Cost-Effectiveness of Axicabtagene Ciloleucel for Adult Patients With Relapsed or Refractory Follicular Lymphoma in the United States.

OBJECTIVES: The results of a recent single-arm trial (ZUMA-5) of axicabtagene ciloleucel (axi-cel) for relapsed/refractory (r/r) follicular lymphoma (FL) demonstrated high rates of durable response and tolerable toxicity among treated patients. To quantify the value of axi-cel compared with standard of care (SOC) to manage r/r FL patients who have had at least 2 prior lines of systemic therapy (3L+), a cost-effectiveness model was developed from a US third-party payer perspective. METHODS: A 3-state partitioned-survival cost-effectiveness model was developed with a lifetime horizon. Patient-level analyses of the 36-month ZUMA-5 (axi-cel) and SCHOLAR-5 (SOC) studies were used to extrapolate progression-free and overall survivals. After 5 years of survival, an estimated 40% of the modeled population was assumed to experience long-term remission based on literature. Results include the incremental cost-effectiveness ratio (ICER) measured as incremental cost per quality-adjusted life year (QALY) gained. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analyses were performed. All outcomes were discounted 3% per year. RESULTS: Axi-cel led to an increase of 4.28 life-years, 3.64 QALYs, and a total cost increase of $321 192 relative to SOC, resulting in an ICER of $88 300 per QALY. Across all parameters varied in the one-way sensitivity analysis, the ICER varied between $133 030 and $67 277. In the probabilistic sensitivity analysis, axi-cel had a 99% probability of being cost-effective across 5000 iterations using a $150 000 willingness-to-pay threshold. CONCLUSIONS: Given the robustness of the model results and sensitivity analyses, axi-cel is expected to be a cost-effective treatment in 3L+ r/r FL.

Cost-effectiveness analysis 3L of axicabtagene ciloleucel vs tisagenlecleucel and lisocabtagene maraleucel in Japan.

Aim: Cost-effectiveness analysis (CEA) was performed to compare axicabtagene ciloleucel (axi-cel) with tisagenlecleucel (tisa-cel) and lisocabtagene (liso-cel) for treatment of relapsed or refractory large B-cell lymphoma in adult patients after ≥2 lines of therapy in Japan. Materials & methods: Cost-effectiveness analysis was conducted using the partition survival mixture cure model based on the ZUMA-1 trial and adjusted to the JULIET and TRANSCEND trials using matching-adjusted indirect comparisons. Results & conclusion: Axi-cel was associated with greater incremental life years (3.13 and 2.85) and incremental quality-adjusted life-years (2.65 and 2.24), thus generated lower incremental direct medical costs (-$976.29 [-¥137,657] and -$242.00 [-¥34,122]), compared with tisa-cel and liso-cel. Axi-cel was cost-effective option compared with tisa-cel and liso-cel from a Japanese payer's perspective.

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Cost-effectiveness of axicabtagene ciloleucel versus lisocabtagene maraleucel for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy in the US.

AIMS: This study evaluated from a US payer perspective the cost-effectiveness of two chimeric antigen receptor T (CAR T) cell therapies, axicabtagene ciloleucel (axi-cel) versus lisocabtagene maraleucel (liso-cel), for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma (LBCL) following two or more systemic therapy lines. METHODS: We developed a 3-state (i.e., pre-progression, post-progression, death) partitioned survival model to estimate patients' lifetime outcomes. Mixture cure models were used for survival extrapolation to account for long-term remission. Survival inputs were based on a matching-adjusted indirect comparison (MAIC) that reweighted the ZUMA-1 population (receiving axi-cel) to match patient characteristics in TRANSCEND-NHL-001 (assessing liso-cel). Costs included apheresis, drug acquisition, and administration for conditioning chemotherapy and CAR T therapies, monitoring, transplant, hospitalization, adverse events, routine care, and terminal care, per published literature and databases. Utilities were derived from ZUMA-1 and literature. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: In the base case, axi-cel was associated with more QALYs (7.76 vs. 5.94) and greater costs overall ($611,440 vs. $597,174) than liso-cel, at $7,843/QALY gained. The incremental costs (+$14,266) were largely driven by higher routine care costs (+$18,596) due to longer survival and hospitalization (+$10,993) but partially offset by reduced costs of CAR T acquisition (‒$11,300) and terminal care (‒$4,025). Sensitivity analyses consistently suggested robustness of base-case results. LIMITATIONS: This study relied on an MAIC in which trial design differences and unobserved confounders could not be accounted for. Future real-world studies for recently approved CAR T are warranted to validate our results. Due to a lack of data, we assumed equivalent use of transplants and treatment for B-cell aplasia between the two therapies based on clinicians' opinions. CONCLUSIONS: In the US, axi-cel is a potentially cost-effective treatment option compared with liso-cel for adult patients with r/r LBCL after two or more systemic therapy lines.

