless of prior lines of treatment, exposure to blinatumomab (Blincyto), or exposure to allogeneic stem cell transplant (alloSCT).1
The data, which were presented during the 2023 Transplantation & Cellular Therapy Meetings, were similar in the set of patients with B-ALL treated in the phase 2 portion of ZUMA-3 (n = 55) and in a pooled analysis of phase 1 and 2 treated patients with B-ALL who received brexu-cel (n = 78).
“With longer follow-up, patients with brexu-cel appeared to be showing continued benefit. There are no new safety signals, and patient response and durability of response were largely preserved across these different subgroups,” lead study author Bijal D. Shah, MD, MS, an associate member in the Department of Malignant Hematology of Moffit Cancer Center, said in a live presentation during the meeting. “There is an intriguing possibility of improved overall survival [OS] in the group of patients who were receiving CAR T early, meaning after 1 line of therapy […] this had led to the development of 2 phase 2 studies that will hopefully open soon.”
Following salvage therapies, OS outcomes in patients with relapsed/refractory B-ALL remain poor, despite the addition of blinatumomab. Brexu-cel is an autologous CD19-directed CAR T-cell therapy that is indicated for the treatment of adult patients with relapsed/refractory B-ALL, as well as adults with relapsed/refractory mantle cell lymphoma. The B-ALL indication is based off findings from the pivotal phase 2 portion of the ZUMA-3 trial. Here, the overall complete response (CR) rate was 72% (95% CI, 57%-82%) and the median OS was 18.2 months.2
At the meeting, Shah reported on the safety and efficacy outcomes of prior treatment subgroups after more than 2 years of follow-up in the phase 2 treated patients and in a pooled analysis of phase 1 and 2 patients who received brexu-cel at 1 x 106 CAR T cells/kg.
In ZUMA-3, patients underwent leukapheresis before getting cerebrospinal fluid prophylaxis and bridging chemotherapy, followed by conditioning chemotherapy with fludarabine at 25 mg/m2 intravenously (IV) on days -4, -3, and -2, and cyclophosphamide at 900 mg/m2 IV on day -2. Brexu-cel was administered next at 1 x 106 CD19-targeted CAR T cells/kg on day 0. Patients underwent a posttreatment assessment period and a long-term follow-up period.
To be eligible for enrollment, patients with relapsed/refractory B-ALL had to be at least 18 years of age and have bone marrow blasts greater than 5%. They could have received prior blinatumomab and/or prior alloSCT.
The primary end point was overall CR rate (CR plus CR with incomplete count recover [CRi]) by central assessment, and key secondary end points were duration of response (DOR), relapse-free survival (RFS), rate of subsequent transplant, OS, safety, and CAR T-cell levels in the blood.
Previously reported results showed that the overall CR/CRi rate was 71%, and the CR rate was 56%. The median relapse-free survival (RFS) censored at subsequent ASCT was 11.6 (95% CI, 2.7-15.5) and the median OS was 25.4 months (18.2-not estimable [NE]).2
The post-hoc analyses presented at the TCT meeting from ZUMA-3 subgroups included those from the phase 2 portion (n = 55) and a newly conducted pooled analysis of phase 1/2 patients treated with the pivotal brexu-cel dose (n = 78). Investigators evaluated efficacy and safety by the number of prior lines of therapy (1 and ≥2), prior blinatumomab (yes or no), prior alloSCT (yes or no), and subsequent alloSCT (yes or no).
Subsequent alloSCT was permitted but not protocol defined. The data cutoff date was July 23, 2021. The median follow-up was 26.8 months (range, 20.7-32.6) for the phase 2 treated patients and 29.7 months (range, 20.7-58.3) for the pooled analysis patients.
The number of prior therapies received was 2 and 47% of patients received 3 or more prior treatments in the phase 2 portion of the research.
