Axicabtagene ciloleucel compared to standard of care in Swedish patients with large B-cell lymphoma: a cost-effectiveness analysis of the ZUMA-7 trial

Abstract

Aim

Our study aimed to evaluate the cost-effectiveness of the chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel (axi-cel), compared to standard of care (SOC) in Sweden for second-line (2L) treatment of adult transplant-intended diffuse large B-cell lymphoma (DLBCL) patients who relapse within 12 months from completion of, or are refractory to (early r/r), first-line (1L) chemoimmunotherapy.

Methods

Cost-effectiveness was assessed using a three-state partitioned survival model. Mixture cure models were used to extrapolate time-to-event data from the ZUMA-7 trial (NCT03391466) beyond the observational period. Sensitivity and scenario analyses were performed to test the robustness of the base case results, including an analysis that assumed no switching to off-protocol CAR T-cell therapy in subsequent lines in the SOC arm.

Results

The model estimated an incremental cost-effectiveness ratio (ICER) of SEK 534,704 (EUR 50,303) per quality-adjusted life year (QALY) gained over a lifetime horizon of 50 years, with an incremental cost of SEK 812,944 (EUR 76,479) and incremental QALY of 1.52 for axi-cel compared with SOC. The probabilistic sensitivity analysis showed that axi-cel was cost-effective in 73% of the simulations when assuming a willingness-to-pay threshold of SEK 1,000,000 (EUR 94,077) per QALY. The ICER was SEK 694,351 (EUR 65,313) in the scenario analysis where the costs and effects of treatment switching were not included.

Conclusion

2L treatment with axi-cel in transplant-intended DLBCL patients with early r/r after completing 1L chemoimmunotherapy was cost-effective compared to SOC in a Swedish setting. Administering axi-cel in 2L is cost-effective as it enhances the possibility of curing more patients, resulting in not just a survival advantage, but also a reduction in the burden on quality of life and cost of subsequent therapy. This will be advantageous to both patients and society.

Keywords:

• Axicabtagene ciloleucel
• chimeric antigen receptor T-cell therapy
• diffuse large B-cell lymphoma
• cost-effectiveness analysis
• health economic analysis
• treatment switching

JEL CLASSIFICATION CODES:

• I10
• I1
• I
• I11

1. Introduction

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and common subtype of lymphoma with an annual incidence of approximately 700 people in Sweden¹. The primary treatment in the first-line (1L) setting comprises chemoimmunotherapy consisting of rituximab and anthracycline-based chemotherapy (normally R-CHOP), which cures three in four patients². For the quarter of patients who are not cured with 1L therapy, prognosis is determined by a range of factors, including response to 1L chemoimmunotherapy and timing of relapse².

Patients who relapse within 12 months from completion of, or are refractory to (early r/r), 1L chemoimmunotherapy have particularly poor survival outcomes. A Swedish study of 736 patients with relapsed or refractory (r/r) DLBCL treated during the period 2007–2018 found that patients with primary refractory disease, which was defined as stable or progressive disease as best response to primary therapy (28% of 736), had a median overall survival (OS) of 4.4 months and a two-year OS of 14%². Early relapse, which was defined as relapse within 12 months of primary diagnosis (62% of 736), was strongly associated with the selection of less intensive treatments, and the two-year OS was less than 20% in this patient group, compared to 55% for patients relapsing after more than two years².

For patients with r/r disease after 1L chemoimmunotherapy, the standard of care (SOC) is platinum-based chemoimmunotherapy followed by consolidation with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) for patients who are treated with curative intent^2,3. However, among patients with early relapse after 1L chemoimmunotherapy, fewer than two-thirds of Swedish patients up to 70 years of age meet these criteria and initiate SOC therapy (i.e. are transplant-intended), and among those who start less than one in three complete ASCT². Overall, 22% of Swedish patients up to 70 years of age with early relapse completed ASCT compared to 57% for those with late relapse².

Axicabtagene ciloleucel (axi-cel) is a CAR T-cell therapy that received market authorization from the European Medicines Agency (EMA) in 2022 indicated for the treatment of adult patients with DLBCL and high-grade B-cell lymphoma with early r/r after completing 1L chemoimmunotherapy. Approval was granted based on results from the pivotal phase 3 trial ZUMA-7 (NCT03391466). The ZUMA-7 trial evaluated the efficacy and safety of axi-cel versus SOC (salvage chemoimmunotherapy with HDT followed by ASCT for responders) in transplant-intended DLBCL patients with early r/r after completing 1L chemoimmunotherapy⁴. At a median follow-up of 24.9 months, the primary analysis found that axi-cel demonstrated a 60% improvement in centrally assessed event-free survival (EFS) compared to SOC (hazard ratio (HR): 0.40; 95% CI: 0.31, 0.51; p< .0001) ⁴. In an interim analysis (including survival data on eight patients that were lost to follow-up at the data cut-off for the primary analysis), the median OS was not reached in the axi-cel group and was 25.7 months in the SOC group (HR: 0.71; 95% CI: 0.52, 0.97)⁵. Off-protocol treatment switching occurred in the ZUMA-7 trial and 56% of patients, i.e. 100 out of the 179 patients in the SOC arm received subsequent cellular therapy⁴. A prespecified sensitivity analysis was performed in ZUMA-7, which adjusted OS for the confounding effect of treatment switching using the rank-preserving structural failure time model (RPSFTM) or the inverse probability of censoring weights (IPCW) method⁶. These analyses showed a greater OS benefit in favour of axi-cel⁴.

Axi-cel is currently recommended and funded in Denmark, Finland and Norway for the treatment of 2L DLBCL, while a decision is pending in Sweden. In third-line or later (3L+) DLBCL, axi-cel is recommended and funded in Norway, Finland and Sweden based on data from the ZUMA-1 trial. 5-year follow-up data from the ZUMA-1 trial showed that 43% of patients treated with axi-cel were alive after five years and a 5-year EFS rate of 30.3% (95% CI: 21.5%, 39.6%) was estimated⁷. 58% of the patients achieved a complete response and, in these patients, the 5-year OS rate was 64.4% (95% CI: 50.8%, 75.1%)⁷. These findings support axi-cel as a curative treatment option for many DLBCL patients⁷.

