Cost-effectiveness of axicabtagene ciloleucel for adult patients with relapsed or refractory large B-cell lymphoma in the United States

Abstract

Purpose: Axicabtagene ciloleucel (axi-cel) was recently approved for treatment of relapsed or refractory (R/R) large B-cell lymphoma (LBCL) following two or more prior therapies. As the first CAR T-cell therapy available for adults in the US, there are important questions about clinical and economic value. The objective of this study was to assess the cost-effectiveness of axi-cel compared to salvage chemotherapy using a decision model and a US payer perspective.

Materials and methods: A decision model was developed to estimate life years (LYs), quality-adjusted life years (QALYs), and lifetime cost for adult patients with R/R LBCL treated with axi-cel vs salvage chemotherapy (R-DHAP). Patient-level analyses of the ZUMA-1 and SCHOLAR-1 studies were used to inform the model and to estimate the proportion achieving long-term survival. Drug and procedure costs were derived from US average sales prices and Medicare reimbursement schedules. Future healthcare costs in long-term remission was derived from per capita Medicare spending. Utility values were derived from patient-level data from ZUMA-1 and external literature. One-way and probabilistic sensitivity analyses evaluated uncertainty. Outcomes were calculated over a lifetime horizon and were discounted at 3% per year.

Results: In the base case, LYs, QALYs, and lifetime costs were 9.5, 7.7, and $552,921 for axi-cel vs 2.6, 1.1, and $172,737 for salvage chemotherapy, respectively. The axi-cel cost per QALY gained was $58,146. Cost-effectiveness was most sensitive to the fraction achieving long-term remission, discount rate, and axi-cel price. The likelihood that axi-cel is cost-effective was 95% at a willingness to pay of $100,000 per QALY.

Conclusion: Axi-cel is a potentially cost-effective alternative to salvage chemotherapy for adults with R/R LBCL. Long-term follow-up is necessary to reduce uncertainties about health outcomes.

Keywords:

• Axicabtagene ciloleucel
• CAR T-cell therapy
• cost-effectiveness
• lymphoma

JEL Classification:

• C44
• C53

View correction statement:

Correction

Introduction

Relapsed or refractory (R/R) Large B-Cell Lymphoma (LBCL) carries an unfavorable prognosis, with median survival of 6.3 months¹. Therapy options are limited for transplant ineligible patients, and particularly for those who relapse following hematopoietic cell transplantation¹. Many receive a salvage chemotherapy regimen including rituximab, but the SCHOLAR-1 study demonstrated that ∼20% survive at 5 years of follow-up, and only 7% achieved a complete response¹.

Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, is approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with R/R LBCL after ≥2 lines of systemic therapy. A prospective, Phase II single-arm study (ZUMA-1, NCT 02348216) showed durable remissions with axi-cel, an objective response rate of 82%, and a complete response rate of 58%². Median overall survival was not reached with a minimum of 1 year of follow-up².

We developed a decision model that synthesizes evidence from the ZUMA-1 trial and SCHOLAR-1 study to better understand the potential comparative effectiveness and value of axi-cel vs salvage chemotherapy for treatment of R/R LBCL. The model was used to evaluate the cost-effectiveness of axi-cel from a US payer perspective. Our findings can inform decisions about clinical implementation and payer considerations.

Materials and methods

Overview

We developed a decision model (Figure 1) in Microsoft Excel for Mac Version 15.32 (Microsoft Inc., Redmond, WA) to evaluate the cost-effectiveness of axi-cel vs rituximab-based salvage chemotherapy for adult patients with R/R LBCL over a lifetime horizon. For the axi-cel strategy, overall and progression free survival were derived from the ZUMA-1 trial². For the salvage chemotherapy strategy, long-term (10-year) survival was derived from the SCHOLAR-1 study—a patient-level retrospective meta-analysis of patients with R/R LBCL similar to those enrolled in ZUMA-1, but treated with salvage chemotherapy¹. Survival beyond the study observation periods was extrapolated using mixture-cure analysis³ (SAS Version 9.4, SAS Institute Inc, Cary, NC), parametric curve fits, and data from government sources (e.g. Centers for Disease Control and Prevention [CDC] life tables⁴). The model tracks progression, post-progression therapy, and associated direct medical expenditure (hereafter termed “costs”) over a lifetime horizon. We account for the downstream costs and effects of stem cell transplantation in both treatment strategies. The primary outcome was the incremental cost-effectiveness ratio (ICER). The analysis was conducted from a US payer perspective and reports costs in 2017 US dollars. Future medical cost, life years, and QALYs are discounted at 3% per year⁵. Model inputs and data sources are provided in Table 1, and additional inputs are described below.