Regarding baseline characteristics in the phase 2 treated patients, 18% of patients had 1 prior line treatment and 82% had at least 2. Moreover, 45% of patients had received prior blinatumomab; of this group, 48% received blinatumomab as their last therapy before receiving brexu-cel. The median time from blinatumomab to brexu-cel in these patients was 4.9 months (range, 2.5-45.7). Furthermore, 42% of patients underwent prior alloSCT, 22% of which had transplant as their last treatment before receiving brexu-cel. The median time from transplant to brexu-cel in these patients was 11.7 months (range, 9.1-45.3.).
When evaluating activity by 1 or at least 2 lines of prior therapy, the overall CR rates were 90% and 67%, respectively, and the blast-free hypoplastic or aplastic bone marrow (BFBM) rates were 10% and 7%, respectively. Twenty percent of patients who had received 2 or more prior treatments did not respond to brexu-cel. All patients who responded to brexu-cel had at least 1 prior treatment. The DOR in patients who had 1 and at least 2 prior lines of therapy were 4.7 months (95% CI, 1.8-NE) and 14.6 months (9.4-NE), respectively. Additionally, the median RFS was 5.6 months (95% CI, 0.0-NE) and 11.0 months (95% CI, 1.8-15.5), respectively; the median OS was not reached ([NR] 95% CI, 2.1-NE) and 25.4 months (95% CI, 14.2-NE), respectively.
“Looking at duration of remission in the phase 2 patients, you can see that there appears to be a lower median DOR in those who come in with less heavily pretreated disease,” Shah explained in his presentation. “On closer inspection though, it is really driven by 2 events total in the 9 [who responded], and it is more a reflection on small sample size.”
In patients who received prior blinatumomab, the overall CR rate was 60% vs 80% for those who did not; the BFBM rates were 8% and 7%, respectively. Twenty-four percent of patients who had prior blinatumomab did not respond to brexu-cel vs 10% of those who did not previously receive the agent. The median DOR, RFS, and OS in patients who had received blinatumomab was 19.1 months (95% CI, 1.3-NE), 11.6 months (95% CI, 0.0-25.4), and 14.2 months (3.2-26.0), respectively; these outcomes were 10.3 months (95% CI, 5.2-NE), 11.7 months (95% CI, 2.8-22.1), and NR (18.6-NE), respectively, in those who did not have prior blinatumomab.
“For those who respond to CAR T, there is no detriment on DOR,” Shah noted. “If anything, there is a slightly higher DOR in the blinatumomab-exposed group vs the blinatumomab-naïve group. In contrast, the survival rate appears to be lower in the blinatumomab-exposed group. Looking closely at the curves, most of the events accumulate over the first 3 months—a reflection of the fact that the blinatumomab-exposed group was more heavily pretreated, with fewer salvage options at the time they progress.”
Finally, in patients who previously underwent alloSCT, the overall CR rate was 70% vs 72% in those who did not receive transplant; the BFBM rates were 9% and 6%, respectively; 17% and 16% of patients, respectively, did not respond to brexu-cel. The median DOR was 14.6 months (95% CI, 8.7-23.6) in those who had prior alloSCT and was NR (95% CI, 4.7-NE) in those who did not. The median RFS was 11.7 months (95% CI, 0.0-20.5) and 6.1 months (95% CI, 2.2-NE) in the alloSCT and no-transplant groups, respectively; the median OS was 25.4 month (95% CI, 14.2-NE) and NR (95% CI, 9.0-NE), respectively.
“None of the patients who had a prior alloSCT who responded went on to a second transplant,” Shah said, adding that about 43.5% of the 23 patients who were transplant naïve went to transplant following brexu-cel.
When evaluating the prior lines of therapy, prior blinatumomab use, and prior alloSCT in the pooled phase 1 and 2 treated patients (n = 78), Shah noted that the datasets were almost identical to the phase 2 portion.
