Efficacy and Safety of Experimental versus Approved CAR T-cell Therapies in Large B-cell Lymphoma Using Matching Adjusted Indirect Comparisons: A Systematic Review and Meta-Analysis Protocol

Background: Relapsed and refractory large B cell lymphomas (RR-LBCL) have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapies have shown considerably high response rates even in RR-LBCL patients who fail to achieve remission after multiple chemotherapy lines. Currently, three CAR T-cell treatments - axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (Breyanzi) - have been approved for adults with RR-LBCL by regulatory agencies. Non-pivotal clinical trials have independently examined different types of CAR T-cells and have demonstrated remarkable clinical benefit and safety. Yet, no comparison of the experimental and approved CAR T-cells has been conducted. Objectives: To address this limitation, we aim to: (1) Identify comparative efficacy and safety of experimental CAR T-cells to the approved CAR T-cells, and (2) Identify how observed differences vary by different CAR T-cell types and regimens differences in CAR T-cell administration. Methodology: This protocol proposes a matching-adjusted indirect comparison (MAIC) of experimental CAR T-cell trials based on individual patient data (IPD) vs. three existing pivotal trials (comparator trials). The MAIC approach is appropriate given that CAR T-cells have solely been assessed in single-arm trials consisting of heterogeneous patient populations and the lack of IPD for the existing pivotal trials (active comparator trials), which hampers the traditional network meta-analysis approach. Conclusion: Knowledge of the relative value of experimental CAR T-cell products compared to the currently approved ones may provide insights for patients, clinicians, and CAR T-cell developers to advance and optimize the balance of potency and toxicity of these targeted immunotherapies.