https://orcid.org/0000-0002-4881-720X
Introduction
Chimera was a three-headed, fire-breathing monster, that was part lion, part goat, and part dragon and it sowed terror in the fields of ancient Lydia. Commonly used as an omen for disaster, chimera portrays the fusion of many different zygotes into one entity and also exemplifies the unachievable and the elusive.
Tide has turned and currently, chimeric antigen receptor (CAR)-T cell therapy marks the dawn of a new era in hematology, aiming to improve outcomes rate of several hematological conditions which has revamped the hopes of patients and health professionals.
Currently, 6 CAR-T agents are commercially available. Among them, 2 are indicated for multiple myeloma (MM). MM has a 55% 5-year survival rate and currently is treatable but not curable. The armamentarium includes chemotherapy, proteasome inhibitors (PI), immunomodulary drugs (IMID), immune-modifying drugs, anti CD-38 monoclonal antibodies and stem cell transplantation. In spite of the potency of the new agents, specifically anti CD-38 monoclonal antibodies, relapses are commonCitation1. This necessitates the introduction of new therapeutic modalities especially in patients presenting with refractory myeloma. In a string of clinical trials, data inferred that CAR-T have a pivotal position in the management of MM, followed by a new chapter starting with Idecabtagene. Idecabtagene demonstrated a 73% response rate in a phase 2 trial, in a sample of which 84% were triple refractory (to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody), 60% were pentaexposed (to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab), and 26% were penta-refractoryCitation2.
Ciltacabtegene’s efficacy was assessed in two clinical trials, Cartitude 1 and 2. Cartitude 1 recruited 97 pts with MM who have received ≥3 prior therapies or were refractory to a PI and an IMiD and had received a PI, IMiD, and an anti-CD38 antibody; among them 83.5% were penta-drug exposed, 87.6% were triple-class refractory, 42.3% were penta-drug refractory, and 99.0% were refractory to last line of therapy. The reported overall response rate was ORR was 97.9% (95% CI: 92.7–99.7)Citation3. Cartitude 2 patients’ had progressive MM after 1–3 prior lines of therapy including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and refractory to lenalidomide. 95% of the recruited patients were refractory to the last line of treatment and 40% were triple refractory. Overall response rate was 95% which concurs well with Cartitude 1Citation4.
The euphoria stemming out of these results had to be weighted up against their financial impact, which constitutes their most iconic blueprint. Their soaring-and in particular- upfront costs are anticipated to foment financial impediments for many healthcare systems world-wide. The ingrained uncertainty is further aggravated by the lack of long-term data, which is usually spanned by extrapolation based on similar patient cohorts. This further annotates the need for high-quality data prior to their reimbursement. In this context, the role of cost-utility analysis has been established as the pinnacle in decision-making and can compound uncertainty, which perpetuates to the efficient use of monetary resources. To our knowledge, currently only two economic evaluations of Idecabtagene vicleucel were published, one combined in France and Canada which reported that their ICER is comparable to other relapsed/refractory MM (RRMM) agents, albeit exceeding Willingness-to-pay (WTP) thresholdCitation5. A second study hailing from USA postulated dominance of Ciltacabtagene autoleucel over idecabtagene and a positive ICER vs belamafCitation6.
Wu et al. manuscript (submitted to Journal of Medical Economics) seeks to address the efficiency of Ciltabtagene and Idecabtagene in China’s Health SystemCitation7. They elaborated a four-state, 20-year horizon Markov Model for RRMM following 4 or more lines of therapy. Clinical data were mined from Cartitude 1, KarMMa and MAMMOTHCitation8 trials. Regarding extrapolation, authors presumed that once patients were on remission for 5 years, they were regarded cured. Due to the fact that all CAR-T studies were single arm, which is further complicated by the multitude of therapeutic regimens across RRMM lines of treatment, the definition of comparative arm was informed by actual Chinese Real World Data (RWD).
Results
Ide-cel brought about $200,577 and it yielded 2.5 life years gained (LYG) and 2.14 quality-adjusted life years (QALY)s. Cilta-cel was associated with a lower discounted cost ($187,013) while its commensurate health gains were 4.77 LYG and 4.26 QALYs respectively. It was noted that a substantial percentage of Cilta-cel patients were classified as long-term survivors, while the corresponding percentage in the Ida-cel arm was 3.5%. The cost of salvage chemotherapy was assessed at $72,129 and it brought about 1.19 LYG years and 0.92 QALYs gained, while it failed to achieve long-term survival in any patient.
