Brexu-Cel Achieves High Response Rates in BTK-Inhibitor-Naive MCL

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The phase 2 ZUMA-2 trial (NCT04880434) demonstrated that brexucabtagene autoleucel (brexu-cel; Tecartus) achieved a high objective response rate (ORR) in patients with relapsed/refractory mantle cell lymphoma (MCL) who were naïve to BTK inhibitors, including those with high-risk disease features.

Findings that were presented at the 2024 ASH Annual Meeting & Exposition with a median follow-up of 15.5 months (range, 5-15) indicated that the ORR was 91% (95% CI, 83%-96%), which included a complete response (CR) rate of 73% and a partial response (PR) rate of 17%. Three percent of patients each had stable disease and progressive disease.

Individual subgroups also exhibited high ORRs, including patients with confirmed TP53 mutations (n = 15/15; 100%), greater than the median tumor burden at baseline (n = 38/39; 97%), Ki-67 scores of at least 50% (n = 17/18; 94%), intermediate- or high-risk simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI) scores (n = 56/63; 89%), and prior bendamustine exposure (n = 19/23; 83%).

“These results support the continued use of brexu-cel in the relapsed/refractory MCL setting, including patients naive to BTK inhibitor therapy,” Tom van Meerten, MD, PhD, lead study author working in the Department of Hematology at the University Medical Center Groningen, Netherlands, said in a presentation of the data.

Despite the availability of BTK inhibitors, therapy remains incurable for patients with MCL, with relapse portending a poor prognosis.

In 2020, the FDA granted accelerated approval to brexu-cel for the treatment of patients with relapsed or refractory MCL based on data from ZUMA-2.² The decision was based on findings from cohort 1, in which treatment with brexu-cel led to an ORR of 91% (95% CI, 81.8%-96.7%), a CR rate of 68% (95% CI, 55.2%-78.5%), and a median overall survival (OS) of 46.6 months (95% CI, 24.9-not estimable [NE]) in patients with relapsed/refractory MCL (n = 68) who had received between 1 and 5 prior lines of therapy.³ However, cohort 1 had enrolled patients who had received a prior BTK inhibitor. As such, cohort 3 was established to better understand brexu-cel’s activity in a BTK-naive population.¹

The phase 2, open-label study enrolled patients at least 18 years of age with relapsed/refractory MCL who had received between 1 and 5 prior regimens, including anthracycline-, bendamustine-, or high-dose cytarabine–containing chemotherapy, and anti-CD20 monoclonal antibody therapy. Prior exposure to BTK inhibitors was not allowed.

Per the protocol, patients underwent screening, followed by leukapheresis and optional bridging therapy consisting of prespecified dexamethasone, radiotherapy, chemotherapy, or any combination of the 3. During lymphodepleting chemotherapy, patients received 30 mg/m² of intravenous (IV) fludarabine and 500 mg/m² of IV cyclophosphamide daily for 3 days, followed by brexu-cel infusion. During infusion, patients received an IV target dose of 2 ´ 10⁶ CAR T cells/kg on day 0.

The primary end point was ORR by independent radiology review committee assessment per Lugano classification. Secondary end points included duration of response (DOR), best objective response, progression-free survival (PFS), overall survival (OS), and safety.

The primary analysis was conducted after 86 patients had been enrolled, treated, and followed for 6 months after the first objective response. The study had at least 90% power to distinguish between a 75% and 57% or lower response rate. All treated patients were included in the efficacy and safety analyses.

As of the data cutoff date of November 26, 2023, 95 patients had been enrolled in cohort 3, 87 of whom received lymphodepleting chemotherapy and 86 (91%) of whom received brexu-cel. Reasons for not receiving treatment included death (n = 1), adverse effect (AE; n = 3), manufacturing failure (n = 1), consent withdrawal (n = 1), progressive disease (n = 2), and rapid disease progression after lymphodepleting chemotherapy (n = 1). The median time from leukapheresis to delivery to the study site was 15 days (range, 14-21) for US sites and 28 days (range, 20-43) for EU sites apart from the United Kingdom.

The median age was 64.0 years (range, 40-82) and most patients were male (78%). Van Meerten noted that high-risk features were common, with a high frequency of patients presenting with a high- or intermediate-risk sMIPI score (73%), extranodal disease (52%), Ki-67 level according to central assessment measuring at least 30% (47%), and bone marrow involvement (40%). TP53 mutational status was evaluated by central laboratory in 69% of patients, 8% of whom had levels measuring at least 50%, and by local laboratory in 38% of cases; 17% of these patient samples came back positive forTP53 mutations. The median tumor burden by central read was 1734 mm² (range, 204-31, 212) and lactate dehydrogenase levels were higher than the upper limit of normal in 57% of patients.

