Cost-effectiveness of treating relapsed or refractory 3L+ follicular lymphoma with axicabtagene ciloleucel vs mosunetuzumab in the United States.

Introduction: Novel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) have been approved recently by the US Food and Drug Administration including anti-CD19 CAR-T therapies such as axicabtagene ciloleucel (axi-cel) and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies such as mosunetuzumab (mosun). The objective of this study was to assess the cost-effectiveness of axi-cel compared to mosun in 3L+ r/r FL patients from a US third-party payer perspective. Methods: A three-state (progression-free, progressed disease, and death) partitioned-survival model was used to compare two treatments over a lifetime horizon in a hypothetical cohort of US adults (age ≥18) receiving 3L+ treatment for r/r FL. ZUMA-5 and GO29781 trial data were used to inform progression-free survival (PFS) and overall survival (OS). Mosun survival was modeled via hazard ratios (HRs) applied to axi-cel survival curves. The PFS HR value was estimated via a matching-adjusted indirect comparison (MAIC) based on mosun pseudo-individual patient data and adjusted axi-cel data to account for trial populations differences. One-way sensitivity analysis (OWSA) and probabilistic sensitivity analyses (PSA) were conducted. Scenario analyses included: 1) the mosun HRs were applied to the weighted (adjusted) ZUMA-5 24-month data to most exactly reflect the MAIC, 2) mosun HR values were applied to axi-cel 48-month follow-up data, and 3) recent axi-cel health state utility values in diffuse large B-cell lymphoma patients. Results: The analysis estimated increases of 1.82 LY and 1.89 QALY for axi-cel compared to mosun. PFS for axi-cel patients was 6.42 LY vs. 1.60 LY for mosun. Increase of $257,113 in the progression-free state was driven by one-time axi-cel treatment costs. Total incremental costs for axi-cel were $204,377, resulting in an ICER of $108,307/QALY gained. The OWSA led to ICERs ranging from $240,255 to $75,624, with all but two parameters falling below $150,000/QALY. In the PSA, axi-cel had an 64% probability of being cost-effective across 5,000 iterations using a $150,000 willingness-to-pay threshold. Scenarios one and two resulted in ICERs of $105,353 and $102,695, respectively. Discussion: This study finds that axi-cel is cost-effective compared to mosun at the commonly cited $150,000/QALY US willingness-to-pay threshold, with robust results across a range of sensitivity analyses accounting for parameter uncertainty.

Medicare Utilization and Cost Trends for CAR T Cell Therapies Across Settings of Care in the Treatment of Diffuse Large B-Cell Lymphoma.

INTRODUCTION: Chimeric antigen receptor T-cell (CAR T) therapies have transformed diffuse large B-cell lymphoma (DLBCL) treatment. It is important to better understand their use in Medicare Fee-for-Service (FFS) patients, who often differ from commercially insured populations in important ways. METHODS: We analyzed Medicare FFS claims data, focusing on the utilization patterns across three CAR T products-lisocabtagene maraleucel (liso-cel), tisagenlecleucel (tisa-cel), and axicabtagene autoleucel (axi-cel)-which are indicated for the treatment of DLBCL. Our investigation covered the period from 2021 through 2022. This analysis spanned a 180-day period prior to CAR T procedure and extended to a 90-day post-CAR T. Utilization of healthcare services, healthcare spending, and comorbidities were assessed in the pre- and post-periods. Clinical trial and PPS-exempt center claims were removed from the analysis. Statistical comparisons between inpatient and outpatient cohorts were made using Wilcoxon's rank-sum tests for continuous variables and Chi-square tests or Fisher's exact tests for categorical variables. RESULTS: Among the total 391 CAR T claims assessed, most of the CAR T therapies were administered in the inpatient setting (79%) compared to outpatient (21%). CAR T therapy in the inpatient setting received an average Medicare cost of US$498,723 ($276,138-$1,066,524), while the average Medicare cost for outpatient CAR T claims was $414,393 ($276,980-$849,878). There was a higher 3-month average post-period cost for those hospitals utilizing CAR T in the outpatient setting than the inpatient setting ($15,794 vs. $10,244). Despite the higher post-period cost, when looking at the CAR T procedure and pre- and post-periods as a single episode, beneficiaries receiving outpatient CAR T had less cost for the total episode of care ($587,908 vs. $529,188). Follow-up inpatient claims were also assessed post-CAR T procedure for 30 days. The rate of post-CAR T inpatient re-admission was significantly lower for beneficiaries receiving the index CAR T in the inpatient setting (21%) compared to outpatient CAR T (59%). Days between index CAR T discharge and IP admission were also significantly shorter for OP CAR T compared to IP CAR T (8.0 vs. 14.1 days, p < 0.0001). Additionally, IP CAR T had a longer ALOS on the admission claim (6.9 vs. 6.2 days). CONCLUSION: CAR T therapy for the treatment of LBCL has become more common within the Medicare population, primarily in the inpatient setting. This study helps understand providers' cost and associated patient care around CAR T administration. The data show that the average cost received by hospitals encompasses the expenses related to both the CAR T drug and the medical services delivered to patients.