Based on China’s WTP threshold, the incremental cost-utility ratio (ICUR) of Cilta-cel vs salvage chemotherapy ($34,351) was considered as cost-effective, while, on the contrary, the corresponding one of Ida-cel vs salvage chemotherapy ($105,285) extended beyond the WTP threshold.
The results were sensitive to the prices of CAR-T, discount rate, cost of salvage chemotherapy, long-term survival utility and PFS, factors which corroborate with previously published economic evaluations of other CAR-T, specifically regarding prices and discountingCitation9.
This is an important study being the first one to assess the efficiency of these agents in China and underpins the contribution of high-quality economic evaluations in the decision-making process for pharmaceuticals. Economic evaluations can cast light to uncertainty and contain irrational decisions, usually driven by short-term political gains. Certain limitations were underlined, such as the use of proxy prices instead of actual ones, the assumptions in the long-term extrapolation and the product composition of salvage chemotherapy, however, the robustness of the methodology safeguards the credibility of the results. Especially, the uncertainty that engulfs the long-term efficacy and safety of CAR-T is yet to be elucidated. In contrast to older agents, we still have not gleaned the coveted long-term data, and in order to span this gap, we rely on extrapolation, with all the limitations this approach yields.
This study adds to the emerging body of evidence pertinent to the efficiency of CAR-T agents. The economic evaluation constitutes a potent tool, however it is important to interlace efficiency to the ability to fund. Budget Impact Analysis has come to the fore as an integral and vital part of the decision-making process. In addition, it is imperative to reimburse these agents on the backdrop of Managed Entry Agreements (MEA). Ideally, these MEA should cover duration of response, assessment of OS and PFS at specific time intervals, number of patients whose treatment failed and the need for bridging therapy, safety issues (I.e serious adverse events and infusion related ones, need for tocilizumab) production time of the agent and availability of accredited centers.
Transparency
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Acknowledgements
None reported.
Declaration of funding
This editorial was written independently; no company or institution supported the authors financially or by providing a professional writer.
Declaration of financial/other relationships
The author and peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
References
- Nijhof IS, van de Donk NWCJ, Zweegman S, et al. Current and new therapeutic strategies for relapsed and refractory multiple myeloma: an update. Drugs. 2018;78(1):19–37. doi: 10.1007/s40265-017-0841-y.
- Munshi NC, Anderson LD, Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705–716. PMID: 33626253. doi: 10.1056/NEJMoa2024850.
- Martin T, Usmani SZ, Berdeja JG, et al. Ciltacabtagene autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: Cartitude-1 2-year follow-up. J Clin Oncol. 2023;41(6):1265–1274. doi: 10.1200/JCO.22.00842.
- Agha ME, Cohen AD, Madduri D, et al. CARTITUDE-2: efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, in patients with progressive multiple myeloma (MM) after one to three prior lines of therapy. J Clin Oncol. 39(15_suppl):8013–8013. doi: 10.1200/JCO.2021.39.15_suppl.8013.
- Karampampa K, Zhang W, Venkatachalam M, et al. Cost-effectiveness of idecabtagene vicleucel compared with conventional care in triple-class exposed relapsed/refractory multiple myeloma patients in Canada and France. J Med Econ. 2023;26(1):243–253. doi: 10.1080/13696998.2023.2173466.
- Kapinos KA, Hu E, Trivedi J, et al. Cost-effectiveness analysis of CAR T-cell therapies vs antibody drug conjugates for patients with advanced multiple myeloma. Cancer Control. 2023;30:10732748221142945. PMID: 36651055; PMCID: PMC9869188. doi: 10.1177/10732748221142945.
- Wu W, Ding S, Mingming Z, et al. Cost effectiveness analysis of CAR-T cell therapy for patients with relapsed/refractory multiple myeloma in China. J Med Econ. 2023;26(1):701–709. doi: 10.1080/13696998.2023.2207742.
- Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266–2275. doi: 10.1038/s41375-019-0435-7.
- Petrou P. Is it a chimera? A systematic review of the economic evaluations of CAR-T cell therapy - an update. Expert Rev Pharmacoecon Outcomes Res. 2023. doi: 10.1080/14737167.2023.2214731.