Our study is the first study in the Nordic countries to evaluate the cost-effectiveness of CAR T-cell therapy using randomized clinical trial evidence, a gap that has been highlighted by all Nordic HTA bodies^8–11. In addition, little is known about the cost-effectiveness of treating patients with CAR T-cell therapy when moving to an earlier line of treatment (from 3L+ to 2L). Therefore, the objective of this study was to evaluate the cost-effectiveness of axi-cel compared to the SOC and the long-term economic implications of introducing axi-cel in Sweden for the treatment of transplant-intended DLBCL patients with early r/r after completing 1L chemoimmunotherapy.

2. Methods

2.1. Model overview

A three-state partitioned survival model was developed in Microsoft Excel and populated with clinical data from ZUMA-7 (NCT03391466) to reflect the target patient population of transplant-intended DLBCL patients with early r/r after completing 1L chemoimmunotherapy. The model simulated the proportions of a theoretical cohort transitioning between each of the three mutually exclusive health states (event-free, post-event and death) over time and assigned corresponding costs and utilities. The patient cohort entered the model in an event-free state. If patients experienced an event, defined as disease progression or initiation of the next line of therapy, they transitioned to the post-event state. To estimate treatment-related and adverse event (AE) costs, sub-states were included in the event-free and post-event health states to reflect whether patients were on or off treatment. Figure 1 illustrates the model structure. The proportion of patients in each health state at a given point in time was determined based on independently fitted parametric extrapolations of centrally-assessed EFS, OS and time-to-next treatment (TTNT), as illustrated in Figure 2.

Figure 1. Model structure. The circles represent mutually exclusive health states, and the arrows represent transitions between or within states.

Figure 2. Health state occupancy. Implementation method of the partitioned survival model estimating health state occupancy through the disaggregation of sequential event curves (illustrative example). The health state occupancy in the event-free and death health states were derived from the centrally-assessed event-free survival (EFS) curve and overall survival (OS) curve, respectively. The health state occupancy in the post-event health state was calculated as the difference between the OS curve and the EFS curve (the proportion of patients who are still alive but are no longer event-free). The post-event subsequent therapy was determined by the time-to-next therapy (TTNT) curve.

Based on previous studies investigating mortality related to DLBCL^12,13, it was assumed that patients who remain event-free after five years are considered long-term responders with resource utilization and utility equivalent to the general population. Furthermore, studies have shown that these patients have a similar or slightly higher mortality rate than the general population^14,15. Thus, a standardized mortality ratio (SMR) of 1.09 was applied to long-term survivors in the model based on the findings by Maurer et al.¹⁵.

The analysis was conducted from a Swedish healthcare perspective with costs and health effects estimated over a lifetime horizon of 50 years and discounted by 3% per annum. The model had a monthly cycle length and half-cycle corrections were applied to account for within-cycle transitions. Finally, the model estimated total costs, life years (LYs), and quality-adjusted life years (QALYs) as well as the incremental cost-effectiveness ratio (ICER).

2.2. Time-to-event outcomes

Time-to-event data from the ZUMA-7 intention to treat (ITT) population (data cut-off date: 18 March 2021) was used to populate efficacy inputs in the model. A prior validation study using long-term data from ZUMA-1 determined that Mixture Cure Models (MCMs) were the most accurate at predicting long-term survival for DLBCL patients treated with axi-cel after at least two prior lines of therapy¹⁶. Hence, MCMs were used to extrapolate time-to-event data (centrally-assessed EFS, OS, and TTNT) from the ZUMA-7 trial beyond the observational period. Statistical fit and clinical plausibility¹⁷ were used to determine the most appropriate extrapolations for the base case analysis. Independent survival models were fitted to individual patient level data from ZUMA-7 (diagnostic plots can be found in Supplementary Figure S4 and Figure S5). The Kaplan-Meier and the extrapolated survival curves applied in the model base case are illustrated in Figure 3. More details on the extrapolation of time-to-event data can be found in the Supplementary Materials.

Figure 3. Survival plots. A) Shows the Kaplan Meier curves and extrapolations for axi-cel, B) Shows the Kaplan Meier curves and extrapolations for standard of care (SOC); and C) Shows the modelled extrapolation curves applied in the model.

2.3. Health-related quality of life

Effects on health-related quality of life (HRQoL) was modelled using state-specific utility values derived from EuroQoL five-dimensions five-levels (EQ-5D-5L) instrument responses collected in ZUMA-7 (event-free state) and ZUMA-1 (post-event state)^18,19. Health state utility values were age-adjusted based on Swedish general population utilities by Burström et al.²⁰ who used the UK EQ-5D index tariff by Dolan²¹.

2.3.1. Event-free utilities

In ZUMA-7, patient-reported outcomes (PROs) were routinely collected during the first 24 months after randomization. 82% (296 of 359) of patients enrolled in ZUMA-7 had reported at least two EQ-5D-5L instrument responses. EQ-5D-5L responses were cross-walked to EQ-5D-3L index values using the van Hout algorithm²². The algorithm uses the UK value set developed by Dolan²¹, in line with TLV standard practice²³. A mixed model with repeated measures (MMRM) was used to estimate state-specific utilities, accounting for multiple observations per patient.

The utility value for the event-free state was disaggregated into the periods on-treatment and off-treatment. This approach has been used in previous models for other CAR T-cell therapies in the 3L+ setting^24,25. The on-treatment utility was applied for the first month for axi-cel and the first three months for the SOC. Patients who were still event-free after five years were reverted to the age- and gender-matched Swedish general population utilities²⁰. Utility decrements due to AEs were not applied in the model, as the potential influence of AEs was assumed to be captured by the event-free on-treatment utility values.

2.3.2. Post-event utilities

The collection of PROs post-event was not mandated in the ZUMA-7 trial, and data collection after switching to subsequent therapy did not usually include PRO reports²⁶. Although some sites continued to collect PROs after EFS events, these comprised a minority of observations (less than 11% of total PRO observations). Because of these limitations, the post-event health state utility value was informed by the ZUMA-1 event-free utility value²⁷. Utility values for patients treated with axi-cel in 3L+ represent a similar patient group, e.g. due to the high amount of subsequent CAR T-cell therapy use post-event in ZUMA-7. Finally, we made the conservative assumption of not including utility decrements due to subsequent therapy use.