Economic evaluation of anti-CD19 CAR T-cell pathway for large B-cell lymphomas in the real-life setting: the experience of an Italian hub center in the first three years of activity.

Poor literature report actual and detailed costs of chimeric antigen receptor (CAR) T-cell pathway in a real-life setting. We retrospectively collect data for all patients with relapsed/refractory aggressive large B-cell lymphoma who underwent leukapheresis between August 2019 and August 2022. All costs and medical resource consumption accountability were calculated on an intention-to-treat (ITT) basis, starting from leukapheresis to the time when the patient (infused or not) exited the CAR T-cell pathway for any reason. Eighty patients were addressed to leukapheresis and 59 were finally infused. After excluding CAR-T product cost, the main driver of higher costs were hospitalizations followed by the examinations/procedures and other drugs, respectively 43.9%, 26.3% and 25.4% of the total. Regarding costs of drugs and medications other than CAR T products, the most expensive items are those referred to AEs, both infective and extra-infective within 30 days from infusion, that account for 63% of the total. Density plot of cost analyses did not show any statistically significant difference with respect to the years of leukapheresis or infusion. To achieve finally 59/80 infused patients the per capita patients without CAR-T products results 74,000 euros. This analysis covers a growing concern on health systems, the burden of expenses related to CAR T-cell therapy, which appears to provide significant clinical benefit despite its high cost, thus making economic evaluations highly relevant. The relevance of this study should be also viewed in light of continuously evolving indications for this therapy.

The importance of a go-to-market strategy in the commercialisation of cellular immunotherapies.

Cellular immunotherapy (CIT) has both demonstrated outstanding levels of efficacy in cancer and presented unique commercialisation challenges. A historical analysis of go-to-market (G2M) strategies used to develop the first chimeric antigen receptor T cells (CAR-Ts) can offer insight into how companies leverage partnership or independence to ensure commercial success. Collaboration-based strategies, such as partnerships, acquisitions, and licensing deals, have predominated in the industry to maximise revenue and patient access. Manufacturing, logistical, and regulatory challenges have hindered independent commercialisation. Nonetheless, the industry is adapting to these challenges: novel technologies show superior affordability and implementability, and commercial solutions organisations (CSOs) increasingly help CIT companies navigate through commercialisation issues independently. G2M strategies in this industry are therefore likely to evolve, with independence becoming a feasible strategy for commercial success.

Hospital healthcare resource utilization and costs for chimeric antigen T-cell therapy and autologous hematopoietic cell transplant in patients with large B-cell lymphoma in the United States.

The efficacy of chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL) is well-established. This study, using the Premier PINC AI Healthcare Database, assessed hospital costs and healthcare resource utilization (HRU) between CAR T-cell therapy and autologous hematopoietic cell transplant (AHCT) for 733 LBCL patients from 01/01/2017-04/30/2021 (166 CAR T and 567 AHCT from 37 US hospital systems. CAR T-cell therapy had higher index costs but lower non-pharmacy costs, shorter hospital stays, lower ICU utilization than AHCT. The CAR T-cell cohort also presented fewer preparatory costs and HRU. At a 180-day follow-up, AHCT had lower hospitalization rates and costs. Overall, despite higher index costs, CAR T-cell therapy has lower non-pharmacy costs and HRU during the index procedure and requires less preparation time with lower preparation HRUs and costs than AHCT. This has important implications for resource management and informed decision-making for stakeholders.