Potentials, challenges and future of chimeric antigen receptor T-cell therapy in non-Hodgkin lymphomas.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. Disease progression or relapse following frontline chemoimmunotherapy, largely in the form of standard R-CHOP, occurs in 30-40% patients. Relapsed/refractory (R/R) DLBCL represents a major unmet medical need. In particular, patients with primary refractory disease or those whose lymphoma relapses after autologous stem cell transplantation have historically had poor outcomes.Material and methods: Chimeric antigen receptor T-cell (CART) therapy is a promising novel treatment with curative potential in this setting. CART is based on ex vivo genetic modification of autologous T-cells to express chimeric receptors targeting antigens highly expressed in tumors such as CD19 in DLBCL. After lymphocyte-depleting therapy, patients are infused with CARTs that expand in vivo and target CD19-positive lymphoma cells.Results: In initial phase I-II trials, investigators have demonstrated complete responses in 40-50% of patients with R/R DLBCL, resulting in durable remission approaching 3 years of follow-up in most of these patients without further treatment. The logistics of delivery are complex as cell products require timely long-distance transfer between hospitals and production facilities. The unique toxicity profile of CARTs, including the risk of fatal immunological and neurologic events, also requires specific hospital wide management approaches and education. The substantial direct and indirect costs of CART will limit access even in countries with well resourced health care systems.Conclusions: While only two products are commercially available at present, further approvals in coming years appear likely. Future directions include CARTs with reactivity to tumor antigens other than CD19 and products targeting multiple tumor antigens to overcome resistance. The availability of CART has altered the current treatment algorithm for R/R DLBCL, and indications will likely expand to earlier lines of therapy and other hematologic malignancies.

Development and Use of the Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy Axicabtagene Ciloleucel in Large B-Cell Lymphoma: A Review.

Importance: Axicabtagene ciloleucel, an anti-CD19-CD28-CD3ζ chimeric antigen receptor T-cell therapy, was the first US Food and Drug Administration-approved, genetically engineered T-cell therapy for adults with relapsed or refractory large B-cell lymphoma (LBCL) after 2 or more lines of systemic therapy. There has not been a US Food and Drug Administration-approved product for these cancers in more than 4 decades. Observations: Unlike traditional anticancer therapies, axicabtagene ciloleucel is a patient-specific, live-cell product that has unique requirements for manufacturing, shipping, and storage, as well as for its administration and management of its adverse events. In addition, axicabtagene ciloleucel has demonstrated efficacy in patients with refractory LBCL. This review presents a timeline of the rapid clinical development of axicabtagene ciloleucel from bench to bedside, highlights how axicabtagene ciloleucel satisfies an unmet medical need for treatment of refractory LBCL, outlines the logistics of the production process and administration of axicabtagene ciloleucel, describes its mechanism of action, and summarizes the results of the pivotal study. This review also provides a survey of adverse events, with attention to the kinetics of their clinical presentation; discusses the management of adverse events; and offers suggestions for appropriate patient selection for safe administration of axicabtagene ciloleucel. Conclusions and Relevance: The integration of axicabtagene ciloleucel therapy into standard-of-care practice for relapsed/refractory LBCL is the beginning of a paradigm shift in the treatment of patients with LBCL and is likely to lead to improvements in their survival and curability. Timely referral to centers offering the therapy is necessary for optimal patient outcomes.

