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Comparative Study
. 2024 May;41(5):1938-1952.
doi: 10.1007/s12325-024-02822-z. Epub 2024 Mar 18.

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

Gilles Salles  1 , Jenny M H Chen  2 , Ina Zhang  3 , Fabio Kerbauy  4 , James J Wu  5 , Sally W Wade  6 , Ana Nunes  5 , Chaoling Feng  5 , Ioana Kloos  5 , Weimin Peng  5 , Julia T Snider  5 , Dylan Maciel  7 , Keith Chan  7 , Sam Keeping  7 , Bijal Shah  8
Affiliations
Comparative Study

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

Gilles Salles et al. Adv Ther. 2024 May.

Abstract

Introduction: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor T cell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes.

Methods: Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs).

Results: In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95% CI 2.81-38.46]) and complete response (OR 10.11 [95% CI 4.26-24.00]), and improved progression-free survival (HR 0.44 [95% CI 0.25-0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses.

Conclusions: Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.

Keywords: Brexu-cel; Brexucabtagene autoleucel; Bruton tyrosine kinase inhibitor; CAR T cell therapy; KTE-X19; MAIC; Mantle cell lymphoma; Matching-adjusted indirect comparison; Non-Hodgkin lymphoma; Pirtobrutinib.

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Conflict of interest statement

Gilles Salles has received consulting fees from Abbvie, Celgene/BMS, Epizyme, Genmab, Incyte, Janssen, Kite, a Gilead Company, Loxo, Milteniy, Molecular Partners, Morphosys, Nordic Nanovector, Novartis, Rapt, and Takeda; has received payment or honoraria for speaking in symposium from Bayer, Epizyme, and Regeneron; has participated on a Data Safety Monitoring board or Advisory Board for Beigene; and has stock or stock options from Owkin. Jenny M.H. Chen, Ina Zhang, Dylan Maciel, Keith Chan, and Sam Keeping are employees of PRECISIONheor, funded by Kite, a Gilead Company for this study. Fabio Kerbauy declares no competing interests. James J. Wu is an employee of Kite, a Gilead Company; has received honoraria from the Patient-Centered Outcomes Research Institute (PCORI), both as a member of the Rare Disease Advisory Panel, and as a grants reviewer for the Improving Methods Program; has received travel/meeting support from Kite, a Gilead Company, and Amgen; owns stock in Gilead Sciences, Amgen, Abbott, AbbVie, Pfizer, Roche, Curis, Avid Biosciences, Evofem, Lensar, VBI Vaccines, and Viracta Therapeutics. Sally W. Wade has received consulting fees from Kite, a Gilead Company, Abbvie, and Johnson & Johnson. Fabio R. Kerbauy declares no competing interests. Ana Nunes is an employee of Gilead Sciences Europe; own stocks in Gilead Sciences and Amgen; and has received support for attending meetings and/or travel from Kite, a Gilead Company. Chaoling Feng is an employee of Kite, A Gilead Company; own stocks in Gilead Sciences, Boston Scientific, and has received support for attending meetings and/or travel from Kite, a Gilead Company. Ioana Kloos is an employee of Kite, A Gilead Company; own stocks in Gilead Sciences; and has been compensated for a leadership role (such as officer or member of a board of directors) for Kite, A Gilead Company. Weimin Peng is an employee of Kite, a Gilead Company; and owns stock in Gilead Sciences. Julia T. Snider is an employee of Kite, a Gilead Company; owns stock in Gilead Sciences. Bijal Shah has received consultant and education fees from Amgen, Pfizer, Novartis, BMS/Celgene/Juno, Kite, a Gilead company, Precision Biosciences, Jazz, Beigene, Adaptive, Century Therapeutics, and Autolus; and clinical trial grants from Kite, a Gilead company, Jazz, and Servier.

Figures

Fig. 1
Fig. 1
Odds ratios for ORR and CR for brexu-cel (ZUMA-2 mITT) versus pirtobrutinib (BRUIN). Across all comparisons, odds ratio estimates were statistically significant at a 0.05 level, indicating that brexu-cel was associated with higher odds of achieving ORR and CR compared with pirtobrutinib. Dashed vertical line indicates an odds ratio of 1. CI confidence interval, CR complete response, MAIC matching-adjusted indirect comparison, mITT modified intention-to-treat, ORR overall response rate
Fig. 2
Fig. 2
Hazard ratios for OS, PFS, and DOR for brexu-cel (ZUMA-2 mITT) versus pirtobrutinib (BRUIN). For PFS, hazard ratio estimates were statistically significant at a 0.05 level, indicating that brexu-cel improved PFS compared with pirtobrutinib. CI confidence interval, DOR duration of response, MAIC matching-adjusted indirect comparison, mITT modified intention-to-treat, OS overall survival, PFS progression-free survival
Fig. 3
Fig. 3
Base-case MAICs of brexu-cel (ZUMA-2 mITT) and pirtobrutinib (BRUIN) for a DOR, b PFS, and c OS. For ZUMA-2, the Kaplan–Meier curves were based on individual patient data whereas for BRUIN, published Kaplan–Meier curves for BRUIN were digitized and individual patient data were reconstructed using the Guyot et al. 2012 algorithm. Tick marks (+) indicate data censoring. CI confidence interval, DOR duration of response, ESS effective sample size, MAIC matching-adjusted indirect comparison, mITT modified intention-to-treat, OS overall survival, PFS progression-free survival
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