2.4. Costs

Treatment specific costs (i.e. costs related to axi-cel treatment and treatment with SOC including subsequent treatments and management of AEs) and state-specific costs (e.g. costs related to monitoring) were included in the model. Table 1 provides an overview of the resource use and unit costs applied in the model. All costs were reported in 2022 Swedish krona (SEK).

Table 1. Overview of model input values and sources.

Model input	Base case	Source
Selected survival models, MCM
Axi-cel, EFS	Loglogistic	ZUMA-7 trial^28
Axi-cel, OS	Generalized gamma	ZUMA-7 trial^28
Axi-cel, TTNT	Loglogistic	ZUMA-7 trial^28
SOC, EFS	Exponential	ZUMA-7 trial^28
SOC, OS	Generalized gamma	ZUMA-7 trial^28
SOC, TTNT	Loglogistic	ZUMA-7 trial^28
Health state utility values
Event-free, axi-cel, on-treatment	0.781	ZUMA-7 trial^28
Event-free, SOC, on-treatment	0.770	ZUMA-7 trial^28
Event-free, off-treatment	0.786	ZUMA-7 trial^28
Post-event	0.722	ZUMA-1 trial^25
Share of patients receiving treatment
Axi-cel, leukapheresis	98.9%	ZUMA-7 trial^28
Axi-cel, conditioning chemotherapy	95.6%	ZUMA-7 trial^28
Axi-cel, axi-cel infusion	94.0%	ZUMA-7 trial^28
SOC, R-DHAP	23.4%	Calculated based on data from the ZUMA-7 trial^28
SOC, R-ICE	51.0%	Calculated based on data from the ZUMA-7 trial^28
SOC, R-GDP	25.4%	Calculated based on data from the ZUMA-7 trial^28
SOC, stem cell harvest	41.3%	ZUMA-7 trial^28
SOC, HDT	35.8%	ZUMA-7 trial^28
SOC, ASCT	34.6%	ZUMA-7 trial^28
Drug acquisition costs, SEK
Axi-cel	3,380,000	Derived from the pharmacy selling price (SEK 3,381,046^29) using the Swedish Dental and Pharmaceutical Benefits Agency’s converter^30
SOC, R-DHAP^a	2975	See Supplementary Materials
SOC, R-ICE^a	6194	See Supplementary Materials
SOC, R-GDP^a	3153	See Supplementary Materials
SOC, HDT (BEAM)^a	31,752	See Supplementary Materials
Axi-cel, conditioning chemotherapy^a	3654	See Supplementary Materials
3L+, R-IVE^a	8903	See Supplementary Materials
3L+, R-Lenalidomide^a	9935	See Supplementary Materials
3L+, Pola-BR^a	118,793	See Supplementary Materials
3L+, Nivolumab^a	62,563	See Supplementary Materials
3L+, Pembrolizumab^a	67,039	See Supplementary Materials
Event-free health state resource use (axi-cel and SOC)
District nurse	1.88	NICE TA872^27 and validated by Swedish KOL
CT scans	0.11	NICE TA872^27 and validated by Swedish KOL
PET-CT	0.11	NICE TA872^27 and validated by Swedish KOL
Outpatient visits (months 1 to 6)	0.69	NICE TA872^27 and validated by Swedish KOL
Outpatient visits (months 7 to 24)	0.34	NICE TA872^27 and validated by Swedish KOL
Outpatient visits (years 2 to 3)	0.20	NICE TA872^27 and validated by Swedish KOL
Outpatient visits (years 4 to 5)	0.14	NICE TA872^27 and validated by Swedish KOL
Nurse visits	1.88	NICE TA872^27 and validated by Swedish KOL
Specialist nurse visits	0.32	NICE TA872^27 and validated by Swedish KOL
Inpatient days	0.18	NICE TA872^27 and validated by Swedish KOL
Blood tests	2.50	NICE TA872^27 and validated by Swedish KOL
Post-event health state resource use (axi-cel and SOC)
District nurse	0	NICE TA872^27 and validated by Swedish KOL
CT scans	0.01	NICE TA872^27 and validated by Swedish KOL
PET-CT	0.01	NICE TA872^27 and validated by Swedish KOL
Outpatient visits (months 1 to 6)	1.00	NICE TA872^27 and validated by Swedish KOL
Outpatient visits (months 7 to 24)	1.00	NICE TA872^27 and validated by Swedish KOL
Outpatient visits (years 2 to 3)	1.00	NICE TA872^27 and validated by Swedish KOL
Outpatient visits (years 4 to 5)	1.00	NICE TA872^27 and validated by Swedish KOL
Nurse visits	0	NICE TA872^27 and validated by Swedish KOL
Specialist nurse visits	1.88	NICE TA872^27 and validated by Swedish KOL
Inpatient days	0.16	NICE TA872^27 and validated by Swedish KOL
Blood tests	0.75	NICE TA872^27 and validated by Swedish KOL
Unit costs, SEK
Leukapheresis	7995	Region Östergötland, tariff ‘Terapeutisk leukaferes’^31 and adjusted to 2022 price level
CAR T-cell infusion and inpatient stay following  infusion	140,136	Södra Regionvårdsnämnden, combination of tariff ‘VARDDAG’, hematology and ‘DR029’^32. 14 days of hospitalization was assumed
Stem cell harvest	31,873	Södra Regionvårdsnämnden, tariff ‘DR027’^32
ASCT	288,442	Södra Regionvårdsnämnden, tariff ‘R23C’^32
Inpatient chemotherapy administration (per  inpatient day)	15,721	Södra Regionvårdsnämnden, combination of tariff ‘DT016’ and tariff ’VARDDAG’, hematology^32
Allo-SCT	744,434	Södra Regionvårdsnämnden, tariff ‘R20N’^32
Radiation therapy	24,466	Södra Regionvårdsnämnden, tariff ‘Strålbehandling av lymfom/sarkom’^32
End-of-life cost	92,014	The Swedish Dental and Pharmaceutical Benefits Agency’s health economic assessment of ipilimumab from 2014^33 and adjusted to a 2022 price level
Nurse/specialist nurse/district nurse visit	1051	Södra Regionvårdsnämnden, tariff ‘BSVB01’, hematology^32
Inpatient stay (per inpatient day)	9684	Södra Regionvårdsnämnden, tariff ‘VARDDAG’, hematology^32
Blood test	357	Södra Regionvårdsnämnden, tariff ‘LA000’^32
PET-CT scan	16,987	Region Skåne, average cost of 70 007–70 012 and 70 030^34
CT scan	2903	Region Skåne, sum of 81 900 and 83 900^34
Outpatient visit	3333	Södra Regionvårdsnämnden, tariff ‘BLÄK01HÅ’^32
Adverse event costs, SEK
CRS^b	105,492	See Supplementary Materials
Neurologic events (i.e. ICANS)^b	62,310	See Supplementary Materials
Thrombocytopenia^b	1147	See Supplementary Materials
Febrile neutropenia^b	6394	See Supplementary Materials
Anemia^b	1140	See Supplementary Materials