"Don't keep me waiting": estimating the impact of reduced vein-to-vein time on lifetime US 3L+ LBCL patient outcomes.

ABSTRACT: Chimeric antigen receptor T-cell therapy (CAR T) has revolutionized the treatment of hematological cancers. Its production requires a complex logistical process, and the time from leukapheresis to patient infusion (known as the vein-to-vein time [V2VT]) can be long during which a patients clinical condition may deteriorate. This study was designed to estimate the benefits of reduced V2VT for third-line or later (3L+) relapsed/refractory large B-cell lymphoma (R/R LBCL) patients treated with CAR T. A mathematical model was developed to estimate the lifetime outcomes of a hypothetical cohort of patients who had either a long or short V2VT. Life-years (LYs), quality-adjusted LYs (QALYs), and costs were estimated. Scenario analyses were performed to assess the robustness of results to key assumptions. The results of the model show that reducing V2VT from 54 days (tisa-cel median V2VT; JULIET) to 24 days (axi-cel median V2VT; ZUMA-1) led to a 3.2-year gain in life expectancy (4.2 vs 7.7 LYs), and 2.4 additional QALYs (3.2 vs 5.6) per patient. Furthermore, a shorter V2VT was shown to be cost-effective under conventional willingness-to-pay thresholds in the United States. Results are driven by a higher infusion rate and a better efficacy of CAR T for those infused. Scenario analyses using a smaller difference in V2VT (24 vs 36 days) produced consistent results. Our study is the first to quantify lifetime V2VT-related outcomes for 3L+ R/R LBCL patients treated with CAR T utilizing currently available evidence. Shorter V2VTs led to improved outcomes, demonstrating the importance of timely infusion achievable by faster manufacturing times and optimization of hospital delivery.

Cost-effectiveness analysis of KTE-X19 CAR T therapy versus real-world standard of care in patients with relapsed/refractory mantle cell lymphoma post BTKi in England.

AIMS: The objective of this study is to estimate the cost-effectiveness of KTE-X19 versus standard of care (SoC) in the treatment of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) post-Bruton tyrosine kinase inhibitor (BTKi) treatment from a UK healthcare perspective. MATERIALS AND METHODS: A three-state partitioned survival model (pre-progression, post-progression and death) with a cycle length of one month was used to extrapolate progression-free and overall survival over a lifetime horizon. Population inputs along with KTE-X19 (brexucabtagene autoleucel) efficacy and safety data were derived from the single-arm trial ZUMA-2 (NCT02601313). The composition of SoC was informed by a literature-based meta-analysis, SoC efficacy data were obtained from the SCHOLAR-2 real-world study. Survival was modelled using standard parametric curves for SoC and a mixture-cure methodology for KTE-X19. It was assumed that patients whose disease had not progressed after five years experienced long-term remission. Costs, resource use and utility, and adverse event disutility inputs were obtained from published literature and publicly available data sources. An annual discount rate of 3.5% was applied to costs and health outcomes. Modelled outcomes for KTE-X19 and SoC included expected life years (LY), quality-adjusted life years (QALY) and total costs. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed. RESULTS: Estimated median survival was 5.96 years for KTE-X19 and 1.38 for SoC. Discounted LYs, QALYs and lifetime costs were 8.27, 5.99 and £385,765 for KTE-X19 versus 1.98, 1.48 and £79,742 for SoC, respectively. The KTE-X19 versus SoC cost per QALY was £67,713 and the cost per LY was £48,645. Influential scenario analyses use alternative KTE-X19 survival curves and discount rates, and shorter time horizons. CONCLUSION: Considering the survival and quality of life benefits compared to SoC, KTE-X19 for R/R MCL appears as a cost-effective treatment in the real-world UK setting.

Health Care Resource Utilization and Total Costs of Care Among Patients with Diffuse Large B Cell Lymphoma Treated with Chimeric Antigen Receptor T Cell Therapy in the United States.

