CAR T-cell therapy shows ‘high and durable response rates’ in adults with B-cell ALL
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Brexucabtagene autoleucel induced an overall remission rate of greater than 70% among adults with relapsed or refractory B-cell acute lymphoblastic leukemia who received a single infusion of the therapy, according to phase 2 study results.
Data from ZUMA-3 trial — presented during the virtual ASCO Annual Meeting — also showed that approximately a quarter of patients treated with the chimeric antigen receptor T-cell therapy experienced grade 3 or greater cytokine release syndrome or neurotoxicity.
The trial represented the largest-ever study of brexucabtagene autoleucel (Tecartus; Kite Pharma/Gilead) — formerly known as KTE-X19 — among adults with relapsed or refractory B-cell ALL, according to Bijal D. Shah, MD, associate professor in the department of malignant hematology at Moffitt Cancer Center.
“Approximately 40% to 50% of adults with B-cell ALL experience relapse after initial treatment,” Shah said during a presentation. “The 1-year overall survival rate for patients with relapsed or refractory B-cell ALL is 26% after first salvage therapy and decreases with subsequent lines of therapy.”
Novel targeted agents have led to improved initial complete response rates, but OS remains less than 8 months or longer depending on whether patients undergo subsequent allogeneic hematopoietic stem cell transplant, Shah said.
Brexucabtagene autoleucel, an autologous, gene-edited CAR T-cell therapy, targets the CD19 protein on the surface of cancer cells.
The therapy previously received FDA approval for the treatment of adults with relapsed or refractory mantle cell lymphoma. The manufacturer has submitted a supplemental biologics license application to the FDA for the B-cell ALL indication based on results of the phase 1 portion of the ZUMA-3 trial.
During ASCO, Shah and colleagues reported on 55 patients (median age, 40 years; range, 19-84; 60% men) in the phase 2 portion of the trial who received brexucabtagene autoleucel and were eligible for efficacy and safety analyses. Twenty-seven percent of patients had Philadelphia chromosome-positive disease.
Baseline patient characteristics indicated a heavily pretreated population. Patients received a median two (range, 1-8) previous lines of therapy, with nearly half (47%) having received three or more previous lines. Forty-two percent had a previous allogeneic HSCT, whereas 78% were relapsed or refractory to two or more previous lines of therapy.
Study participants underwent lymphodepletion chemotherapy with 900 mg/m2 cyclophosphamide and 25 mg/m2 fludarabine followed by a single IV infusion of 1 × 106 CAR-T cells/kg.
Overall complete remission rate — calculated as the rate of complete remission (CR) plus the rate of complete remission with incomplete hematologic recovery (CRi) — by central review served as the study’s primary endpoint. Secondary endpoints included minimal residual disease (MRD) status, duration of remission, RFS, OS and safety.
Median follow-up was 16.4 months (range, 10.3-22.1) as of the data cutoff date of Sept. 9, 2020.
The study met its primary endpoint, with an overall complete remission rate of 70.9%, including 31 patients (56.4%) with CR and eight patients (14.5%) with CRi. Four patients (7.3%) had blast-free hypoplastic or aplastic bone marrow after therapy.
The MRD-negativity rate was 97% among those who responded to therapy.
Median time to initial CR or CRi was 1.1 months (range, 0.85-2.99). Median duration of remission was 12.8 months, regardless of whether patients underwent subsequent allogeneic HSCT. Twelve patients who had CR or CRi after therapy and did not have a subsequent allogeneic HSCT remained in remission as of the data cutoff point.
Median RFS was 11.6 months (95% CI, 2.7-15.5) and median OS was 18.2 months (95% CI, 15.9-not estimable). Among those with CR or CRi, median RFS was 14.2 months and median OS was not reached.
Five patients died during the study, with two deaths — one of brain herniation and another of septic shock — related to the CAR T cells used in the study.
The most common grade 3 or greater treatment-related adverse events included anemia (49%) and pyrexia (36%).
CRS occurred in 89% of patients, with 24% having grade 3 or greater CRS. No deaths related to CRS occurred.
Median duration of CRS was 7.5 days, with a median time to onset of 5 days.
Neurotoxicity occurred in 60% of patients, with 25% of patients experiencing grade 3 or greater neurotoxicity.
Median duration of neurotoxic events was 7 days, with a median time to onset of 9 days.
"The safety profile remains consistent with what we saw in phase 1 of the ZUMA-3 study and the [adverse events] are largely reversible,” Shah said.
“A single infusion of KTE-X19 showed high and durable response rates in heavily pretreated adults with relapsed or refractory B-cell ALL, most of whom had high disease burden,” he added. “The efficacy, rapid manufacturing, and manageable safety support the promising potential of KTE-X19 to provide long-term clinical benefit in adults with relapsed or refractory B-cell ALL.”
Perspective
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Elizabeth L. Budde, MD, PhD
The final results of this study are eagerly awaited by those who treat ALL because it is the largest study of CAR T-cell therapy in adults with ALL. Tisagenlecleucel (Kymriah, Novartis) was approved for younger patients with ALL in 2017, and since that time we have been anticipating a CAR-T product being approved for adults with ALL.
This study showed very positive results and has met its primary endpoints of ORR and duration of response. Additionally, there are no surprising safety signals to be concerned about, and over the years clinicians have learned how to manage the toxicities related to CAR T-cell treatment.
The prognosis for adults with ALL is typically worse than that for pediatric patients. If brexucabtagene autoleucel were approved by the FDA, it would not just mean an additional treatment option but a hopeful treatment that can potentially lead to a cure.
Although it may be too early to call this a potentially curative therapy for some patients, it does appear from the current data that a subset of patients will benefit from a very durable remission. Hopefully, longer follow-up will show these patients experience lasting remissions, much as we have seen for a subset of patients who received CAR-T for lymphoma and younger patients with ALL.
Now we must await a final decision on the FDA application for this therapy and, hopefully, approval will come soon so we can offer it to our patients.
Perspective
Back to TopMatthew J. Wieduwilt, MD, PhD
Tisagenlecleucel (Kymriah, Novartis) is FDA-approved for relapsed or refractory B-cell ALL in patients up to age 26 years, with a CR rate of 82% and an MRD-negativity rate of 95%. The rates for brexucabtagene autoleucel reported in this phase 2 study are similar at 71% and 97%, respectively.
There may be a role for CAR T cells as front-line therapy moving forward. The need for intensive post-remission therapy — including allogeneic HSCT — in the era of highly active, targeted therapies is unknown but an area of active study, and longer follow-up will be needed.
Risk stratification with MRD and molecular resistance monitoring and molecular/cytogenetic risk assessment may allow de-intensification of therapy without compromising cure rates.
Reference:
Maude SL, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1709866.
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Shah BD, et al. Abstract 7002. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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