Abbreviations. MCM, Mixture cure model; EFS, Event-free survival; NICE, National Institute for Health and Care Excellence; OS, Overall survival; TTNT, Time to next therapy; axi-cel, axicabtagene ciloleucel; SOC, Standard of care; R-DHAP, Rituximab, cisplatin, cytarabine, and dexamethasone; R-ICE, Rituximab, ifosfamide, carboplatin and etoposide; R-GDP, Rituximab, cisplatin, gemcitabine and dexamethasone; HDT, High dose therapy; BEAM, Carmustine, cytarabine, etoposide and melphalan; R-IVE, Rituximab, ifosfamide, epirubicin and etoposide; R-Lenalidomide, Rituximab, lenalidomide, pola-BR, Polatuzumab vedotin, bendamustine and rituximab; 3L+, Third-line or later; CAR T-cell, Chimeric antigen receptor T-cell; ASCT, Autologous stem cell transplantation; SCT, Stem cell transplantation; SEK, Swedish krona; CRS, Cytokine release syndrome; ICANS, Immune effector cell-associated neurotoxicity syndrome; KOL, Key opinion leader.

^a Total cost per cycle.

^b Total treatment cost per event.

2.4.1. Treatment costs

The cost of 2L treatment with axi-cel included the costs of leukapheresis, conditioning chemotherapy, CAR T-cell infusion and hospitalization following infusion in addition to the drug acquisition cost for axi-cel. The share of patients in the ZUMA-7 trial who underwent leukapheresis, received conditioning chemotherapy and completed the axi-cel infusion are presented in Table 1. The cost of 2L treatment with SOC included salvage chemoimmunotherapy followed by HDT and ASCT for patients with complete or partial response. In ZUMA-7, salvage chemoimmunotherapy consisted of R-ICE, R-GDP, R-DHAP and R-ESHAP regimens. According to the Swedish clinical guidelines for treatment of DLBCL³, R-ESHAP is not used as salvage chemoimmunotherapy in Sweden, thus, patients receiving R-ESHAP in the trial were uniformly allocated to the other regimens in the model. The share of patients who received salvage chemoimmunotherapy (R-ICE, R-GDP and R-DHAP), stem cell harvest, HDT and who completed ASCT in the model are presented in Table 1. A weighted average cost of subsequent therapy (3L+) was applied in the model when a patient experienced a TTNT event. The proportion of patients receiving each subsequent therapy was collected in ZUMA-7 and applied in the model. Tender prices from Region Stockholm³⁵ were applied in the model to calculate the drug acquisition costs. Pharmacy selling prices were used in cases where tender prices were not available (see Supplementary Materials). For axi-cel, the pharmacy purchasing price was used (derived from pharmacy selling price²⁹). Unit costs were sourced from price lists from Region Östergötland³¹ and Södra Regionvårdsnämnden³². The Swedish Regions’ Price Index (LPIK) 1980–2021³⁶ and forecast for LPIK in 2022³⁷ (excluding pharmaceutical costs) were used to adjust the cost of leukapheresis to a 2022 price level. Additional information on 2L and subsequent therapies is provided in the Supplementary Materials.

2.4.2. Health state costs

Health state resource utilization was assumed to be independent of treatment arm and included outpatient visits, nurse visits, inpatient stays, CT scans, PET-CT scans, and blood tests. Resource use was stratified into event-free and post-event and adjusted to reflect Swedish clinical practice. The event-free resource use included the resource use for follow-up after ASCT and axi-cel treatment. The resource use for patients who were still event-free after five years was reverted to zero based on the assumption that patients who are still event-free after five years are effectively considered long-term responders with minimal healthcare resource utilization. Patients transitioning to the death health state incurred a one-off end-of-life cost. The number of visits and tests included per month are presented in Table 1. Unit costs were sourced from price lists from Södra Regionvårdsnämnden³² and Region Skåne³⁴. The Swedish Regions’ Price index (LPIK) 1980–2021³⁶ and forecast for LPIK in 2022³⁷ (excluding pharmaceutical costs) were used to adjust end-of-life cost to a 2022 price level.

2.4.3. Cost of adverse events

The model included the following Grade 3 and 4 AEs observed in ZUMA-7 that required treatment: cytokine release syndrome (CRS), neurologic events (i.e. immune effector cell-associated neurotoxicity syndrome (ICANS)), thrombocytopenia, anaemia and febrile neutropenia. Cost of managing AEs was not included for subsequent therapies. Unit costs were sourced from price lists from Södra Regionvårdsnämnden³². More details can be found in the Supplementary Materials.

2.5. Sensitivity and scenario analyses

Deterministic sensitivity analyses (DSA) and a probabilistic sensitivity analysis (PSA) with 1,000 iterations were conducted to assess robustness of the results. In the DSA, baseline characteristics (proportion of females, mean age, and mean body weight and body surface area), resource use, utilities, AE rates, proportion of patients receiving each type of subsequent therapy and unit costs were varied. The PSA probability distributions are presented in the Supplementary Table S7.

Several scenario analyses were conducted to assess the impact of key inputs and assumptions, including the time horizon (5, 10, 20, 30 and 40 years), the hazard of death compared to the general Swedish population for those who were assumed to achieve long-term remission (SMRs of 1.18 and 1.00), the utility values for patients who were still event-free after five years (reverting to general population vs not reverting) and the perspective of the analysis (healthcare vs societal).