Figure 1. Simplified model schematic.

Table 1. Model input values, distributions, and data sources.

Model input	Point estimate	Low value	High value	Distribution	Data source
Axi-cel treatment inputs
Long-term remission fraction	50.2%	36.3%	64.1%	Beta	Bansal et al.^10 (2017)
Total initial hospitalization days	17.6	6.8	28.4	Normal	Data on File
Proportion of hospitalization days in intensive care unit	21.0%	10.5%	31.5%	Beta	Data on File
Axi-cel adverse events (% with event)
Grade 3/4 cytokine release syndrome	13.0%	11.7%	14.3%	Beta	YESCARTA US Prescribing Information
Hypogammaglobulinemia & treated with IVIG	8.0%	7.2%	8.8%	Beta	Neelapu et al.^11 (2017)
Salvage chemotherapy adverse events (% with event)
Grade 3/4 Febrile Neutropenia	23.0%	18.4%	27.6%	Beta	Crump, JCO, 2014
Grade 3/4 Infection	16.0%	12.8%	19.2%	Beta	Crump, JCO, 2014
Grade 3/4 Fatigue	9.0%	7.2%	10.8%	Beta	Crump, JCO, 2014
Grade 3/4 Nausea	8.0%	6.4%	9.6%	Beta	Crump, JCO, 2014
Grade 3/4 Thrombosis/embolism	6.0%	4.8%	7.2%	Beta	Crump, JCO, 2014
Stem cell transplant use
Proportion with stem cell transplant following Axi-cel	11.0%	8.8%	13.2%	Beta	Data on File
Proportion with stem cell transplant following salvage chemotherapy	27.4%	21.9%	32.9%	Beta	Crump et al.^1 (2017)
Health state utility values
Axi-cel on treatment utility	0.740	0.680	0.800	Beta	Lin et al.^18 (2018)
Salvage chemotherapy on treatment utility	0.672	0.623	0.773	Beta	Huntington et al.^20 (2015)
Both strategies, in remission utility for <6 months of follow-up	0.782	0.736	0.828	Beta	Lin et al.^18 (2018)
Both strategies, in remission utility for ≥6 months of follow-up	0.823	0.741	0.905	Beta	Sullivan and Ghushchyan^19 (2006)
Progressive disease utility	0.390	0.310	0.470	Beta	Chen et al.^21 (2017)
Direct medical expenditures
Axi-cel drug cost	$373,000	$317,050	$428,950	Normal	Kite Pharma List Price
Rituximab cost per 1 mg/ml	$8.48	$6.78	$10.18	Normal	Average Sales Price, 2017
Dexamethasone cost per 1 mg/ml	$0.33	$0.26	$0.40	Normal	Average Sales Price, 2017
Cytarabine cost per 1 mg/ml	$0.01	$0.008	$0.012	Normal	Average Sales Price, 2017
Cisplatin cost per 1 mg/ml	$0.21	$0.17	$0.25	Normal	Average Sales Price, 2017
Stem cell transplant cost (total)	$175,547	$140,438	$210,656	Normal	Pelletier et al.^13 (2008)
Palliative care monthly cost	$18,653	$14,922	$22,384	Normal	Kutikova, Leuk Lymph, 2006^34
Office visit cost	$146	$117	$176	Normal	(CPT 99215)^35
Infusion cost per hour	$59	$47	$70	Normal	(CPT 96360)^35
PET/CT scan cost	$1,355	$1,084	$1,626	Normal	(CPT 78816)^35
Pyrexia treatment cost	$6,549	$5,239	$7,859	Normal	AHRQ HCUP^17 (2014)
Neutropenia treatment cost	$12,359	$9,887	$14,831	Normal	AHRQ HCUP^17 (2014)
Anemia treatment cost	$6,410	$5,128	$7,692	Normal	AHRQ HCUP^17 (2014)
Hypotension treatment cost	$6,853	$5,482	$8,224	Normal	AHRQ HCUP^17 (2014)
Thrombocytopenia treatment cost	$9,621	$7,697	$11,545	Normal	AHRQ HCUP^17 (2014)
Hypocalcemia treatment cost	$6,461	$5,169	$7,753	Normal	AHRQ HCUP^17 (2014)
Febrile neutropenia treatment cost	$7,104	$5,683	$8,525	Normal	AHRQ HCUP^17 (2014)
Encephalopathy treatment cost	$9,908	$7,926	$11,890	Normal	AHRQ HCUP^17 (2014)
Leukopenia treatment cost	$7,890	$6,312	$9,468	Normal	AHRQ HCUP^17 (2014)
Infection treatment cost	$6,815	$5,452	$8,178	Normal	AHRQ HCUP^17 (2014)
Fatigue treatment cost	$6,613	$5,290	$7,936	Normal	AHRQ HCUP^17 (2014)
Nausea treatment cost	$5,506	$4,405	$6,607	Normal	AHRQ HCUP^17 (2014)
Apheresis cost	$1,093	$874	$1,312	Normal	CMS^16 (2017) (CPT 36511)
Intravenous immunoglobulin cost per 1 mg/ml	$0.08	$0.06	$0.10	Normal	Average Sales Price, 2017
Cost per initial hospitalization day (non-ICU)	$2,357	$1,886	$2,828	Normal	Kaiser Family Foundation, 2017^36
Cost per initial hospitalization intensive care unit day	$5,167	$4,134	$6,200	Normal	Dasta, Critical Care Med, 2005^37
Annual healthcare cost in remission in Medicare	$10,986	$8,789	$13,183	Normal	CMS, 2014^38
Annual healthcare cost in remission in commercial plan	$5,141	$4,113	$6,169	Normal	AHRQ HCUP^17 (2015)

