In the pre-CAR T cell therapy era, the prognosis of patients with R/R MCL who discontinued cBTKi therapy as a result of disease progression or intolerance was poor following treatment with conventional subsequent therapies. Use of these non-curative interventions aimed to palliate and prolong survival, though median OS typically remained around 1 year or less in the post-BTKi setting [10, 27, 28]. Advancements in treatment options such as CAR T cell therapy and non-covalent BTKi therapy have substantially improved patient outcomes. In the ZUMA-2 trial evaluating patients with MCL who failed prior BTKi, brexu-cel therapy for the mITT cohort was associated with a median OS of 46.4 months (95% CI 24.9–58.7) at 4-year follow-up. At 2-year follow-up in the BRUIN trial evaluating patients with MCL who failed or were intolerant to prior BTKi, median OS was 23.5 months (95% CI 15.9–NE) in the post-cBTKi therapy patient cohort [20]. Given the therapeutic needs experienced by patients with R/R MCL post-cBTKi therapy and the potential benefits in clinical outcomes associated with these new treatment options, it is important to understand their relative clinical efficacy.

In the absence of direct comparative evidence, this study presents an indirect comparison of the treatment effects of brexu-cel and pirtobrutinib using MAIC methodology to adjust for study-level differences between the ZUMA-2 and BRUIN single-arm trials where possible. In the base-case MAIC, the odds of ORR and CR were significantly better for brexu-cel-infused patients than those treated with pirtobrutinib therapy. Brexu-cel was also associated with significant improvements in PFS compared to pirtobrutinib. Although HR point estimates trended in favor of brexu-cel regarding DOR and OS, differences in both outcomes crossed the boundary for statistical significance. DOR among patients achieving a CR (n = 46 [67.6%] complete responders in ZUMA-2 vs n = 17 [18.9%] complete responders in BRUIN) or duration of CR was not included for analysis as data were not reported in BRUIN. It is important to highlight the relatively shorter median follow-up for OS in BRUIN (23.5 months in BRUIN versus 47.5 months in ZUMA-2). As an MAIC cannot be considered equivalent to a randomized controlled study, the ability to detect statistically significant differences for outcomes with low starting sample sizes and small number of events is limited. As such, given the high degree of censoring in BRUIN, an updated analysis incorporating longer follow-up data containing more events from BRUIN could provide more reliable treatment effect estimates. Note, outcomes for a larger sample of patients from BRUIN than used for this analysis were recently presented at ASH; however, the median follow-up was only 14.7 months [21].

Treatment with CAR T cell therapy involves a multistep process that begins with leukapheresis to obtain leukocytes for the manufacturing of brexu-cel. Although understanding treatment efficacy among patients who received brexu-cel infusion (the mITT population) is important, it is similarly critical to understand efficacy among those who initiate leukapheresis (the ITT population) as hazard rates in the pre-infusion period may not be comparable between the mITT and ITT populations. A total of six patients who underwent leukapheresis did not received infusion (n = 3 deaths, n = 1 full consent withdrawal, n = 1 adverse event, and n = 1 not meeting inclusion criteria for infusion). Findings from the main analysis (based on ZUMA-2 mITT population) and scenario analysis (based on ZUMA-2 ITT population) were consistent, suggesting that the results were not sensitive to which ZUMA-2 population sets were used for analysis. In addition, subgroup analyses restricted to BRUIN patients (85.6%) who received the recommended phase 2 pirtobrutinib dose of 200 mg at study start were not performed as subgroup data by treatment dose were not reported in BRUIN.

Considered collectively, the results of the MAIC provide important insights to clinical decision makers when determining the optimal approach to management of R/R MCL post-cBTKi therapy. Efficacy and toxicity outcomes in real-world settings identified from a systematic literature review and the US Lymphoma CAR T Consortium reported findings that are consistent with those of ZUMA-2 [28,29,30,31,32,33]. In an adjusted comparison using inverse probability weighting between ZUMA-2 and SCHOLAR-2, brexu-cel was associated with improved OS compared to non-CAR T cell standard of care (HR 0.38, 95% CI 0.23–0.61) [34]. Efficacy of CAR T cell therapy should be considered alongside potential class-specific toxicities, such as immunologic effector cell-associated cytokine release syndrome and neurotoxicity, among other potential constraints to successful CAR T cell therapy [35]. To our knowledge, pirtobrutinib has yet to be evaluated in the real-world setting; however, the therapy is currently undergoing phase 3 evaluation in the cBTKi-naive setting of MCL, with comparison to ibrutinib, acalabrutinib, or zanubrutinib (BRUIN MCL-321 trial; NCT04662255). The findings of this trial will provide further information relevant for clinical treatment decision-making for R/R cBTKi-treated MCL.