The societal perspective included costs of productivity loss, patient and caregiver time spent on treatment-specific activities, and transportation costs to and from the hospital. The patient time ascribed to each treatment-related activity is presented in Table 2. The applied hourly wages by age in Sweden are presented in Table 3. For the cost of transportation, it was assumed that patients have a one-hour drive each way to and from the hospital for any inpatient or outpatient visits. The transportation cost per visit was assumed to be SEK 300. For multi-day inpatient stays, the cost was only triggered once. AEs did not trigger additional transportation costs, as these were assumed to be treated during the inpatient stay at follow-up. As per TLV guidelines, the human capital approach was used to calculate the productivity loss³⁸. The productivity loss for patients in the pre- and post-event health states was included together with the productivity loss caused by premature death. The share of patients who are able to work per month is presented in Table 4.

Table 2. Patient time included in the scenario analysis, applying a societal perspective.

Model input	Patient time-use	Note	Source
Treatment-related activities in the axi-cel arm
Leukapheresis	18 h per cycle	Based on one inpatient day (an inpatient day was assumed to be 16 h) + two hours of transportation. In the model, the patient time spent on treatment-related activities in the axi-cel arm was weighted by survival.	1177 Region Skåne^39
Conditioning chemotherapy	50 h per cycle	Based on 16 x 3 hours of inpatient stay + two hours of transportation. In the model, the patient time spent on treatment-related activities in the axi-cel arm was weighted by survival.	Kunskapsbanken^40
Axi-cel procedure	226 h per cycle	Based on 14 days x 16 h + 2 hours of transportation. In the model, the patient time spent on treatment-related activities in the axi-cel arm was weighted by survival.	Clinical expert input^17
Disease management and monitoring activities
District nurse visits	Per visit: 15 min Total patient time: 2.25 h	Total patient time includes 2 hours of transportation.	Clinical expert input^17
Outpatient visits	Per visit: 30 min Total patient time: 2.50 h	Total patient time includes 2 hours of transportation.	Clinical expert input^17
Nurse visits	Per visit: 30 min Total patient time: 2.50 h	Total patient time includes 2 hours of transportation.	Clinical expert input^17
Specialist nurse visits	Per visit: 30 min Total patient time: 2.50 h	Total patient time includes 2 hours of transportation.	Clinical expert input^17
CT scan	Per visit: 60 min Total patient time: 3.00 h	Total patient time includes 2 hours of transportation.	Clinical expert input^17
PET-CT scan	Per visit: 120 min Total patient time: 4.00 h	Total patient time includes 2 hours of transportation.	Clinical expert input^17
Blood test	Per visit: 30 min Total patient time: 1.50 h	Total patient time includes 2 hours of transportation. The expert noted that all blood tests may occur on the day of outpatient visits but may also be done the day before and that the split between the day before and the same day is probably around 50/50.	Clinical expert input^17
Inpatient days	Per visit: 16 h Total patient time: 18 h	Total patient time includes 2 hours of transportation.	Clinical expert input^17
Outpatient visit (months 1 to 6)	Per visit: 30 min Total patient time: 2.50 h	Total patient time includes 2 hours of transportation.	Clinical expert input^17
Outpatient visit (months 7 to 24)	Per visit: 30 min Total patient time: 2.50 h	Total patient time includes 2 hours of transportation.	Clinical expert input^17
Outpatient visit (years 2 to 3)	Per visit: 30 min Total patient time: 2.50 h	Total patient time includes 2 hours of transportation.	Clinical expert input^17
Outpatient visit (years 4 to 5)	Per visit: 30 min Total patient time: 2.50 h	Total patient time includes 2 hours of transportation.	Clinical expert input^17
Salvage chemotherapy regimens in the SOC arm
R-ICE	66 h	Based on four days x 16 h + 2 hours of transportation time.	Kunskapsbanken^40. Assumed transportation time
R-GDP	34 h	Based on two days x 16 h + 2 hours of transportation time.	Kunskapsbanken^40. Assumed transportation time
R-DHAP	36 h	Based on two days x 16 h + 2 hours of transportation time.	Kunskapsbanken^40. Assumed transportation time
Autologous stem cell transplantation
Stem cell harvest	18 h	Based on one day x 16 h + 2 hours of transportation time.	Kunskapsbanken^40 and input from clinical expert^17
HDT (BEAM)	114 h	Based on seven days x 16 h + 2 hours of transportation time.	Kunskapsbanken^40 and input from clinical expert^17
Hospital admission	336 h	Three weeks, including infusion of stem cells and subsequent monitoring: 21 days x 16 h.	Kunskapsbanken^40 and input from clinical expert^17
Adverse events
CRS	72 h	No additional transportation time was assumed since patients would be admitted to the ICU following a regular inpatient follow-up visit, from where they would need transport home regardless.	Clinical expert input^17
Neurologic events	40 h	The patient time was estimated as a mean of the additional treatment time for Grade 3 events, which was zero hours, and the treatment time for Grade 4 events, which was five inpatient days. No additional transportation time was assumed since patients would be admitted to the ICU following a regular inpatient follow-up visit, from where they would need transport home regardless.	Clinical expert input^17
Thrombocytopenia	0 h	Treated while the patient was hospitalized for a regular follow-up.	Clinical expert input^17
Febrile neutropenia	0 h	Treated while the patient was hospitalized for a regular follow-up.	Clinical expert input^17
Anemia	0 h	Treated while the patient was hospitalized for a regular follow-up.	Clinical expert input^17
Subsequent therapy
Chemotherapy	50 h	Based on three inpatient days: Three days x 16 h + two hours of transportation.	Kunskapsbanken^40
Nivolumab	18 h	Based on one inpatient day: one day x 16 h + two hours of transportation.	Assumption
Pembrolizumab	18 h	Based on one inpatient day: one day x 16 h + two hours of transportation.	Assumption
Pola-BR	34 h	Based on two inpatient days: two days x 16 h + two hours of transportation.	Kunskapsbanken^40
R-lenalidomide	72 h	Based on four inpatient days: four days x 16 h + 4 × 2 h of transportation.	Kunskapsbanken^40
Radiotherapy	27 h	The same patient time-use for radiotherapy in subsequent therapy was assumed for radiotherapy as bridging therapy: 15 min x 12 courses + two hours x 12 courses.	Assumption
Allogeneic SCT	336 h	The patient time-use for ASCT in 2L was also applied for ASCT in subsequent lines, i.e. 21 inpatient days: 21 days x 16 h.	Clinical expert input^17
CAR T-cell therapy: Leukapheresis	18 h	Based on one inpatient day + two hours of transportation.	1177 Region Skåne^39
CAR T-cell therapy:  Bridging therapy	25.17 h	Estimated as the mean of 23.33 h and 27 h.	Assumption
CAR T-cell therapy: Conditioning  therapy	50 h	Based on 16 x three hours of inpatient stay + two hours transportation.	Kunskapsbanken^40
CAR T-cell therapy: Hospital  admission (14 days)	226 h	Based on 14 days x 16 h + two hours of transportation.	Clinical expert input^17
ASCT: Stem cell harvest	18 h	Based on one inpatient day + two hours of transportation.	Kunskapsbanken^40 and input from clinical expert^17
ASCT: HDT (BEAM)	114 h	Seven days x 16 h + two hours of transportation.	Kunskapsbanken^40 and input from clinical expert^17
ASCT: Hospital admission (21 days)	336 h	Based on 21 days x 16 h.	Kunskapsbanken^40 and input from clinical expert^17