Patient population and model structure

The patient population for the analysis is based on the ZUMA-1 trial population (Figure 1). The model uses a partitioned survival framework—dividing patient time into pre-progression, post-progression, and death states⁶. Patients who never progressed (hereafter “remission”) were assigned age-specific mortality rates from the most recent (2014) Centers for Disease Control and Prevention (CDC) US life tables⁴ in the period after study follow-up. For those who progressed, time in the post-progression state was calculated as the difference in progression-free survival (PFS) and overall survival (OS) curves in the ZUMA-1 and SCHOLAR-1 studies. PFS was not reported in SCHOLAR-1, so we imputed PFS using the time-dependent ratio of PFS to OS in ZUMA-1. The effect of this approach is that patients treated with axi-cel and salvage chemotherapy have equal time from progression to death. Outcomes were tracked in 1-month cycles across each health state.

Survival

Axi-cel survival

To estimate mean progression-free survival (PFS) for patients treated with axi-cel, we fit a range of curves (Weibull, LogLog, LogLogistic, Gompertz) to 12-month ZUMA-1 PFS data, selected the curve (Gompertz) that minimized the Akaike information criterion (AIC)⁷, and extrapolated the curve to 5 years of follow-up. We assumed that patients who had not progressed by 5 years did not have subsequent progression based on the small fractions experiencing progression after this time point in a number of prior LBCL studies evaluating long-term outcomes^8,9.

Based on 1-year follow-up data from ZUMA-1, the mixture cure model estimated that 50.2% (95% CI = 36.3–64.1%) of patients treated with axi-cel would achieve long-term remission. We attributed age-matched general US population mortality rates to this fraction, resulting in a mean overall survival of 28.1 years¹⁰ among those with long-term remission. Average survival for the remaining 49.8% of axi-cel patients without long-term remission was estimated to be 0.95 years¹⁰. The weighted average of these two survival curves closely replicated 12-month observed overall survival in ZUMA-1 (see Supplementary Appendix, Figure A1), and resulted in minimal AIC⁷ compared to traditional parametric fits (Weibull, LogLog, LogLogistic, Gompertz).

