Cost effectiveness of axicabtagene ciloleucel in R/R DLBCL

Introduction

Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is a high-risk non-Hodgkin lymphoma that accounts for about one-third of cases of non-Hodgkin lymphoma in the United States. About 60% of patients with DLBCL respond well to frontline treatment with rituximab in combination with an anthracycline-based regimen; however, patients who experience disease progression following frontline treatment have poor outcomes, demonstrating an unmet need for optimal treatment strategies in this population. Chimeric antigen receptor (CAR) T‐cell therapies have greatly improved clinical outcomes for patients with DLBCL who relapse after two prior therapies and, following the recent Food and Drug Administration (FDA) approval of axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel, may now be considered for second-line treatment.¹

Although CAR T-cell therapies have significantly changed the landscape of DLBCL treatment, associated toxicities such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and financial toxicities remain concerning. The considerable cost of drug acquisition, procedures, supportive care, and hospitalization restricts patient access and is a financial burden on hospitals.²

The Lymphoma Hub previously published primary analysis results and patient-reported outcomes from the phase III ZUMA-7 trial of second-line axi-cel versus standard-of-care (SoC) in patients with R/R DLBCL (NCT03391466). Below, we summarize an article by Kambhampati, et al. published in Blood on the cost-effectiveness of second-line axi-cel in the ZUMA-7 trial.²

Design and methods

• A Markov model was developed to simulate a cohort of US adults (mean age, 65 years) with R/R DLBCL who had either primary refractory disease or early relapse (<12 months from initial therapy). The model was used to examine the impact of two treatment regimens in the ZUMA-7 trial

1. 1. SoC, defined as two cycles of salvage chemoimmunotherapy followed by high-dose chemotherapy, auto-SCT (if the patient responds to salvage chemoimmunotherapy), and CAR T-cell therapy in the third-line setting for non-responders and patients who relapsed.
   2. Second-line CAR T-cell therapy, which consisted of conditioning chemotherapy with cyclophosphamide and fludarabine before a single infusion of axi-cel (salvage chemoimmunotherapy and possible transplant were given for non-responders and patients who relapsed).

• Event-free survival (EFS) and overall survival (OS) were estimated from the ZUMA-7 trial.
• Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150,000/quality-adjusted life-year (QALY).

• One-way sensitivity analyses were performed to evaluate the effect of all defined variables according to each strategy, including age, life expectancy after long-term remission, and costs/outcomes of cellular therapy for R/R DLBCL. During the Monte Carlo probabilistic sensitivity analysis, 10,000 iterations were performed using gamma distributions for cost and beta distributions for transition probabilities.

Results

• Detailed analysis of outcomes and cost-effectiveness of the SoC and second-line CAR-T in primary refractory/early relapse patients are summarized in Table 1.
• Assuming a 5-year EFS of 35% and 10% with second line axi-cel and SOC, respectively, axi-cel was found to be cost-effective at a WTP of $150,000/QALY ($93,547/QALY) (Table 1).
• Sensitivity analyses of 5-year EFS in different scenarios (Table 2) showed that
  • 5-year EFS of 40% with second line axi-cel was cost-effective at WTPs of $100,000/QALY and $150,000/QALY.
  • 5-year EFS of 20% with second line axi-cel therapy was not cost-effective at WTPs of $100,000/QALY and $150,000/QALY.
  • Second-line axi-cel was the cost-effective strategy in 73% of the 10,000 Monte-Carlo iterations at a WTP of $150,000.

Table 1. Outcomes and cost-effectiveness of SoC and second line axi-cel in primary refractory/early relapse patients with DLBCL*

axi-cel, axicabtagene ciloleucel; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; OS, overall survival; QALY, quality-adjusted life year; ICER, incremental cost-effectiveness ratio; SoC, standard of care; USD, U.S. Dollar. *Adapted from Kambhampati, et al.1 †Base case where 6% rate of relapse after 24-month EFS is achieved with second-line axi-cel. ‡Second-line axi-cel has a low rate of relapse after between 2 and 5 years. §Second line axi-cel has a high rate of relapse after between 2 and 5  years.
Parameters	SoC	Second-line axi-cel
		Scenario 1†	Scenario 2‡	Scenario 3§
2-year OS, %	53	62	62	62
2-year EFS, %	16	41	41	41
5-year OS, %	26	41	49	32
5-year EFS, %	10	35	40	20
Life, years	3.67	6.96	7.55	4.69
Cost- effectiveness, QALY	2.60	5.42	5.90	3.99
Increased cost effectiveness, QALY	—	2.82	3.29	1.39
Cost, USD	508,034	771,838	751,602	832,497
Increased cost, USD	—	263,804	243,568	324,463
ICER	—	93,547	73,968	233,967

Table 2. Sensitivity analyses of the 5-year EFS with second-line axi-cel in primary refractory/early relapse patients with DLBCL*

axi-cel, axicabtagene ciloleucel; DBCL, diffuse large B-cell lymphoma; EFS, event-free survival; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; USD, U.S. Dollar; WTP, willingness to pay. *Adapted from Kambhampati, et al.1 †Proportion of simulations that second-line axi-cel is cost-effective at various WPP thresholds.
5-year EFS with second line axi-cel	20%	25%	30%	35%	40%
Life gained, years	1.02	2.12	2.65	3.29	3.88
Cost-effectiveness, QALY	3.99	4.47	4.95	5.42	5.90
Increased cost-effectiveness, QALY	1.39	1.87	2.35	2.82	3.29
Cost, USD†	832,497	812,288	792,068	771,838	751,602
Increased cost, USD	324,463	304,254	284,033	263,804	243,568
ICER	233,967	162,778	121,024	93,547	73,968
50,000 USD†	4	7	15	34	41
100,000 USD†	19	26	44	57	72
150,000 USD†	31	47	61	73	84

• Treatment with second-line axi-cel in patients with R/R DLBCL is cost-effective vs SoC if the total benefit in EFS is maintained over time at a WTP threshold of $150,000/QALY. However, this cost-effectiveness is considerably dependent on the long-term outcomes (5-year EFS of at least 26.4%).
• Limitations of the analysis included a lack of long-term follow-up data from the ZUMA-7 trial, with only one CAR T-cell product (axi-cel) used for modelling, and strict exclusion criteria including the use of bridging therapy except for glucocorticoids.

Conclusion

The results of this analysis demonstrated the cost-effectiveness of axi-cel vs SoC in the second-line setting for primary refractory/ early relapse DLBCL at WTP thresholds of $100,000 and $150,000, providing that the response was durable. Despite the positive results, routine use of second-line CAR T-cell therapy for patients with primary refractory/ early relapse DLBCL in the United States will significantly increase healthcare costs; therefore, further cost-reduction strategies are warranted to reduce the healthcare expenditure burden of CAR T-cell therapies.