Cost-Effectiveness of Lisocabtagene Maraleucel Versus Axicabtagene Ciloleucel and Tisagenlecleucel in the Third-Line or Later Treatment Setting for Relapsed or Refractory Large B-cell Lymphoma in the United States

Overview

In line with other published models of CAR T-cell therapies [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28], a Microsoft Excel®-based partitioned survival model was developed to estimate the cost-effectiveness of liso-cel versus axi-cel and tisa-cel in accordance with International Society for Pharmacoeconomics and Outcomes Research good modeling practice guidelines [29]. The modeled population was adults with R/R LBCL after at least two prior therapies including an anthracycline and rituximab (or other CD20-targeted agent), per the TRANSCEND NHL 001 (TRANSCEND) trial [30]. The model assumed the starting age was 60 years and 36% of patients were female, per TRANSCEND. The analysis considered direct medical costs only. A lifetime horizon (up to 50 years) was used to fully capture outcomes, and an annual discount rate of 3% was applied to cost and health outcomes as recommended by the Second Panel on Cost-Effectiveness in Health and Medicine [31]. The main outcome was incremental cost per quality-adjusted life-year (QALY) gained.

Kaplan-Meier survival curves for CAR T-cell therapies in 3L+ LBCL exhibit a plateau [32,33,34] in the long-term follow-up, indicating a fraction of patients may achieve durable remission. To capture this heterogeneity in survival outcomes, we used mixture cure models (MCM) to extrapolate progression-free survival (PFS) and overall survival (OS). MCMs assume that the population is a mixture of noncured (worse prognosis; shorter OS) and cured (better prognosis; OS similar to general population) patients. MCM simultaneously estimates the fraction of the studied population achieving cure and survival of those not achieving cure using parametric survival distributions [35]. Parametric distributions were selected on the basis of goodness of fit criteria and clinical plausibility of long-term projections and cure fractions (OS vs PFS) for each treatment [36].

Model Structure

The model included three health states: PFS, progressed disease, and death (Fig. 1). OS projections were used to determine those alive (and dead) over time, and PFS projections were used to further partition patients into PFS and progressed disease states. Patients remaining progression-free beyond 2 years were assumed to require less-frequent monitoring over time, and patients who progressed were assumed to receive subsequent treatment. A weekly cycle length was used for the first 5 years to enable accurate calculation of costs and QALYs associated with the relatively high rate of events in this interval, after which an annual cycle length was used to simplify model calculations without jeopardizing accuracy.

Fig. 1figure 1

Model structure. Patients intended to receive CAR T-cell therapy have a pretreatment period from leukapheresis until CAR T-cell infusion, during which patients receive lymphodepleting chemotherapy and bridging therapy (if needed). Some patients may not receive their CAR T-cell infusion owing to manufacturing errors, disease progression, or death; therefore, the model stratified patients according to the proportions who did not receive CAR T-cell infusion, per the respective trials, to accurately calculate the associated costs and outcomes before entering the partitioned survival model. CAR chimeric antigen receptor

Patients’ treatment experience from leukapheresis to CAR T-cell infusion can vary (Fig. 1). Patients who died before CAR T-cell infusion accrued QALYs during the pretreatment period and the cost of leukapheresis. Those who failed to receive CAR T-cell therapy for other reasons accrued costs and outcomes associated with salvage chemotherapy, the historical 3L+ standard of care, based on data from SCHOLAR-1 [1]. Total costs and outcomes of each treatment arm were an average of costs and outcomes for these cohorts and the respective CAR T-cell therapy, weighted according to this pretreatment period stratification as observed in the trials. Bridging chemotherapy (systemic, radiation, or both) for disease control during CAR T-cell product manufacturing is needed for some patients during the pre-infusion period. Bridging therapy protocols differed across clinical trials.

Model InputsSurvival Projections and Comparative Efficacy

For OS and PFS, patient-level data from TRANSCEND were used for liso-cel. For axi-cel, tisa-cel, and salvage chemotherapy, reconstructed patient-level data from ZUMA-1 [37, 38], JULIET [39], and SCHOLAR-1 [1] were used, respectively. For axi-cel, OS is based on a later data cut than those for PFS and safety as the latter were not published with the most recent ZUMA-1 follow-up [33].