Abbreviations. Axi-cel, axicabtagene ciloleucel, R-ICE, rituximab, ifosfamide, carboplatin, etoposide, R-DHAP: rituximab, cisplatin, cytarabine, dexamethasone; R-GDP, cisplatin, gemcitabine, dexamethasone, Pola-BR, polatuzumab vedotin in combination with bendamustine and rituximab, CT scan: computerized tomography scan; PET, positron emission tomography; HDT, high-dose chemotherapy; ASCT; autologous stem cell transplantation; AE, adverse event; CRS, cytokine release syndrome.

Table 3. Average age-adjusted hourly wage and workforce.

Age groups	Mean hourly wage (SEK)	Proportion of age group in workforce
18–24	165.00	75%
25–34	175.00	75%
35–44	180.00	75%
45–54	185.00	75%
55–64	185.00	75%
65–74	180.00	75%
75+	180.00	0%

Abbreviations. SEK, Swedish krona.

Source: Average hourly wages by age, 2021 Statistics Sweden⁴⁵ and Labour Force Surveys 15–74 years, 2022 Statistics Sweden⁴⁶. It was assumed that 0% of the patients aged 75 years or older were in the workforce.

Table 4. Proportion (percentage) of patients being absent from work per month in the pre-event and post-event states in the model.

	Pre-event	Post-event
Axi-cel	50%	80%
SOC	30%	80%

Abbreviations. SoC, standard of care; Axi-cel, axicabtagene ciloleucel;

Source: Clinical expert input¹⁷.

It was expected that the off-protocol treatment switching in ZUMA-7 heavily confounded the OS and costs. Therefore, a scenario analysis was conducted that accounted for the treatment switching from SOC to CAR T-cell therapy by not including the cost and effects of treatment switching in the SOC arm. Established statistical methods such as the RPSFTM and IPCW are generally regarded as appropriate for handling treatment switching⁴¹ and were applied to model the OS benefit in the absence of switching⁶. The two methods are described further in the Supplementary Materials. Both IPCW and RPSFTM were pre-specified in the ZUMA-7 protocol, and for the RPSFTM model full, partial or no re-censoring were performed following the guidance in the National Institute for Health and Care Excellence technical support document 16⁶. Clinical validation and external controls were used to assess the plausibility of resultant curves. The resultant curve was expected to fall in between the OS curves from the ORCHARRD⁴² and SCHOLAR-1⁴³ as these two trials represent pre-CAR T-cell therapy use in a similar population. The RPSFTM with full re-censoring (HR: 0.416) gave the most clinically plausible estimates and has been accepted by the National Institute for Health and Care Excellence in their assessment of axi-cel in 2L DLBCL⁴⁴. The resultant HR (0.416) was applied to the modelled axi-cel arm to estimate the OS curve for SOC in the absence of subsequent cellular therapy (Figure 4). The proportion of patients who received subsequent cellular therapy (including axi-cel) were redistributed to the chemotherapy regimens to account for costs. As in the base case, the impact on HRQoL of subsequent therapy was not accounted for in the scenario analysis.

Figure 4. Validation of the modelled treatment switching adjusted SOC OS curve. ZUMA-7 modelled SOC OS curve adjusted for treatment switching using the RPSFTM model with full re-censoring and HR approach, ZUMA-7 modelled axi-cel OS curve and Kaplan Meier curves from ORCHARRD⁴⁹ and SCHOLAR-1⁴⁵.

3. Results

3.1. Cost-effectiveness analysis

Over a lifetime horizon of 50 years, the model estimated an ICER of SEK 534,704 per QALY gained with an incremental discounted cost of SEK 812,944 and incremental discounted QALY gain of 1.52 for axi-cel compared to SOC. The total discounted cost per patient was SEK 4,137,997 and SEK 3,325,053 for axi-cel and SOC, respectively, and the total discounted QALY gain was 7.51 and 5.99 for axi-cel and SOC, respectively. The model estimated an incremental undiscounted LY gain of 2.56 years for axi-cel compared to SOC, with an average of 14.24 and 11.68 LYs for axi-cel and SOC, respectively. A detailed overview of the results is provided in Table 5. Furthermore, the model estimated 5-year survival rates of 51.3% and 42.9% and 10-year survival rates of 48.9% and 39.6% for patients treated with axi-cel and SOC, respectively. The median OS gain for axi-cel versus SOC was 70 months.

Table 5. Base case cost-effectiveness results.

