Brexu-Cel Displays Superior Responses vs Pirtobrutinib in Relapsed/Refractory MCL Matching-Adjusted Indirect Comparison

Lymphoma

Patients with relapsed/refractory mantle cell lymphoma (MCL) who received prior treatment with a covalent BTK inhibitor experienced statistically significant benefits regarding objective response rate (ORR) with brexucabtagene autoleucel (brexu-cel; Tecartus) vs pirtobrutinib (Jaypirca), according to findings from a matching-adjusted indirect comparison of the phase 2 ZUMA-2 (NCT02601313) and the phase 1/2 BRUIN (NCT03740529) trials.¹

Results from the base-case model demonstrated that treatment with brexu-cel was associated with a higher ORR and complete response (CR) rate compared with pirtobrutinib, with respective odds ratios of 10.39 (95% CI, 2.81-38.46) and 10.11 (95% CI, 4.26-24.00). Additionally, the CAR T-cell therapy bested pirtobrutinib in terms of progression-free survival (PFS; HR, 0.44; 95% CI, 0.25-0.75). Brexu-cel also provided an overall survival (OS) and duration of response (DOR) benefit over pirtobrutinib, but the differences crossed the bounds for statistical significance.

“Brexu-cel may offer clinically and statistically significant benefits regarding objective response, CR, and PFS compared [with] pirtobrutinib among patients with relapsed/refractory MCL after prior covalent BTK inhibitor therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive OS results,” study authors wrote.

ZUMA-2 was a single-arm, multicenter trial that evaluated brexu-cel in adult patients with histologically confirmed relapsed or refractory MCL who received up to 5 prior regimens including an anthracycline-containing or bendamustine-containing chemotherapy, an anti-CD20 monoclonal antibody, and a BTK inhibitor. The matching-adjusted indirect comparison focused on the modified intention-to-treat (ITT) population (n = 68) who were treated with brexu-cel at a target dose of 2 × 106 anti-CD19 CAR T cells/kg. The latest data cutoff for ORR, DOR, CR, and PFS had a median follow-up of 35.6 months and was July 24, 2021; the OS data cutoff had a median follow-up of 47.5 months and was July 23, 2022.

BRUIN was a multicenter, open-label study that examined pirtobrutinib in adult patients with non-Hodgkin lymphoma who had received at least 2 prior lines of therapy, regardless of previous covalent BTK inhibitor treatment. The matching-adjusted indirect comparison included patients with MCL from the study who received prior covalent BTK inhibitor treatment (n = 90). Patients were included from the dose-escalation portion, where pirtobrutinib was given at a dose of 25 mg to 300 mg once daily, or the dose-expansion portion, with 85.6% receiving at least 1 dose of the agent at 200 mg once daily.

Brexu-cel was approved by the FDA for the treatment of patients with relapsed/refractory MCL based on findings from ZUMA-2 in July 2020. Then, in January 2023, the agency granted accelerated approval to pirtobrutinib for the treatment of patients with MCL following at least 2 lines of systemic therapy, including a BTK inhibitor; the approval was supported by findings from BRUIN.^2,3

The primary outcomes of the matching-adjusted indirect comparison were ORR and CR per independent radiologic review committee assessment, which aligned with the primary end points of ZUMA-2 and BRUIN. Secondary outcomes included PFS and DOR per independent radiologic review committee assessment, as well as OS.²

At baseline, most patients in both the ZUMA-2 and BRUIN populations had stage IV disease (85% vs 78%, respectively), were male (84% vs 80%), and received prior ibrutinib (85% vs 66%); 37% and 34% of patients received more than 3 prior lines of treatment, respectively. More patients in ZUMA-2 received autologous stem cell transplantation (43% vs 19%, respectively).

Additional findings from the matching-adjusted indirect comparison revealed that the unadjusted ORR in ZUMA-2 was 91% vs 57% in BRUIN; the unadjusted CR rate was 68% vs 19%, respectively. The adjusted odds ratios for ORR and CR were 18.95 (95% CI, 1.50-238.71; P = .02) and 15.01 (95% CI, 4.20-53.70; P < .01) in favor of brexu-cel, according to the sensitivity analysis. The matching-adjusted base-case analysis HR for DOR was 0.60 (95% CI, 0.31-1.17; P = .13) and the sensitivity analysis matching-adjusted HR was 0.59 (95% CI, 0.25-1.39; P = .23), both in favor of brexu-cel.

In terms of survival, the median PFS in the matching-adjusted ZUMA-2 cohort was 29.3 months (95% CI, 9.2-48.0) compared with 6.9 months (95% CI, 5.3-13.3) in BRUIN (HR, 0.44; 95% CI, 0.25-0.75). The median OS in the matching-adjusted ZUMA-2 cohort was 47.6 months (95% CI, 0.34-1.10) compared with 23.5 months (95% CI, 15.9-not reached) in BRUIN (HR, 0.61; 95% CI, 0.34-1.10). The PFS and OS HRs in the sensitivity analysis were 0.41 (95% CI, 0.20-0.85) and 0.50 (95% CI, 0.23-1.11), both in favor of brexu-cel.

“Given the need for model assumptions, limitations related to covariate adjustment, and the relatively modest size of the trial cohorts, some caution should be used in interpreting the results. Still, the outcomes suggest that brexu-cel remains an important standard treatment option and may be the preferred therapy for patients with relapsed/refractory MCL who have previously received covalent BTK inhibitor therapy,” study authors wrote in conclusion.

References

1. Salles G, Chen JMH, Zhang I, et al. Matching-adjusted indirect comparison of brexucabtagene autoleucel (ZUMA-2) and pirtobrutinib (BRUIN) in patients with relapsed/refractory mantle cell lymphoma previously treated with a covalent bruton tyrosine kinase inhibitor. Adv Ther. Published online March 18, 2024. doi:10.1007/s12325-024-02822-z
2. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. July 24, 2020. Accessed March 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-mantle-cell-lymphoma
3. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. January 27, 2023. Accessed March 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-relapsed-or-refractory-mantle-cell-lymphoma