For liso-cel, gamma and log-logistic distributions were chosen to extrapolate OS and PFS, respectively. These were fit independently and were used as the reference curve to which relative treatment effects were applied to project PFS and OS for axi-cel and tisa-cel (Fig. 2). Two-dimensional treatment effects (i.e., the effect on the estimated cure fraction and survival of noncured patients) were estimated by fitting joint MCM. In the base case, liso-cel data incorporated weights derived from pairwise unanchored matching-adjusted indirect comparisons (MAIC) versus tisa-cel [40] and axi-cel [41] (Supplemental Table 1) to minimize bias induced when comparing these single-arm studies. It should be noted that the MAIC versus axi-cel used in the base case did not match on use of bridging therapy because of its impact on the effective sample size [41], though this was an important difference between ZUMA-1 and TRANSCEND (bridging therapy was permitted in TRANSCEND but not in ZUMA-1). MAIC that matched on bridging therapy was used in the scenario analysis. A naïve comparison was also conducted in a scenario analysis.

Fig. 2figure 2

Long-term OS (A) and PFS projections (B). axi-cel axicabtagene ciloleucel, KM Kaplan-Meier, liso-cel lisocabtagene maraleucel, OS overall survival, PFS progression-free survival, tisa-cel tisagenlecleucel

OS of cured patients was simulated as the age- and sex-adjusted US general population mortality [42]. An excess mortality risk was also applied to account for any secondary malignancies and long-term adverse effects of cancer-specific treatment. A standardized mortality ratio of 1.40 was applied for the first 2 years, followed by a standardized mortality ratio of 1.18 for the remainder of the patients’ lifetimes [43].

Adverse Events

The model included adverse events (AE) associated with liso-cel, axi-cel, and tisa-cel but not subsequent treatment or regimens administered as pretreatment given these would have negligible impacts on incremental outcomes. In the base case, odds ratios estimated from MAICs of safety data from the trials from updates of previously published analyses [40, 41] were applied to the liso-cel rates to derive AE rates for each comparator (Table 1). Observed rates for each comparator were used in scenario analysis.

Table 1 Clinical efficacy and AE inputs

The model included all grade 3 or higher AEs occurring in at least 5% of patients in any trial. Additionally, all-grade cytokine release syndrome (CRS), neurological events (NE), and hypogammaglobulinemia were included irrespective of incidence to capture resource use and health-related quality of life (HRQOL) associated with CAR T-cell therapy AEs of special interest (AESI) [30, 44]. Only grade 3 or higher AEs were assumed to impact HRQOL.

Utilities

Utility values were applied for the duration of the pretreatment period and the remaining time in each health state, with decrements due to AEs applied in PFS (Table 2). Utilities were estimated using EQ-5D data from TRANSCEND using a mixed-effects model for repeated measures (MMRM) that included baseline EQ-5D, AEs, and progressive disease as predictors. The analysis was conducted using US tariffs and a crosswalk algorithm [45] to convert from EQ-5D-5L to the EQ-5D-3L value sets.

Table 2 Utility and cost inputsa

Grade 3 or higher CRS disutility could not be estimated from TRANSCEND data owing to its low incidence and duration. Instead, a vignette-based time trade-off study designed to specifically estimate CRS disutility was used [46].

Resource Use and Costs

The model incorporated costs associated with CAR T-cell therapy pretreatment, treatment acquisition (using wholesale acquisition cost prices) and administration, postinfusion hospitalization, AE management, monitoring (by health state), subsequent treatment, and end-of-life costs. All costs were expressed as 2020 US dollars. Key cost inputs are presented in Table 2.

All patients accrued the cost of leukapheresis. In the base case, 62% of liso-cel–treated patients, 92% of tisa-cel–treated patients, and 0% of axi-cel–treated patients were assumed to receive bridging therapy per their respective trials, and these costs were reflected in the cost estimates. Lymphodepleting chemotherapy, modeled as one cycle of fludarabine plus an alkylating agent, was then applied for the patients who received CAR T-cell infusion [6, 7, 47].

Acquisition costs for liso-cel (50–110 × 106 CAR-positive T-cells), axi-cel (2 × 106 CAR-positive T-cells), tisa-cel (0.6–6.0 × 108 CAR-positive T-cells), and chemotherapies used for lymphodepletion, bridging, salvage (for those failing to receive CAR T-cell infusion), and subsequent treatment were sourced from the IBM® Micromedex® RED BOOK® pricing file [48]. Salvage chemotherapy was modeled as a mix of chemotherapy regimens (40% rituximab plus gemcitabine and oxaliplatin; 30% rituximab plus gemcitabine, dexamethasone, and cisplatin [R-GDP]; and 30% rituximab plus dexamethasone, cytarabine, and cisplatin [R-DHAP]). R-GDP and R-DHAP comprise the treatment arms in the LY.12 trial [49] (the largest contributing trial to SCHOLAR-1) [1].