Per patient	Axi-cel	SOC	Difference
Mean LYs gained (undiscounted)	14.24	11.68	2.56
Event-free	10.13	4.39	5.74
Post-event	4.11	7.29	−3.18
QALYs (discounted)	7.51	5.99	1.52
Event-free	5.48	2.38	3.10
Post-event	2.03	3.60	−1.58
Cost, SEK (discounted)	4,137,997	3,325,053	812,944
2L treatment-related costs	3,330,092	279,711	3,050,380
Subsequent treatment-related costs	304,877	2,552,470	−2,247,594
Disease management costs	417,390	420,275	−2885
Adverse event costs	20,393	2795	17,598
End-of-life costs	65,246	69,801	−4556
ICER, SEK per QALY	534,704

Abbreviations. Axi-cel, axicabtagene ciloleucel; SOC, Standard of care; Lys, Life years; QALYs, Quality-adjusted life years; SEK, Swedish krona; ICER, Incremental cost-effectiveness ratio.

The costs included both 2L and subsequent therapy-related costs as well as costs related to disease management, AEs and end-of-life care. The cost of 2L therapy was highest for patients receiving axi-cel, whereas the subsequent therapy costs were highest for patients receiving SOC due to the high use of CAR T-cell therapy in subsequent treatment lines.

3.2. Sensitivity and scenario analyses

Figure 5 presents a tornado diagram with the 10 most influential model parameters from the DSA. The top three influential parameters were identified to be the post-event utility value, mean age and the number of specialist nurse visits in the post-event state for SOC.

Figure 5. Tornado diagram. The figure illustrates the 10 most influential parameters of the DSA. The base case parameters were varied based on their standard errors. If the standard errors were not reported, the parameters were varied by an arbitrary ±20% around the mean.

The PSA resulted in an incremental discounted cost of SEK 801,930 and an incremental QALY gain of 1.33. The estimated ICER from the PSA was SEK 491,868 per QALY gained. Figure 6 presents the PSA cost-effectiveness plane, and Figure 7 illustrates the probability of axi-cel being cost-effective at different willingness-to-pay thresholds. If assuming a willingness-to-pay threshold of SEK 1,000,000, axi-cel was cost-effective versus SOC in 73% of the simulations. The PSA results are presented in more detail in the Supplementary Table S8.

Figure 6. PSA cost-effectiveness plane (SEK). The figure illustrates that the majority of the alternative ICERs in the cost-effectiveness plane are located in the Northeast quadrant of the graph, where axi-cel is more effective and more costly compared to SOC. A small proportion is placed in the Northwest quadrant, where axi-cel is more costly and less effective compared to SOC.

Figure 7. Cost-effectiveness acceptability curve (SEK). The figure illustrates the cost-effectiveness probability at different willingness-to-pay thresholds. At a willingness to pay threshold of SEK 1,000,000, axi-cel is cost-effective in 73% of the simulations.

The results of the scenario analyses are presented in Table 6. Most scenario analyses had a minor impact on the results, and the robustness of the base case result was confirmed. However, shortening the time horizon greatly increased the ICER, especially for time horizons of five or 10 years. The scenario analysis, where costs and effects for SOC were adjusted for off-protocol treatment switching, increased the ICER to SEK 694,351 per QALY gained.

Table 6. Results of scenario analysis.

	Costs, axi-cel	Costs, SOC	Incremental cost, SEK	QALY, axi-cel	QALY, SOC	Incremental QALY	ICER	Difference from base case
Base case	4,137,997	3,325,053	812,944	7.51	5.99	1.52	534,704	–
1: Time horizon, 5 years	4,024,856	3,144,313	880,543	2.27	1.94	0.33	2,639,710	2,105,006
2: Time horizon, 10 years	4,053,104	3,195,774	857,330	3.85	3.18	0.67	1,276,598	741,895
3: Time horizon, 20 years	4,097,508	3,269,101	828,407	6.12	4.93	1.19	695,149	160,446
4: Time horizon, 30 years	4,126,533	3,311,544	814,988	7.25	5.79	1.46	559,234	24,530
5: Time horizon, 40 years	4,137,536	3,324,604	812,932	7.50	5.98	1.52	535,212	509
6: Hazard of death for long-term remission, SMR 1	4,139,558	3,327,290	812,268	7.62	6.08	1.55	524,977	−9726
7: Hazard of death for long-term remission, SMR 1.18	4,136,546	3,323,032	813,514	7.40	5.90	1.50	544,077	9374
8: Perspective, societal perspective*	5,141,597	4,452,915	688,682	7.51	5.99	1.52	452,972	−81,732
9: Accounting for treatment switching, HR 2.4	4,137,997	960,744	3,177,253	7.51	2.93	4.58	694,250	159,547
10: Not reverting the utility values for the patients who were still event-free after five years to those of the general population	4,137,997	3,325,053	812,944	7.38	5.93	1.45	562,172	27,469

* Including costs of productivity loss, patient and caregiver time spent on treatment-specific activities as well as transportation costs to and from the hospital.

Abbreviations. QALYs, Quality-adjusted life years; SEK, Swedish krona; ICER, Incremental cost-effectiveness ratio; SMR, Standardized mortality ratio; HR, Hazard ratio; axi-cel: axicabtagene ciloleucel, SOC, Standard of care.

4. Discussion

This study is the first study in the Nordic countries to evaluate the cost-effectiveness of axi-cel. The results of our analysis indicate that axi-cel is a cost-effective treatment option in 2L for transplant-intended DLBCL patients with early r/r after completing 1L chemoimmunotherapy.

In Sweden, the New Therapies Council, representing regional payers, has outlined criteria to determine the willingness to pay for new medicines. These criteria consider disease severity, clinical benefit, rarity of the disease and uncertainty in the clinical evidence. Based on these criteria and assuming a willingness to pay of SEK 1,000,000, axi-cel can be considered a cost-effective 2L treatment alternative for this patient population in Sweden. Axi-cel is currently recommended and funded by regional healthcare providers for the 3L+ treatment of r/r DLBCL in Sweden based on the ZUMA-1 trial. In the cost-effectiveness analysis of axi-cel compared to SOC for 3L+ r/r DLBCL, the estimated ICER was on par with the ICER estimated in the scenario analysis accounting for treatment switching in our study²⁹. This is a conservative scenario, as 3L+ use of axi-cel is approved in Sweden but indicates that axi-cel is a cost-effective 2L treatment alternative and that the use should not be restricted to 3L+.