Is it a Chimera? A systematic review of the economic evaluations of CAR-T cell therapy.

Introduction: The new category of chimeric antigen receptor T - cell raised hopes for a more effective treatment of large B cell lymphoma and acute lymphoblastic leukemia. Nevertheless, their soaring acquisition costs will stretch the fiscal capacity of the health systems worldwide. To this direction, the scope of this study is to provide a systematic review of their economic evaluations. Areas covered: A systematic review of the economic evaluations of tisagenlecleucel and axicabtagene was performed. Expert opinion: The available data indicate that these products demonstrate a potentially favorable cost-effectiveness ratio. Nevertheless, their budget impact is of overriding importance and it should be incorporated in any economic evaluation. Moreover, more affirmative clinical data are imperative in order to mitigate uncertainty.

The potential impact of CAR T-cell treatment delays on society.

OBJECTIVES: To date, breakthrough chimeric antigen receptor (CAR) T-cell therapies, such as tisagenlecleucel, indicated for pediatric acute lymphoblastic leukemia (pALL) and diffuse large B-cell lymphoma (DLBCL), and axicabtagene ciloleucel, indicated for DLBCL, although clinically effective, have been limited by treatment delays. Our study measured the social value of CAR T-cell therapy (CAR T) for relapsed or refractory pALL and DLBCL in the United States and quantified social value lost due to treatment delays. STUDY DESIGN: We used an economic framework for therapy valuation, measuring social value as the sum of consumer surplus and manufacturer profit. Consumer surplus is the difference between the value of health gains from a therapy and its incremental cost, while accounting for indirect costs and benefits to patients. METHODS: For 20 incident cohorts of pALL (n = 20 × 400 = 8000) and DLBCL (n = 20 × 5902 = 118,040), we quantified patient value, calculated as the value of additional quality-adjusted life-years gained with CAR T, minus the incremental cost of CAR T compared with standard of care (SOC). We calculated manufacturer profits using a range of production costs given uncertainties in the production process. Patient value and manufacturer profits were summed to obtain total social value. We measured social value lost from treatment delays, assuming that patients received the SOC while awaiting CAR T-cell treatment. RESULTS: Depending on production costs, as much as $6.5 billion and $34.8 billion in social value was generated for patients with pALL and DLBCL, respectively. However, with 1, 2, or 6 months of treatment delay (assuming $200,000 production costs), the pALL population lost 9.8%, 36.2%, and 67.3% of social value, respectively, whereas the DLBCL population lost 4.2%, 11.5%, and 46.0%, relative to no delay. CONCLUSIONS: The social value of CAR T is significantly limited by treatment delays. Efficient payment mechanisms, adequate capital, and payment policy reform are urgently needed to increase patient access and maximize the value of CAR T.

Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Multiply Relapsed or Refractory Adult Large B-Cell Lymphoma.