Administration costs for CAR T-cell therapy were based on the infusion setting (inpatient vs outpatient) per the trials and prescribing information. For patients who received CAR T-cell therapy in the outpatient setting, cost estimation was based on analysis of Medicare 2019 claims data inflated to 2020. For patients who received infusions in the inpatient setting, the duration of the inpatient stay for CAR T-cell administration was assumed to be the same across all CAR T-cell therapies (11 days total) based on TRANSCEND, as differences in inpatient stays due to AEs were captured separately through treatment-specific AE rates. The cost per inpatient infusion was assumed to be the same as an outpatient administration plus the cost of one additional hospital bed day per the Healthcare Cost Utilization Project (HCUP) [50]. The cost of the remaining 10 days of the inpatient stay were based on the per-day cost from HCUP (Table 2). Patients in TRANSCEND who received nonconforming product accrued pretreatment, administration, and AE costs but did not accrue liso-cel acquisition costs.

Subsequent treatment was modeled as a mix of allogeneic hematopoietic stem cell transplantation, salvage chemotherapy, radiotherapy, and no active treatment, per TRANSCEND. This was assumed to be the same for all CAR T-cell therapies owing to the absence of published data from ZUMA-1 and JULIET. The distribution of salvage chemotherapy regimens was assumed to be the same as in the preprogression state.

For all-grade CRS and NEs and grade 3 or higher hypogammaglobulinemia, a microcosting approach was used. This considered the costs of drug therapy, diagnostics, and inpatient stays associated with the events. A similar approach was taken in other cost-effectiveness studies of CAR T-cell therapy [51, 52] because traditional costing approaches tend to underestimate the resources required to manage these AEs [53]. Microcosting inputs for CRS and NE were based on an analysis of the resources used for managing these events during the TRANSCEND trial [54] (Supplemental Table 2). Hypogammaglobulinemia inputs were based on the Institute for Clinical and Economic Review’s 2018 assessment of CAR T-cell therapies for B-cell cancers [52] (Supplemental Table 3). For all other grade 3–4 AEs, per-event costs were sourced from the HCUP [50] (Supplemental Table 4); management of grade 1–2 AEs only were assumed to require a single general practitioner visit.

Overall costs of monitoring were calculated from the unit costs for each resource and their frequencies (Supplemental Table 5). The types of resources and frequencies associated with the 28 days after infusion and PFS are modeled separately for CAR T-cell therapy and salvage chemotherapy (for those who failed to receive CAR T-cell infusion), to reflect different treatment-specific monitoring requirements. Monitoring frequencies are treatment-independent once patients remain in PFS for more than 2 years or enter a postprogression period.

Model Verification and Validation

Model programming underwent technical validation by a modeler not involved in its development. Additionally, model projections of PFS and OS for liso-cel were compared with the Kaplan-Meier data for the leukapheresed population in TRANSCEND to ensure model assumptions and survival analyses were valid.

Analyses

The model estimated incremental cost-effectiveness ratios using life-years (LY) and QALYs over a lifetime horizon; the incremental net monetary benefit (INMB) was calculated basis on a willingness-to-pay (WTP) threshold of $100,000 as the recommended lower bound by the Institute for Clinical and Economic Review [55]. Deterministic sensitivity analyses, probabilistic sensitivity analyses (PSA), and scenario analyses were conducted to explore the impact of uncertainty in model parameters and structural assumptions (Supplementary Material).

Scenario analyses were performed to test alternative settings and data sources for the model inputs (Supplemental Tables 6 and 7). Two key scenarios focused on differences between the CAR T-cell therapy trials. The first assumed that all patients received their CAR T-cell infusion as this may differ between clinical practice and the trials. The second explored the impact of potential bias resulting from a difference in the ZUMA-1 and TRANSCEND designs regarding bridging therapy use. This scenario compared liso-cel with axi-cel using an MAIC that matched on bridging (i.e., excluding patients from TRANSCEND who received bridging therapy).

Compliance with Ethics Guidelines

Data used in this analysis were derived from three previously conducted CAR T-cell therapy trials and does not contain any new studies on human participants or animals performed by any of the authors.

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