CAR T-cell product performance in haematological malignancies before and after marketing authorisation

Abstract

Chimeric antigen receptor (CAR) T cells represent a potent new approach to treat haematological malignancies. Two CAR T-cell therapies, tisagenlecleucel and axicabtagene ciloleucel, have been approved in Europe and the USA, as well as several other countries, for the treatment of leukaemia and lymphoma. These approvals marked a major milestone in the field of cell and gene therapies. However, the clinical development and regulatory evaluation of these innovative therapies faced several challenges that are considered important lessons learned for future similar products. Here, we examine the products' non-clinical and clinical data packages to outline the challenges encountered during the regulatory evaluation process in Europe, and to provide an update on their performance after authorisation.

Figure 1:. Development timeline of axicabtagene ciloleucel and tisagenlecleucel

The spaces between the lines are not to scale. EMA=European Medicines Agency. FDA=US Food and Drug Administration. NICE=National Institute for Health and Care Excellence. UPenn=University of Pennsylvania. NCI=National Cancer Institute. DLBCL=diffuse large B-cell lymphoma. PRIME scheme=Priority Medicines scheme. PMBCL=primary mediastinal B-cell lymphoma. FL=follicular lymphoma. ALL=acute lymphoblastic leukaemia. NHL=non-Hodgkin lymphoma. *Points on the same line represent the events arranged chronologically from top to bottom.

Figure 2:. Unadjusted aggregated efficacy results for JULIET (tisagenlecleucel), ZUMA-1 (axicabtagene ciloleucel), SCHOLAR-1, and CORAL extension studies with different analysis populations for the treatment of DLBCL

Error bars represent the CI. The number of patients in each study analysis group (n=165, 93, 111, 101, 523, or 278) in order of the key from top to bottom. Data cutoff for ZUMA-1: Aug 11, 2017, with a median follow-up of 15·1 months. Data cutoff for JULIET: Dec 8, 2017, with a median follow-up of 13·9 months. DLBCL=diffuse large B-cell lymphoma.

Figure 3:. Matched comparisons of results from axicabtagene ciloleucel and tisagenlecleucel pivotal clinical trials with historical comparators for the treatment of DLBCL

Figures are reproduced from data presented in the European public assessment reports for both products, and a published article.^,, (A) Comparison of responses between ZUMA-1 and SCHOLAR-1 (data cutoff ZUMA-1: Aug 11, 2017, median follow-up 15·1 months). (B) The differences in overall response and complete response between JULIET and SCHOLAR-1 by analysis population (data cutoff: Dec 8, 2017, median follow-up 13·9 months). (C) The differences in overall response and complete response between JULIET and CORAL extension studies (data cutoff: Dec 8, 2017, median follow-up 13·9 months). *No significant difference in responses (p>0·05).