Salvage chemotherapy survival

Overall survival for patients treated with salvage chemotherapy was derived from SCHOLAR-1¹. Because SCHOLAR-1 was not designed to assess progression (and, therefore, did not report PFS), we imputed the PFS function for the salvage chemotherapy cohort by assuming the same ratio of monthly PFS to OS as observed in ZUMA-1. All patients alive at the end of the 10-year period were assumed to have mortality similar to the age-matched general US population⁴.

The ZUMA-1 and SCHOLAR-1 cohorts had statistically significant differences in age (p = .01), Stage (p = .001), and proportions diagnosed with primary mediastinal B-cell lymphoma (p < .001) and transformed follicular lymphoma (p < .001). These factors could be associated with survival, so we also conducted a sensitivity analysis using propensity-score adjusted survival results restricted to a sub-set of SCHOLAR-1 patients matched to ZUMA-1 patients on age, sex, refractory sub-types, and ECOG status. After matching, the cohorts did not have significant differences in any of the factors measured (Supplementary Appendix A, Table A1). The resulting propensity-score adjusted SCHOLAR-1 cohort OS curve differed by no more than 4% in any month over follow-up (Supplementary Appendix A, Figure A1), and undiscounted mean OS was virtually identical in adjusted (2.3 years) and unadjusted (2.2 years) analyses. Given the lack of impact of matched results, our analyses used unadjusted OS data.

Resource use and cost

Axi-cel infusion and related resource use

The cost of axi-cel was based on the manufacturer’s list price as of August 2018 ($373,000). Additional resources included in the cost calculation included: leukapheresis to harvest T-cells; infusion of the CAR T-cells; hospitalization for observation following the infusion, and four office visits in the initial month after hospital discharge.

Axi-cel adverse events

Grade 3/4 adverse events associated with axi-cel—most notably cytokine release syndrome (CRS) and neurotoxicity—were assumed to occur during the initial treatment and hospitalization period. Based on the 1-year follow-up of ZUMA-1, mean hospitalization days were 17.6 standard inpatient days. We also assumed a cohort average of 3.7 intensive care unit (ICU) days (as a sub-set of hospitalization days), based on the duration of CRS events. To also account for possible prolonged hypogammaglobulinemia, we modeled use of intravenous immunoglobulin (IVIG) for the proportion of patients who received IVIG in ZUMA-1¹¹. In the ZUMA-1 trial, hypogammaglobulinemia occurred in 15% of patients, and 8% have received IVIG at the 1-year follow-up¹¹. We assumed that patients required 0.5 g/kg of intravenous immunoglobulin every 4 weeks for 12 months. Costs for both treatments were derived from 2017 average sales prices.

Salvage chemotherapy resource use

Salvage chemotherapy consisted of rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP). The cost of this regimen was calculated based on a 21-day cycle with rituximab 375 mg/m² weekly for 4 weeks, starting on Day 1, and three cycles of 40 mg dexamethasone on days 1–4, cytarabine 2 g/m² every 12 h for two doses on Day 2, and cisplatin 100 mg/m² on Day 3. Drug costs were set up to represent the balance of Medicare (24%) and commercial insurance (76%) patients in the ZUMA-1 trial². We applied the 2017 average sales price (ASP) plus 6% for the Medicare fraction and ASP plus 100% for the commercial plan fraction to represent typical reimbursement in these settings. Infusion costs derived from CMS reimbursement schedules were also included.

Salvage chemotherapy adverse events

Grade 3/4 adverse events for salvage chemotherapy included thrombosis/embolism, febrile neutropenia, infection, fatigue, and nausea¹¹ (Table 1). Treatment costs for these events were based on Agency for Healthcare Research and Quality (AHRQ) Healthcare Utilization Project (HCUP) mean inpatient charges by ICD-9 for each AE¹².

Stem cell transplant (SCT) use and cost

The proportion receiving SCT after treatment with axi-cel and salvage chemotherapy was based on results from ZUMA-1 (11%) and SCHOLAR-1 (27%)^1,2. As the effects of transplant were already represented in the survival outcomes of each study, no additional effects were modeled. We based the cost of SCT on the cost from mobilization through 100 days post-SCT reported by Pelletier et al.¹³.

