Long-Term Data Support Continued Use of Brexu-Cel in R/R Mantle Cell Lymphoma

Five-year follow-up data from cohorts 1 and 2 of the phase 1/2 ZUMA-2 trial (NCT02601313) showed that treatment with the CAR T-cell therapy brexucabtagene autoleucel (brexu-cel; Tecartus) led to durable responses and high overall survival (OS) rates in patients with relapsed/refractory mantle cell lymphoma (MCL).1

In an updated analysis presented at the 2024 ASH Annual Meeting, lead study author Michael Wang, MD, of The University of Texas MD Anderson Cancer Center in Houston, and colleagues noted that patients treated in cohort 2 experienced similar efficacy and safety outcomes compared with those enrolled in cohort 1 despite receiving a lower dose of brexu-cel. However, they cautioned that the small sample size limits the interpretation of the results in cohort 2.

Findings showed that at a median follow-up of 67.8 months (range, 58.2-88.6) for cohort 1 (n = 68) and 72.3 months (range, 70.1-74.3) for cohort 2 (n = 14), the median duration of response (DOR) was 36.5 months (95% CI, 17.7-48.9) for responders in cohort 1 (n = 60) and 57.5 months (95% CI, 4.7-not evaluable [NE]) for responders in cohort 2 (n = 12). At the data cutoff, 17 patients in cohort 1 and 3 patients in cohort 2 had ongoing responses, which were comprised exclusively of complete responses (CRs).

Additionally, investigators presented results from the primary analysis of cohort 2, which showed that at a median follow-up of 16.0 months (range, 13.9-18.0), the objective response rate (ORR) was 93% (95% CI, 66.1%-99.8%). The CR and partial response (PR) rates were 64% and 29%, respectively; no patients had stable disease or progressive disease, and 1 patient was not assessed for response prior to the July 24, 2019, data cutoff.

“Despite the less robust CAR T-cell expansion in cohort 2 than in cohort 1, a high response rate and DOR were observed,” Wang and colleagues wrote in the poster. “It is unclear why the lower dose resulted in durable responses, but [they] may be due to the high CD19 expression of MCL cells, small patient numbers, and differences in patient and disease characteristics.”

Wang currently serves as a professor of medicine in the Department of Lymphoma – Myeloma in the Division of Cancer Medicine at MD Anderson.

Understanding the Background of Brexu-Cel and ZUMA-2

In July 2020, the FDA approved brexu-cel for the treatment of adult patients with relapsed/refractory MCL.2The decision was based on previously reported data from ZUMA-2, which showed that patients in cohort 1 (n = 60) achieved an ORR of 93% and a CR rate of 67%.1

The study enrolled patients at least 18 years of age with relapsed/refractory MCL who received 1 to 5 prior lines of therapy that included an anthracycline- or bendamustine-containing chemotherapy; an anti-CD20 monoclonal antibody; and a BTK inhibitor.

After undergoing leukapheresis, participants enrolled in both cohorts had the option to receive bridging therapy with dexamethasone, ibrutinib (Imbruvica), or acalabrutinib (Calquence). On days –5 to –3, patients underwent lymphodepleting chemotherapy consisting of 30 mg/m2 of fludarabine and 500 mg/m2 of cyclophosphamide per day before receiving a single infusion of brexu-cel on day 0. Brexu-cel was administered at 2 x 106 cells/kg in cohort 1 and 0.5 x 106 cells/kg in cohort 2. The first tumor assessment occurred on day 28. After ZUMA-2, patients could participate in a long-term follow-up study (NCT05041309), where follow-up was planned for up to 15 years.

Investigators planned to conduct the primary efficacy analysis for cohort 2 after approximately 40 patients were enrolled and infused with the lower dose level of brexu-cel; however, a modified intention-to-treat analysis was used after the group did not reach full enrollment.

Independent radiology review committee–assessed ORR served as the trial’s primary end point. Secondary end points included DOR, best overall response, progression-free survival (PFS), and overall survival (OS). In the long-term follow-up study, the primary end point was the incidence of late-onset targeted adverse effects (AEs) possibly related to brexu-cel. Secondary end points were OS, causes of death, and rates of replication-competent retrovirus (RCR) and replication-competent lentivirus (RCL).

Patient Characteristics

Wang and colleagues noted that the baseline characteristics for patients enrolled in cohort 2 were similar those of patients treated in cohort 1. The median age in cohort 2 was 61.5 years (range, 52-73), and most were male (79%). Half of patients had an ECOG performance status of 1, and half had intermediate- or high-risk disease per simplified MCL International Prognostic Index classification. Seventy-one percent of patients in cohort 2 had a Ki-67 expression of at least 30%.