Efforts were made in our cost-effectiveness analysis to reflect Swedish clinical practice. Therefore, the patient characteristics from the ZUMA-7 trial and other parameters that informed the model were aligned with a Swedish clinical expert’s inputs as part of the model validation process. Several scenario analyses were undertaken to investigate the implication of using alternative model inputs and assumptions. The robustness of the base case result was confirmed as most scenario analyses had a minor impact on the result. The scenario analyses using different time horizons stood out, as the ICER was greatly impacted by the shorter (five- and 10-year) time horizons. As axi-cel is a one-off treatment, treatment costs are incurred upfront, whereas the benefits of receiving treatment are accumulated over the patients’ lifetime. Axi-cel has the potential to be a curative therapy for approximately 50% of DLBCL patients and shortening the time horizon will therefore significantly reduce the number of QALYs and LYs gained while most of the costs remain, leading to a higher incremental cost per QALY. The scenario analysis accounting for treatment switching was conducted because 56% of patients randomized to the SOC arm in ZUMA-7 received off-protocol CAR T-cell therapy as subsequent therapy. This is possibly higher than the use in Swedish clinical practice, meaning that the ICER could potentially be higher in a Swedish setting than the base case ICER reported in our study, due to the lower use of subsequent therapy in the SOC arm in Sweden. It is likely that the ICER for axi-cel compared to SOC in Sweden lies between the result of our base case analysis and the scenario analysis, where the OS for SOC was adjusted for treatment switching. However, the ICER is still relatively contained even in the extreme scenario of 0% CAR T-cell therapy use in subsequent treatment lines in the SOC arm. According to the Swedish HTA agency, TLV, cost-effectiveness analyses should include scenarios with and without indirect costs⁴⁷. We therefore performed a scenario analysis, changing the perspective of the analysis from a Swedish healthcare perspective to a social perspective. The analysis showed that changing the perspective reduces the ICER by SEK −81,732 compared to the base case.

Tisagenlecleucel, lisocabtagene maraleucel, tafasitamab, and glofitamab are all recently EU-approved treatments for use in r/r DLBCL^38,48–50. However, none of these drugs are currently recommended or reimbursed in Sweden for r/r DLBCL. The New Therapies Council has issued negative reimbursement recommendations for tisagenlecleucel and tafasitamab, and recommendations are pending for lisocabtagene maraleucel and glofitamab⁵¹. At the time of the analysis, these treatments were not available to patients in Sweden and were therefore not seen as relevant to the decision problem. In addition, these drugs are approved for different indications, and only lisocabtagene maraleucel and tafasitamab have EU approval in 2L DLBCL (tafasitamab only for transplant-ineligible patients)³³.

Using the ZUMA-1 event-free utility value as input for the post-event utility value in our analysis may overestimate the utility in the post-event health state. To address this, the post-event utility was included in the DSA, where the base case value was increased/decreased by 20%. The DSA showed that varying the post-event utility value impacted the ICER by less than SEK 51,000 (Figure 5). Applying ZUMA-1 event-free utility values in the post-event state is further supported by the fact that CAR T-cell therapy is reimbursed and used in 3L in Sweden as well as by the fact that around 80% of ZUMA-7 SOC patients receiving 3L treatment ended up receiving CAR T-cell therapy.

The robustness of the results of our study was also supported by Perales et al. 2022⁵², which evaluated the cost-effectiveness of axi-cel compared to SOC for 2L DLBCL in the US. Despite the application of different resource use and other costs for treating DLBCL due to the US setting as well as different utility values, Perales et al. 2022 reported comparable results: an ICER of USD 66,381 per QALY (approx. SEK 700,000 [converted to SEK in November 2022]) compared to the SEK 534,704 per QALY reported in our study. Furthermore, the US study demonstrated a discounted QALY gain for axi-cel of 7.08, which is close to the QALY gain of 7.51 in our study.

This cost-effectiveness analysis utilized data from the randomized controlled trial ZUMA-7. The ZUMA-7 trial is the first and largest (N = 359) head-to-head randomized trial comparing CAR T-cell therapy to SOC with a long follow-up duration. Previous CAR T-cell therapies have been investigated in clinical studies using a single-arm study design. The comparative and randomized trial design of the ZUMA-7 trial also supports the validity of the findings of this study. We explored various approaches to extrapolating survival outcomes beyond the ZUMA-7 trial data. These suggest that the existing OS trend observed in the ZUMA-7 trial will develop into substantial long-term benefits for patients. Furthermore, prolonged EFS as observed for treatment with axi-cel, is a key factor for the improvement in quality of life (QoL). These results are supported by the recently published primary PRO analysis of ZUMA-7, which shows a quicker return to baseline QoL in the axi-cel arm compared to SOC⁵³.

In this cost-effectiveness analysis, a comparison was made between the use of 2L treatment with axi-cel and SOC in transplant-intended DLBCL patients with early r/r after completing 1L chemoimmunotherapy in Sweden. The results show that introduction of axi-cel comes at a higher total cost, but that this cost is offset by the clear clinical benefit of axi-cel compared to SOC. Treating patients in 2L instead of 3L+ is cost-effective as it increases the possibility of curing more patients leading to not only a gain in survival, but also a reduction in the burden on QoL and cost of subsequent therapy. This will benefit both patients and society.

Transparency

Declaration of financial/other interests

Axicabtagene ciloleucel is a product of Gilead Sciences (funder). Gilead Sciences provided support in the form of payments to Incentive Denmark. Authors O.E, S.V and V.K are employees at Gilead Sciences and Kite Pharma, a Gilead company. Incentive Denmark was a paid vendor to Gilead Sciences, and authors A.L, E.M and A.D were paid employees of Incentive Denmark.

Author contributions

A.L, E.M and A.D: Methodology, formal analysis, validation, and writing - original draft. O.E: Methodology, validation, writing - review & editing, project administration and funding acquisition. S.V and V.K: Methodology, validation, and writing - review & editing. All authors have approved the final version of the manuscript to be published and agree to be accountable for all aspects of the work.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have done consulting for Gilead SRL. The other peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Acknowledgement

No assistance in the preparation of this article is to be declared.

Data availability statement

Due to ethical, legal and commercial reasons supporting data is not available beyond what is already disclosed in the Supplementary Materials.

Additional information

Funding

This study was sponsored by Gilead Sciences.