A Review of Two Regulatory Approved Anti-CD19 CAR T-Cell Therapies in Diffuse Large B-Cell Lymphoma: Why Are Indirect Treatment Comparisons Not Feasible?

Abstract

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapies can be effective for diffuse large B-cell lymphoma (DLBCL), a cancer with limited treatment options and poor outcomes, particularly for patients with relapsed or refractory (r/r) disease. Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CAR T-cell therapies approved by regulatory bodies for certain patients with r/r DLBCL on the basis of demonstrated treatment effects in their pivotal single-arm trials, ZUMA-1 and JULIET, respectively. In the absence of head-to-head trials, the question of whether a valid indirect treatment comparison (ITC) between axi-cel and tisa-cel could be performed using existing evidence is of interest to patients, physicians, payers, and other stakeholders. This article addresses that question by summarizing the current evidence from clinical trials and realworld studies and discussing the challenges and limitations of potential analytical approaches associated with an ITC. Two ITC approaches attempting to adjust for cross-trial heterogeneity between ZUMA-1 and JULIET, matchingadjusted indirect comparison and regressionprediction model analysis, were evaluated. After evaluating the current clinical trial data and real-world evidence, and present and prior ITC analyses of axi-cel and tisa-cel, the authors conclude that a valid comparative analysis is not currently feasible. The substantial differences (e.g., timing of leukapheresis and enrollment, use of bridging chemotherapy [90% in JULIET vs. 0% in ZUMA-1], lymphodepleting regimens) between the two trials' designs and patient populations preclude a robust and reliable ITC. No other approaches are able to account for such differences. The current realworld data are still too immature to be used for ITCs. Thus, drawing conclusions from such ITCs should be avoided to prevent misinforming treatment choices or limiting patient access to effective treatment options. Additional data from ongoing or future real-world studies with appropriate statistical analyses are needed to provide insights into the comparative effectiveness and safety of these two treatments.

Cost effectiveness of axicabtagene ciloleucel versus tisagenlecleucel for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy in the United States

“…Finally, Zhang et al have argued that an indirect comparison between axi-cel and tisa-cel is not feasible due to important differences between the two trials' designs and patient populations. In particular, as pointed out by Zhang et al [53,54], ZUMA-1 and JULIET differed substantially in terms of timing of leukapheresis and enrollment, use of bridging chemotherapy (approximately 90% in JULIET vs. 0% in ZUMA-1), and lymphodepleting regimens, among others. We acknowledge that the MAIC has important limitations as noted above [55].…”

DDX3X Loss is Associated with Aggressive Phenotypes in Non-Hodgkin’s Lymphomas

“…Trans-well cell migration assays were carried out using the Corning™ 5.0 µm pore polycarbonate membrane insert (Corning) in a 24-well plate, without or with BD Matrigel™ Basement Membrane (8-μm pore; BD Falcon). Briefly, 1.5×10 5…”

“…Unfortunately, approximately 40% of DLBCL cases remain refractory to or relapse (R/R-DLBCL) after R-CHOP 4 . Recently developed immunotherapeutic approach utilizing CD19-targeted chimeric antigen receptor (CAR) T-cells has led to a new standard of care for R/R-DLBCL 5 ; however, unique toxicities associated with anti-CD19 CAR T-cells remain a major challenge 6 .…”

Co-expression of IL-7 and PH20 Promote anti-GPC3 CAR-T Tumor Suppressor Activity in Vivo and in Vitro

“…CAR-T cell therapy has demonstrated encouraging therapeutic effects when treating hematological malignancies [1,2]. Two CAR-T treatments targeting CD19 have been launched successfully [3,4]. CAR-T targeting the B-cell maturation antigen (BCMA) has also shown positive therapeutic effects in clinical trials [5][6][7].…”