Patients in cohort 2 received a median of 3 prior lines of therapy (range, 2-5), which comprised platinum-based chemotherapy (43%), an anthracycline (79%), bendamustine (50%), lenalidomide (Revlimid; 7%), a proteasome inhibitor (21%), and autologous stem cell transplant (ASCT; 43%). All patients received a prior BTK inhibitor, including ibrutinib (93%), acalabrutinib (14%), or both (7%).

Forty-three percent of patients had relapsed disease after ASCT, half had disease refractory to their last therapy, and 7% experienced relapse after their last therapy.

Additional Long-Term Data and Safety Findings

The median PFS was 25.3 months (95% CI, 12.7-46.6) for patients in cohort 1 and 29.5 months (95% CI, 3.3-NE) for those in cohort 2. The respective 54-month PFS rates were 32% (95% CI, 20.0%-44.2%) and 46% (95% CI, 17.3%-70.5%).

Among all enrolled patients, the median OS was 46.5 months (95% CI, 24.9-60.2) in cohort 1 and not reached (95% CI, 9.4-NE) in cohort 2. Complete responders in cohort 1 (n = 46) had a median OS of 60.2 months (95% CI, 42.8-NE); partial responders in this cohort (n = 16) had a median OS of 16.3 months (95% CI, 3.8-46.6).

The overall 60-month OS rates were 39% (95% CI, 26.7%-50.1%) and 54% (95% CI, 23.8%-76.2%) for cohorts 1 and 2, respectively.

All patients in both cohorts experienced any-grade treatment-emergent AEs (TEAEs), and the rates of grade 3 or higher TEAEs were 99% for cohort 1 and 93% for cohort 2. Any-grade TEAEs related to brexu-cel were reported in 97% of patients in cohort 1 and all patients in cohort 2. The rates of grade 3 or higher brexu-cel–related TEAEs were 79% and 71%, respectively.

The most common any-grade TEAEs reported in at least 40% of patients in either cohort were pyrexia (cohort 1, 94%; cohort 2, 93%), anemia (68%; 50%), decreased neutrophil count (54%; 43%), hypotension (53%; 79%), decreased platelet count (51%; 36%), chills (41%; 43%), decreased white blood cell count (41%; 50%), fatigue (38%; 50%), tremor (35%; 50%), nausea (32%; 50%), decreased appetite (22%; 50%), confusional state (21%; 43%), and dyspnea (21%; 43%).

Regarding AEs of special interest, any-grade cytokine release syndrome (CRS) was reported in 91% of patients in cohort 1 and 93% of patients in cohort 2. The rates of grade 3 or higher CRS were 15% and 14%, respectively. Any-grade neurologic events occurred in 63% and 93% of patients, respectively; the respective grade 3 or higher rates were 31% and 43%.

Other any-grade AEs of special interest included thrombocytopenia (cohort 1, 74%; cohort 2, 50%), neutropenia (87%; 79%), anemia (69%; 50%), infection (54%; 50%), and hypogammaglobulinemia (21%; 0%).

In cohort 1, 40% of patients died to progressive disease, and 22% died due to reasons other than progressive disease.

In long-term follow-up, 1 patient had 3 ongoing AEs, which included hypogammaglobulinemia and 2 viral infections. Two patients died in long-term follow-up due to progressive disease. Notably, no instances of secondary T-cell malignancies were reported in ZUMA-2.

Pharmacokinetic data showed that the median time to peak CAR T-cell levels was 15 days (interquartile range [IQR], 8-15) in cohort 1 and 15 days (IQR, 15-29) in cohort 2. The respective median peaks of CAR T-cell levels were 83.12 cells/µL (IQR, 17.40-265.71) and 688.40 cells/µL (IQR, 286.72-1477.66). The median area under the curve at day 28 was 1112.86 cells/µL per day (IQR, 230.75-3005.32) and 688.40 cells/µL per day (IQR, 286.2-1477.66), respectively.

References

1. Wang M, Goy A, Munoz J, et al. Five-year outcomes of patients (Pts) with relapsed/refractory mantle cell lymphoma (R/R MCL) treated with brexucabtagene autoleucel (brexu-cel) in ZUMA-2 cohorts 1 and 2. Blood. 2024;144(suppl 1):4388. doi:10.1182/blood-2024-198018
2. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. July 24, 2020. Accessed December 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-mantle-cell-lymphoma