The use of chimeric antigen receptor (CAR) T-cell therapy after a second relapse of diffuse large B-cell lymphoma (DLBCL) has shown favorable efficacy in clinical trials; however, little is known about health care resource utilization (HCRU) and costs of CAR T cell therapy for patients treated in real-world settings. We assessed treatment patterns, HCRU, costs, and safety in patients receiving CAR T cell therapy for relapsed or refractory DLBCL across 3 US commercial claims databases. Adults with DLBCL treated with CAR T cell therapy were identified in the following 3 claims databases: Optum® Clinformatics® Data Mart, IBM MarketScan® Commercial & Medicare Database, and IQVIA PharMetrics® Plus. Mean total costs were calculated and adjusted to 2019 US dollars. HCRU and costs within 3 months of infusion were stratified by safety events of interest, including neurological events (NEs) and cytokine release syndrome (CRS), identified via unvalidated algorithms designed based on expert medical opinion. A total of 191 patients receiving CAR T cell therapy were identified across the databases; their median age ranged from 56 to 67 years, and 63% to 75% were male. Most patients (88% to 98%) received CAR T cell infusions in the inpatient setting; 30% to 75% received bridging therapy. CRS was reported in 75% to 84% of patients (severe CRS, 15% to 32%), and NEs were reported in 58% to 69% (severe NEs, 25% to 43%). Mean total inpatient hospital days ranged from 17 to 22 days and increased with severe CRS (19 to 27 days) or severe NEs (22 to 29 days). Mean total health care expenditures ranged from $380,000 to $526,000 and were generally higher with severe CRS or NEs (∼$406,000 to $679,000). HCRU and costs associated with CAR T cell therapy may vary in the real world depending on several factors, including occurrence and severity of adverse events.

[CAR-T CELLS: How does the EBMT registry monitor European activities, identify hurdles and prepare for changes in regulations]. / CAR-T cells : comment le registre de l'EBMT monitore les activités en Europe, identifie les contraintes et prépare l'évolution des régulations.

CAR-T Cells are gene therapy medicinal products, a subcategory of Advanced Therapy Medicinal Products as defined in the EC Regulation 1394/2007. They may represent the first example of such medicinal products that are industry-manufactured and commercialized on a large scale. Their very nature, their manufacturing processes, pricing and conditions upon which they were approved by regulatory agencies, all lead the latter to require long-term follow-up after marketing approval with a view for a better definition of CAR-T Cells safety profile and efficacy profile in real world conditions. Collection and analysis of data over a 15-year period of time represents a technical and political challenge. So does the a priori definition of data to be collected for a wealth of forthcoming analyses that focus on the interests of a variety of stakeholders. EBMT has been collecting and analyzing data on hematopoietic cell transplants for decades. EBMT currently works with many interested parties to collect data on patients treated with CAR-T Cells.

Challenges raised by the economic evaluation of CAR-T-cell therapies. The review by the French National Authority for Health.

Since 2013, the process of pricing of innovative drugs by the French National Health Insurance has considered both cost-effectiveness and budget impact. CAR-T cell therapies were first subject to economic evaluation from 2019 in France. We aim to describe the process and results of the economic evaluation of tisagenlecleucel and axicabtagene ciloleucel as well as the challenges these evaluations raised. Evaluations submitted by the firms were reviewed by HAS and submitted to the Committee of Economic Evaluation and Public Health (CEESP). The CEESP issued opinions related to: (1) the methodological quality of economic evidence and, (2) the cost-effectiveness and budget impact of the drugs. The CEESP invalidated the estimated incremental cost-utility ratios (ICUR) of tisagenlecleucel due to the insufficient clinical evidence and methodological quality to extrapolate the long-term progression of the disease after treatment and compare tisagenlecleucel with alternatives. The CEESP concluded that tisagenlecleucel was not proven cost-effective. The estimated ICUR of axicabtagene ciloleucel at €114,509/QALY vs. chemotherapies was associated with an acceptable level of methodological quality despite being based on a weak indirect comparison and limited data on quality of life. The CEESP considered axicabtagene ciloleucel ICUR to be "very high" and questioned the societal/community willingness-to-pay of the claimed price. The primary source of uncertainty surrounding the ICUR estimates of both drugs was the lack of hindsight on effectiveness. The economic evaluation of CAR-T cell therapies highlights the risk of inefficient resource allocation driven by limited clinical data. It calls for payment schemes accounting for this risk and effective collection of post-marketing data.

How much does the hospital stay for infusion of anti-CD19 CAR-T cells cost to the French National Health Insurance?

