Are CAR-T therapies living up to their hype? A study using real-world data in two cohorts to determine how well they are actually working in practice compared with bone marrow transplants

Abstract

With the increasing use of new regulatory tools, like the Food and Drug Administration’s breakthrough designation, there are increasing challenges for European health technology assessors (HTAs) to make an accurate assessment of the long-term value and performance of chimeric antigen receptor T-cell (CAR-T) therapies, particularly for orphan conditions, such as acute lymphoblastic leukaemia. The aim of this study was to demonstrate a novel methodology harnessing longitudinal real-world data, extracted from the electronic health records of a medical centre functioning as a clinical trial site, to develop an accurate analysis of the performance of CAR-T compared with the next-best treatment option, namely allogeneic haematopoietic cell transplant (HCT). The study population comprised 43 subjects in two cohorts: 29 who had undergone HCT treatment and 14 who had undergone CAR-T therapy. The 3-year relapse-free survival probability was 46% (95% CI: 08% to 79%) in the CAR-T cohort and 68% (95% CI: 46% to 83%) in the HCT cohort. To explain the lower RFS probability in the CAR-T cohort compared with the HCT cohort, the authors hypothesised that the CAR-T cohort had a far higher level of disease burden. This was validated by log-rank test analysis (p=0.0001) and confirmed in conversations with practitioners at the study site. The authors are aware that the small populations in this study will be seen as limiting the generalisability of the findings to some readers. However, in consultation with many European HTAs and regulators, there is broad agreement that this methodology warrants further investigation with a larger study.

From Laboratory to Patient: The Evolving Path to Become a Medicine

“…At present we can say that although some HTAs have been involved with ATMPs, including in initiatives like PRIME, in general they are not equipped to deal with these types of innovative therapies with curative potential; they are currently adapting their methods to deal with them. Novel approaches are already being tested, for example creative use of real world data 4 .…”

“…At the point of treatment, targeting a specifi c gene is not as precise as we would like it to be. Off target effects are common and the effi cacy of many of these therapies is well below 100% 4 .…”

“…Developers should consider from very early on which type of data HTAs and payers will require and discuss with regulators and others how to produce and collect data that serve relevant stakeholders down the line. A balance will need to be found between budget impacts and societal benefi ts 4 .…”

“…The sometimes perceived slow translation of experimental therapies to the clinic is a consequence of the rapid scientifi c progress rather than a reluctance to move with the times of regulators or health systems. It is true that some of these therapies highlight unexpected shortcomings, but they stimulate rethinking and improvements in several areas 4 . In this article, four areas where the regulatory system is being challenged, and is adapting to the new paradigms, are discussed.…”

Application of a simple unstructured kinetic and cost of goods models to support T‐cell therapy manufacture

“…The launch of CAR-T cell therapy products including Kymriah and Yescarta are the first in a significant pipeline of T-cell based therapeutic products 1,2 . Such cell-based immunotherapies are set to change the treatment options for a range of previously hard to treat or fatal haematological malignancies 3,4 .…”