Other drug and procedure costs

The costs of post-relapse palliative care were derived from cost estimates in the last year of life among patients who died of lymphoma in a prior health economic analysis of NHL outcomes¹⁴.

Future healthcare costs

Based on the recommendations of the Second-Panel on Cost-Effectiveness in Health and Medicine¹⁵, we included future healthcare costs for patients in the “long-term remission” state. These patients incur typical healthcare costs based on annual Medicare ($10,986 in 2014 USD, 24% of the cohort)¹⁶ and commercial plan ($5,141 in 2015 USD, 76% of the cohort)¹⁷ spending per enrollee.

Health state utilities

Values for the “axi-cel on treatment” utility (0.740) and “in remission with <6 months of follow-up” utility (0.782) were derived from mean EQ-5D-5L scores with US tariffs from a patient-level analysis in the ZUMA-1 trial cohort¹⁸. The long-term (≥6 month) in remission utility was assumed to be equivalent to the mean EQ-5D-5L score with US tariffs of the 60–69 US general population (0.823) from a prior study with a large national sample of US adults¹⁹. Patients in the “salvage chemotherapy on treatment” state were assigned a utility of 0.673 based on the utility decrement (–0.15) from a prior cost-effectiveness analysis in LBCL²⁰ applied to the long-term remission utility. The “progressive disease” utility was 0.390, based on the value used in prior cost-effectiveness analyses in LBCL^21,22.

Outcomes

We estimated expected life years, QALYs, and total costs for the axi-cel and salvage chemotherapy strategies. The ICER was also calculated as the ratio of the difference in costs and the difference in effects (e.g. QALYs) between strategies.

Scenario analysis

Given uncertainty about long-term failure patterns in patients with durable responses after treatment with axi-cel, we also conducted scenario analyses in which patients in remission had mortality rates 10% and 20% higher than the age-matched general US population. These scenarios represent a “worst case scenario”, as evidence from long-term follow-up of relapsed/refractory LBCL patients alive >5 years after salvage chemotherapy treatment demonstrate annualized mortality rates similar to the US general population¹.

Additionally, we conducted a scenario analysis evaluating the intention-to-treat cohort from ZUMA-1. In that study, 9% (10 of 111) of the cohort was unable to receive treatment with axi-cel due to adverse events, progression of disease, and/or unsuccessful manufacturing of the CAR T-cell product. In this scenario, we attributed costs and outcomes from the salvage chemotherapy strategy to this fraction, assuming they would eventually go on to standard treatment. We attributed axi-cel outcomes to the other 91% of the sample.

Threshold analyses

Due to the high initial price of axi-cel vs traditional therapies, there is also uncertainty about how healthcare provider charging practices may change the payer’s end price of axi-cel in the future. Our base case analysis used the manufacturer’s list price ($373,000), but anecdotal reports suggest that some providers could add a surcharge, particularly when billing commercial insurers. We conducted threshold analyses to determine the drug + additional provider charges where the incremental cost per quality-adjusted life year gained would exceed $100,000 and $150,000 per QALY gained—commonly cited willingness-to-pay thresholds for cancer therapies in the US²³.

Uncertainty analyses

We evaluated uncertainty with one-way and probabilistic sensitivity analyses. We present one-way sensitivity analysis results as a tornado diagram displaying the 10 most influential model inputs. The probabilistic sensitivity analysis results are presented in the form of a cost-effectiveness acceptability curve^24–27.

Results

Base case results

In the base case analysis, 5- and 10-year overall survival was 40% and 37% for the axi-cel group, and 17% and 16% for the salvage chemotherapy group, respectively. Over a lifetime horizon, these differences between axi-cel and salvage chemotherapy translated into 9.49 and 2.60 life years, 7.67 and 1.13 QALYs, and lifetime costs of $552,921 and $172,737, respectively (Table 2).

Table 2. Base case health outcomes. The cost per life year gained was $55,128, and the cost per quality-adjusted life year gained was $58,146.