In patients who had previously received 1 or at least 2 lines of therapy, the overall CR rate was 87% and 70%, respectively, and the BFBM rate was 7% and 8%, respectively. Seven percent of patients who had received 1 prior treatment did not respond to brexu-cel; 17% of patients who had at least 2 prior treatments did not respond to the CAR T-cell therapy. The DOR in patients who had 1 or at least 2 prior lines of therapy were 4.9 months (95% CI, 1.8-NE) and 20.0 months (10.3-NE), respectively. The median RFS was 6.1 months (95% CI, 2.8-NE) and 11.7 months (95% CI, 2.7-20.5), respectively; and the median OS was not reached (95% CI, 7.6-NE) and 25.4 months (95% CI, 15.9-NE), respectively.
Regarding prior blinatumomab use, the overall CR rate was 63% in patients who previously received the agent vs 83% for those who did not; the BFBM rates were 11% and 5%, respectively. Twenty-one percent of patients who had prior blinatumomab did not respond to brexu-cel vs 10% in those who did not. The median DOR, RFS, and OS in patients who had received prior blinatumomab was 14.6 months (95% CI, 9.6-NE), 7.3 months (95% CI, 0.0-15.5), and 15.9 months (8.3-25.4), respectively; these outcomes were 18.6 months (95% CI, 5.2-NE), 11.7 months (95% CI, 6.1-NE), and 47.0 (18.6-NE), respectively, in those who did not have prior blinatumomab.
In patients who previously underwent alloSCT, the overall CR rate was 76% vs 71% in those who did not receive transplant; the BFBM rates were 7% and 8%, respectively. Additionally, 14% and 16% of patients, respectively, did not respond to brexu-cel. The median DOR was 14.6 months (95% CI, 8.7-23.6) in those who had prior alloSCT and was NR (95% CI, 5.2-NE) in those who did not. The median RFS was 12.3 months (95% CI, 2.7-20.5) and 10.3 months (95% CI, 2.7-NE) in the alloSCT and no-transplant groups, respectively; the median OS was 25.4 months (95% CI, 14.2-NE) and 47.0 months (95% CI, 10.9-NE), respectively.
Regarding subsequent transplant outcomes, 11 of 55 treated patients—10 who had a CR/CR with incomplete platelet recovery, and 1 with blast-free hypoplastic or aplastic bone marrow— proceeded to subsequent alloSCT. The median OS was not reached in the patients with subsequent alloSCT and was 25.4 months in those without subsequent transplant at the time of the data cutoff.
However, Shah noted the caveat that the median time to transplant was approximately 100 days. “With that backdrop, you must be in remission, and be alive to get there. This comes back to the idea of landmark analyses—tough to do with a small sample size,” he said.
With respect to safety, incidences of grade 3 or higher cytokine release syndrome (CRS) and neurologic events were generally similar across the prior treatment subgroups. Grade 3 or higher CRS occurred in 1 patient who received 1 prior therapy, 12 who received at least 2 prior therapies, 6 who received prior blinatumomab and 7 who did not, and 4 who underwent prior alloSCT and 9 who did not have transplant.
Grade 3 or higher neurologic events occurred in 3 patients who received 1 prior treatment and in 11 who received at least 2 prior treatments, 5 patients who had prior blinatumomab and 9 who did not, and 6 who had prior alloSCT and 8 who did not.
Shah also noted that although the median peak CAR T-cell expansion appeared to trend lower at approximately 3-fold in those who were previously treated with blinatumomab compared with those who did not, they were not statistically significant differences regardless of whether the agent was the last prior treatment before brexu-cel was infused. This is also potentially due to the small sample size, Shah said.
“This is going to continue to generate future investigation,” Shah concluded.
Editor’s Note: Dr Shah disclosed honoraria from Pharmacyclics, Janssen, Acrotech, Spectrum, BeiGene, and Gilead Sciences; consultancy or advisory for Adaptive Biotechnologies, Bristol Myers Squibb/Celgene, Novartis, Pfizer, Amgen, Precision Biosciences, and Kite; research funding from Incyte, Jazz Pharmaceuticals, Gilead Sciences, and Kite; and travel support from Celgene, Novartis, Pfizer, Janssen, Seattle Genetics, Stemline Therapeutics, and Kite.