The median number of prior regimens received was 1 (range, 1-5) and included an anti-CD20 antibody (100%), platinum-based therapy (13%), an anthracycline (79%), bendamustine (27%), lenalidomide (Revlimid; 2%), and a proteasome inhibitor (7%). Most patients had relapsed after their last MCL therapy (86%) and 14% were refractory to their last therapy. Approximately half of patients (48%) underwent prior autologous stem cell transplant and 8% had received prior hyper-CVAD. Thirty-six percent of patients received bridging therapy consisting of systemic therapy only (28%), radiotherapy only (5%), or a combination of the two (3%).

Additional efficacy findings illustrated that responses were durable, with medians that had not been reached regardless of whether patients had CR (n = 63; 95% CI, 17.4-NE) or PR (n = 15; 95% CI, 2.5-NE). The 12-month DOR rate was 80% for all responders (n = 78), with 69% (n = 54) of responses ongoing at the data cutoff. The 12-month DOR rates for patients in CR or PR were 84% and 63%, respectively.

Moreover, median PFS and OS estimates were not reached in the overall population, although nonresponders had a median PFS of 1.6 months (95% CI, 1.0-NE). The 12-month PFS rates were 75% for all patients, 84% for those with CR, and 65% for those with PR. The 12-month OS rate was 90%, with 85% of patients still alive at data cutoff. Notably, when investigators evaluated PFS according to the percentage of naive or juvenile cells in the CAR therapy they found that patients with a percentage above the median had significantly improved PFS (P =.0031).

In terms of safety, serious AEs occurred in most patients (all grade, 59%; grade ≥3, 47%). The most common treatment-emergent AEs (TEAEs) that occurred in at least 25% of patients were pyrexia (any grade, 94%; grade ≥3, 17%), anemia (57%; 26%), hypotension (51%; 8%), neutropenia (45%; 43%), decreased neutrophil count (42%; 42%), decreased white blood cell count (40%; 37%), nausea (33%; 1%), confusional state (29%; 8%), headache (29%; 0%), decreased platelet count (29%; 17%), tremor (29%; 2%), constipation (28%; 0%), and decreased lymphocyte count (27%; 27%).

AEs of special interest included cytokine release syndrome (CRS; any grade, 95%; grade ≥3, 6%), neurological events (78%; 27%), immune effector cell–associated neurotoxicity syndrome (ICANS; 66%; 21%), thrombocytopenia (52%; 34%), neutropenia (86%; 85%), anemia (57%; 26%), serious infection (24%; 23%), and hypogammaglobulinemia (8%; 0%).

“No new safety signals were detected, with a low rate of grade 3 or greater CRS and a similar rate of grade 3 or greater neurologic events to cohort 1,” van Meerten said.

The median time to onset and duration of CRS was 4 (range, 1-12) and 6 (range, 1-36) days, respectively. The median time to onset and duration of ICANS was 7 (range, 1-31) and 7 (range, 1-122) days. No cases of replication-competent retrovirus or brexu-cel–related secondary T-cell malignancies were reported.

At data cutoff, 73% (85%) of patients were alive. Reasons for death included AEs (n = 7), progressive disease (n = 5), and other (n = 1). Notably, no deaths occurred within 30 days after brexu-cel infusion. AEs resulting in death included progressive multifocal leukoencephalopathy, septic shock, polymicrobial infection, and human herpesvirus 6 encephalitis. AEs not related to treatment included intracranial hemorrhage, hepatocellular carcinoma, and pneumonia.

CAR T-cell expansion according to grade 3 or greater CRS and ICANS was also evaluated. Van Meerten explained that no significant differences were seen in peak CAR T-cell expansion according to response status, noting that small patient numbers make it difficult to draw definitive conclusions. Additionally, CAR T-cell expansion was only significantly associated with grade 3 or greater ICANS.

“Longer follow-up is needed to further understand long-term outcomes for these patients,” van Meerten said in conclusion.

Disclosures: Dr van Meerten cited no relevant disclosures.

References

1. Van Meerten T, Kersten MJ, Iacoboni G, et al. Primary analysis of ZUMA-2 cohort 3: brexucabtagene autoleucel (brexu-cel) in patients (pts) with relapsed/refractory mantle cell lymphoma (r/r MCL) who were naive to Bruton tyrosine kinase inhibitors (BTKi). Blood. 2024;144(suppl 1):748. doi:10.1182/blood-2024-198021

2. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. Updated July 27, 2020. Accessed December 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-mantle-cell-lymphoma

3. Wang M, Munoz J, Goy A, et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study. J Clin Oncol. 2023;41(3):555-567. doi:10.1200/JCO.21.02370