Strategy	Initial treatment cost	Adverse event cost	Stemcell transplant cost	Remissioncost	Palliative care cost	Totalcost	Lifeyears	Quality-adjustedlife years(QALYs)	Cost per life year gained	Costper QALYgained
Axi-cel strategy	$426,548	$3,745	$19,310	$67,063	$36,256	$552,921	9.49	7.67	$55,128	$58,146
Salvage chemotherapy strategy	$48,403	$4,337	$48,100	$6,457	$65,438	$172,737	2.60	1.13	–	–
Difference	+$326,276	–$592	–$28,790	+$60,606	–$29,182	+$380,184	6.90	6.54	–	–

The base case incremental cost per life year and QALY gained for treatment with axi-cel vs salvage chemotherapy was $55,128 and $58,146, respectively.

Scenario analysis

In scenarios where survival for axi-cel treated patients achieving long-term remission was 10% and 20% below the age-matched US general population, incremental life years were 6.39 and 6.01, incremental QALYs were 6.12 and 5.81, and incremental cost was $376,596 and $373,855, respectively. The corresponding ICERs for axi-cel were $58,906 and $62,219 per life year gained, and $61,492 and $64,370 per QALY gained, respectively.

In the intention-to-treat scenario, axi-cel strategy life years were reduced to 8.87 (incremental life years were 6.28), axi-cel QALYs were reduced to 7.08 (incremental QALYs were 5.95), and axi-cel cost was reduced to $518,705 (incremental cost was $345,967). The corresponding ICERs were $55,128 per life year gained and $58,146 per QALY gained as in the base case, given the proportional reductions in costs and effects in the axi-cel strategy.

Threshold analyses

Threshold analyses demonstrated that additional provider charges beyond the list price of axi-cel of $263,500 ($636,500 total cost) and $590,500 ($963,500 total cost), respectively, would result in costs per QALY gained of $100,000 and $150,000, respectively.

Sensitivity analysis results

In one-way sensitivity analysis, ICER results were most sensitive to the fraction with long-term remission with axi-cel, the discount rate, and the axi-cel price (Figure 2). In probabilistic sensitivity analysis, axi-cel was cost-effective in 95% and >99% of simulations at willingness-to-pay thresholds of $100,000 and $150,000 per QALY, respectively (Figure 3).

Figure 2. One-way sensitivity analysis tornado diagram for the incremental cost-effectiveness ratio.

Figure 3. Cost-effectiveness acceptability curve. The figure displays the probability that the axi-cel strategy is the most cost-effective strategy across the implied range of willingness-to-pay per QALY gained in cancer in the US. The probability of cost-effectiveness at willingness-to-pay thresholds of $50,000, $100,000, and $150,000 per QALY gained was 14.9%, > 99%, and >99%, respectively.

Discussion

Patients with R/R LBCL after two lines of systemic therapy have few options and limited chances for long-term survival. Axi-cel has shown promising results for these patients, but the economic implications of treatment have not yet been evaluated in the peer-reviewed literature. In this modeling study, we find that axi-cel is a potentially cost-effective treatment when compared to common willingness-to-pay thresholds evaluated in the US²³. As this analysis used axi-cel 1-year follow-up data², it will be prudent to re-examine cost-effectiveness after additional follow-up.

In addition to the immediate cost of therapy, other costs are of concern for patients receiving CAR T therapies. Cytokine release syndrome (CRS) and neurologic toxicity have been identified as major adverse events of therapy, and US label of axi-cel carries a box warning from the FDA. CRS can manifest as fever, hypotension, altered mental status, and seizures, with some patients requiring intensive care. CRS-related deaths have been reported for patients receiving CAR T therapy, although no CRS-related deaths have occurred to date for patient receiving axi-cel². In one-way sensitivity analysis, varying hospitalization days from 6.8 to 28.4 did not appreciatively impact the cost-effectiveness of therapy (Figure 2). A second important complication of anti-CD 19 CAR T therapies, but with limited long-term data, is hypogammaglobulinemia, rendering patients susceptible to potentially serious infections and often requires ongoing infusions of intravenous immune globulin (IVIG). The average sales price of IVIG is ∼ $4,000 per month. In the ZUMA-1 trial, hypogammaglobulinemia occurred in 15% of patients, and 8% have received IVIG at the 1 year follow-up². Further monitoring for the incidence of hypogammaglobulinemia in non-trial settings, including the proportion developing serious infections and requiring IVIG treatment, will be necessary in future updates of the cost-effectiveness evaluation. However, at current treatment costs for IVIG, even if all axi-cel patients who developed hypogammaglobulinemia received IVIG, the cost-effectiveness ratio did not exceed $100,000 per QALY.