PURPOSE: Two anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies are approved for diffuse large B-cell lymphoma, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel; each costs $373,000. We evaluated their cost effectiveness. METHODS: We used a decision analytic Markov model informed by recent multicenter, single-arm trials to evaluate axi-cel and tisagenlecleucel in multiply relapsed/refractory, adult, diffuse large B-cell lymphoma from a US health payer perspective over a lifetime horizon. Under a range of plausible long-term effectiveness assumptions, each therapy was compared with salvage chemoimmunotherapy regimens and stem-cell transplantation. Main outcomes were undiscounted life years, discounted lifetime costs, discounted quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (3% annual discount rate). Sensitivity analyses explored uncertainty. RESULTS: In an optimistic scenario, assuming a 40% 5-year progression-free survival (PFS), axi-cel increased life expectancy by 8.2 years at $129,000/QALY gained (95% uncertainty interval, $90,000 to $219,000). At a 30% 5-year PFS, improvements in life expectancy were more modest (6.4 years) and expensive ($159,000/QALY gained [95% uncertainty interval, $105,000 to $284,000]). In an optimistic scenario, assuming a 35% 5-year PFS, tisagenlecleucel increased life expectancy by 4.6 years at $168,000/QALY gained (95% uncertainty interval, $105,000 to $414,000/QALY). At a 25% 5-year PFS, improvements in life expectancy were smaller (3.4 years) and more expensive ($223,000/QALY gained [95% uncertainty interval, $123,000 to $1,170,000/QALY]). Administering CAR-T to all indicated patients would increase US health care costs by approximately $10 billion over 5 years. Price reductions to $250,000 and $200,000, respectively, or payment only for initial complete response (at current prices) would allow axi-cel and tisagenlecleucel to cost less than $150,000/QALY, even at 25% PFS. CONCLUSION: At 2018 prices, it is possible that both CAR-T therapies meet a less than $150,000/QALY threshold. This depends on long-term outcomes compared with chemoimmunotherapy and stem-cell transplantation, which are uncertain. Widespread adoption would substantially increase non-Hodgkin lymphoma health care costs. Price reductions or payment for initial response would improve cost effectiveness, even with modest long-term outcomes.

Long-term Survival and Cost-effectiveness Associated With Axicabtagene Ciloleucel vs Chemotherapy for Treatment of B-Cell Lymphoma.

Importance: Axicabtagene ciloleucel, a chimeric antigen receptor T-cell therapy, represents a new and potentially curative treatment option for B-cell lymphoma. It is expected to have long-term survival benefits; however, long-term survival data are limited. Objective: To estimate the long-term survival and cost-effectiveness of axicabtagene ciloleucel for treatment of relapsed or refractory B-cell lymphoma. Design, Setting, and Participants: Economic evaluation study using a survival analysis that digitized and extrapolated survival curves published in the ZUMA-1 trial (Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma), which enrolled patients between November 2015 and September 2016 and had a maximum follow-up of 24 months. Five different survival models (standard parametric, flexible parametric, 2 mixture cure models, and a flexible parametric mixture model) were used to extrapolate the survival curves to a lifetime horizon from January through June 2018. A cost-effectiveness analysis, from both a trial-based and lifetime horizon, was also conducted to inform the value of this novel therapy. The model was based on data from 111 patients with B-cell lymphoma who were enrolled in the ZUMA-1 trial. Interventions: One-time administration of axicabtagene ciloleucel compared with chemotherapy. Main Outcomes and Measures: Undiscounted and discounted life-years (LYs) and quality-adjusted life-years (QALYs), total costs, and incremental costs per LY and QALY gained. Results: The modeled cohort of 111 patients started at 58 years of age. At the end of the trial, treatment with axicabtagene ciloleucel resulted in 0.48 more LYs and 0.34 more QALYs than chemotherapy, producing a cost-effectiveness estimate of $896 600 per QALY for public payers and $1 615 000 per QALY for commercial payers. Extrapolated long-term survival for patients treated with axicabtagene ciloleucel ranged from 2.83 to 9.19 discounted LYs and from 2.07 to 7.62 discounted QALYs. Incrementally, treatment with axicabtagene ciloleucel was associated with 1.89 to 5.82 discounted LYs and 1.52 to 4.90 discounted QALYs vs chemotherapy. With the use of these incremental estimates of survival, cost-effectiveness estimates ranged from $82 400 to $230 900 per QALY gained for public payers and from $100 400 to $289 000 per QALY gained for commercial payers. Conclusions and Relevance: Treatment with axicabtagene ciloleucel appears to be associated with incremental gains in survival over chemotherapy. The range in projected long-term survival was wide and reflected uncertainty owing to limited follow-up data. Cost-effectiveness is associated with long-term survival, with further evidence needed to reduce uncertainty.