Although outside the scope of the current study, the impact of brexu-cel and pirtobrutinib on health-related quality of life and economic outcomes is also of interest from a decision-making perspective. Such analyses would therefore be of value in the future should sufficiently detailed data be made available to facilitate them. In addition, efficacy of CAR T cell therapy should be considered alongside potential class-specific toxicities, such as immunologic effector cell-associated cytokine release syndrome and neurotoxicity, among other potential constraints to successful CAR T cell therapy. In ZUMA-2, 14.7% of patients experienced grade ≥ 3 cytokine release syndrome, 30.9% of patients experienced grade ≥ 3 neurological events, and 85.3% of patients experienced neutropenia while grade ≥ 3 adverse events were less frequent with pirtobrutinib in BRUIN, with infections (17.1%) and neutropenia (13.4%) being the most frequent grade ≥ 3 adverse events.

Some potential limitations that may influence the findings of this study should be recognized. In general, analysis of data from single-arm or non-comparative studies is associated with uncertainty regarding any unknown or unmeasured prognostic factors and effect modifiers that are not included in the model. As such, although every effort was taken to ensure a robust approach to prognostic factor selection, the possibility of residual confounding variables cannot be ruled out. Similarly, in the absence of individual patient-level data for the BRUIN trial, it was challenging to quantify the extent of residual bias in the treatment effect estimates; therefore, some confounding variables may remain unbalanced. Per clinician input, TP53 mutation status, Ki-67 proliferation index, response to prior cBTKi, response to last therapy, and duration on prior cBTKi therapy were identified as covariates of high importance. However, given data availability, these variables could not be evaluated in the base-case analysis and only TP53 mutation status and Ki-67 proliferation index ≥ 30% were explored in a sensitivity analysis.

It is also important to highlight that other observed differences between the two phase 2 trials could not be adjusted for in the MAIC. Mostly notably, reasons for prior BTKi discontinuation varied across trials. While 95.6% of patients in ZUMA-2 had previously discontinued BTKi as a result of disease progression and 4.4% because of adverse events, 82.2% of BRUIN patients had discontinued prior BTKi to disease progression, with the remaining discontinuing as a result of intolerance/toxicity (13.3%) or other reasons (4.4%) without disease progression [36]. As patients who discontinued BTKi as a result of intolerance may be associated with better clinical outcomes than those who discontinued because of progression, the treatment effect estimates from the current analyses are considered conservative [36, 37]. Additionally, differences in subsequent therapy between the two trials may also impact OS results as 17 (18.9%) of patients in BRUIN went on to receive subsequent CAR T cell therapy after pirtobrutinib. In the BRUIN trial, 4.4% of patients received prior allogeneic stem cell transplant and 4.4% received prior CAR T cell therapy; in ZUMA-2, such patients were ineligible for enrollment. Previous SCT and CAR T cell therapy are unknown prognostic factors in the R/R MCL, post-BTKi setting. Still, given the small numbers of such patients in this study, it is unlikely that treatment effect estimates were impacted. Other discrepancies in the patient selection criteria that may have introduced bias into the trial comparisons were the exclusion of patients with possible need for urgent oncological therapy in ZUMA-2 which was not mentioned as an exclusion criterion in BRUIN, inclusion criteria of Eastern Cooperative Oncology Group performance status score of 0–1 in ZUMA-2 compared to 0–2 in BRUIN (although only one patient with a score of 2 was enrolled), inclusion criteria of creatine clearance being ≥ 60 cc/min in ZUMA-2 and ≥ 30 mL/min in BRUIN, exclusion of patients with atrial fibrillation in ZUMA-2 but not in BRUIN, and exclusion criteria of patients with history of clinically significant cardiac disease within 12 months in ZUMA-2 versus within 6 months in BRUIN.