Chimeric antigen receptor T-cells (CAR-T cells) have the potential to be a major innovation as a new type of cancer treatment, but are associated with extremely high prices and a high level of uncertainty. This study aims to assess the cost of the hospital stay for the administration of anti-CD19 CAR-T cells in France. Data were collected from the French Medical Information Systems Program (PMSI) and all hospital stays associated with an administrated drug encoded 9439938 (tisagenlecleucel, Kymriah®) or 9440456 (axicabtagene ciloleucel, Yescarta®) between January 2019 and December 2020 were included. 485 hospital stays associated with an injection of anti-CD19 CAR-T cells were identified, of which 44 (9%), 139 (28.7%), and 302 (62.3%) were for tisagenlecleucel in acute lymphoblastic leukaemia (ALL), tisagenlecleucel in diffuse large B-cell lymphoma (DLBCL), and axicabtagene ciloleucel respectively. The lengths of the stays were 37.9, 23.8, and 25.9 days for tisagenlecleucel in ALL, tisagenlecleucel in DLBCL, and axicabtagene ciloleucel, respectively. The mean costs per hospital stay were € 372,400 for a tisagenlecleucel in ALL, € 342,903 for tisagenlecleucel in DLBCL, and € 366,562 for axicabtagene ciloleucel. CAR T-cells represented more than 80% of these costs. n=13 hospitals performed CAR-T cell injections, with two hospitals accounting for more than 50% of the total number of injections. This study provides original data in a context of limited information regarding the costs of hospitalization for patients undergoing CAR-T cell treatments. In addition to the financial burden, distance may also be an important barrier for accessing CAR T-cell treatment.

Anti B-cell maturation antigen CAR T-cell and antibody drug conjugate therapy for heavily pretreated relapsed and refractory multiple myeloma.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Beinfeld, Fluetsch, and Pearson are employed by ICER. Ollendorf received funding from ICER for work on this summary and reports consulting and other personal fees from EMD Serono, Amgen, Analysis Group, Aspen Institute/University of Southern California, GalbraithWight, Cytokinetics, Executive Insight, Sunovion, University of Colorado, World Health Organization, and Eli Lilly, unrelated to this work. Lee and McQueen received funding from ICER for work on this summary.

Does Cost-Effectiveness Analysis Overvalue Potential Cures? Exploring Alternative Methods for Applying a "Shared Savings" Approach to Cost Offsets.

OBJECTIVES: To evaluate alternative methods to calculate and/or attribute economic surplus in the cost-effectiveness analysis of single or short-term therapies. METHODS: We performed a systematic literature review of articles describing alternative methods for cost-effectiveness analysis of potentially curative therapies whose assessment using traditional methods may suggest unaffordable valuations owing to the magnitude of estimated long-term quality-adjusted life-year (QALY) gains or cost offsets. Through internal deliberation and discussion with staff at the Health Technology Assessment bodies in England and Canada, we developed the following 3 alternative methods for further evaluation: (1) capping annual costs in the comparator arm at $150 000 per year; (2) "sharing" the economic surplus with the health sector by apportioning only 50% of cost offsets or 50% of cost offsets and QALY gains to the value of the therapy; and (3) crediting the therapy with only 12 years of the average annual cost offsets or cost offsets and QALY gains over the lifetime horizon. The impact of each alternative method was evaluated by applying it in an economic model of 3 hypothetical condition-treatment scenarios meant to reflect a diversity of chronicity and background healthcare costs. RESULTS: The alternative with greatest impact on threshold price for the fatal pediatric condition spinal muscular atrophy type 1 was the 12-year cutoff scenario. For a hypothetical one-time treatment for hemophilia A, capping cost offsets at $150 000 per year had the greatest impact. For chimeric antigen receptor T-cell treatment of non-Hodgkin's lymphoma, capping cost offsets or using 12-year threshold had little impact, whereas 50% sharing of surplus including QALY gains and cost offsets greatly reduced threshold pricing. CONCLUSIONS: Health Technology Assessment bodies and policy makers will wrestle with how to evaluate single or short-term potentially curative therapies and establish pricing and payment mechanisms to ensure sustainability. Scenario analyses using alternative methods for calculating and apportioning economic surplus can provide starkly different assessment results. These methods may stimulate important societal dialogue on fair pricing for these novel treatments.