An economic analysis of axi-cel was sponsored by the Institute for Clinical and Cost-Effectiveness Research (ICER)—a private non-profit that performs independent analyses of the effectiveness and costs of medical technologies. In the ICER’s final evidence report²⁸, the cost-effectiveness of axi-cel vs salvage chemotherapy was determined to be $112,168 per life year gained and $136,078 per QALY gained. The differences in results between the ICER study and this study are primarily due to use of differences in survival modeling methods. This study used a mixture cure regression analysis of patient-level data from the ZUMA-1 trial to (1) estimate the fraction of patients with long-term remission (50.2%), and (2) fit separate survival curves for those with and without long-term remission. Alternatively, the ICER study fit a Weibull curve to cohort-level 12-month ZUMA-1 survival data, extrapolated the survival curve to 5 years of follow-up, and assumed that the fraction alive beyond that point (43.8%) had a mortality rate similar to the age-matched US general population. The ICER study estimated 7.35 life years for patients treated with axi-cel, whereas we find 9.49 life years. Prior studies show that our mixture cure modeling approach can provide a more accurate estimate of mean survival vs traditional survival modeling methods if a large fraction of patients achieve long-term remission^29–32. As a large fraction of axi-cel patients achieve complete remission (58%)² and are likely to have a durable response (as shown in phase 1 long-term follow-up data)³³, we believe our survival modeling approach more accurately represents axi-cel long-term survival, and therefore the cost per QALY gained with axi-cel is likely to be < $100,000 (based on the probabilistic results). Nonetheless, it should be noted that results in both studies fall below the commonly cited $150,000 per QALY willingness-to-pay threshold²³, so both studies support the same qualitative conclusion that axi-cel is a potentially cost-effective alternative to treatment with salvage chemotherapy in relapsed/refractory LBCL.

This study has several key limitations. First, although axi-cel is the CAR T-cell therapy with the longest follow-up in adults with R/R LBCL, the current data of ZUMA-1 is limited at a median follow up of 15.4 months. It will be important to continue monitoring clinical outcomes and costs as ZUMA-1 follow-up continues. Second, there remains much uncertainty about the degree of additional provider charges that payers will permit for CAR T-cell treatments. CMS and some commercial insurers have signaled that they plan to negotiate a fixed reimbursement that will include drug costs plus associated care. Our threshold analysis suggests that there is considerable room for markup before axi-cel would fall into an unfavorable value range, but this is contingent on a large proportion of patients achieving long-term remission. Third, it is possible that treatment with axi-cel could result in different effects, costs, or health-related quality-of-life in some R/R LBCL clinical sub-groups (e.g. mediastinal large B-cell lymphoma). However, due to data limitations, we only examine overall outcomes in R/R LBCL. Future studies should evaluate differential effects in more granular clinical sub-groups. Lastly, we model the comparator treatment strategy using the R-DHAP regimen because it is a common guideline-recommended treatment used in a large fraction of the SCHOLAR-1 cohort, but we acknowledge that alternative regimens could be considered.

Conclusions

Axi-cel is a clinically promising and potentially cost-effective alternative to salvage chemotherapy for adults with R/R LBCL. Future studies should track and compare the long-term outcomes of both strategies, given uncertainties about incremental health outcomes over a long-term horizon.

Transparency

Declaration of funding

This study was funded by Kite, a Gilead Company.

Declaration of financial/other relationships

JAR, SDS, AB, and SDR are consultants for Kite, a Gilead Company. VWL, AGP, LN, and PC are employees of Kite, a Gilead Company. Peer reviewers on this manuscript have received an honorarium from JME for their review work. One reviewer discloses their role as an investigator for the Canadian Cancer Trials Group, which receives research funding from Kite Pharma Inc., Gilead, Novartis, Janssen, Roche, AbbVie, Takeda, Amgen, Seattle Genetics, and Pfizer. The remaining reviewers have no other relevant financial relationships to disclose.

Acknowledgements

None reported.