Background. Targeted therapy with Bruton's tyrosine kinase inhibitors (BTKI) has significantly improved progression-free (PFS) and overall survival (OS) outcomes when compared with chemoimmunotherapy in the front line setting of CLL. Following the approval of the first generation of BTKI (ibrutinib, IBR) in 2016 as first line (1L) treatment of CLL, second generation BTKIs with more favorable safety profiles were approved/recommended in 2020 (acalabrutinib, ACA) and 2021 (zanubrutinib, ZAN). We performed a network meta-analysis (NMA) of these three BTKIs in terms of PFS in support of cost-effectiveness analyses from US payer perspective.

Methods. We conducted a NMA of 5 trials (Woyach 2018, Burger 2015, Sharman 2020, Tam 2021, Goede 2014) on the PFS hazard ratios (HR) of the 3 BTKIs and any other CLL interventions that connected in the network. We specified a 5-state Markov model to capture the disease and clinical pathway for CLL patients over a 10 years' time horizon: progression free (PF) on 1L treatment [PF1]; progression before initiating second line (2L) treatment [P1]; PF on 2L treatment [PF2]; progression after 2L treatment [P2]; and death. Patients started PF on 1L treatment with a BTKI and moved to other states based on extracted transition probabilities from lognormal parametric distributions fitted to Kaplan-Meier PFS curves of phase III trials of IBR, ACA and ZAN. Venetoclax plus rituximab (VR) was considered the 2L treatment with PF2, P2 and death in 2L extracted from Seymour 2018. The transition probabilities of PF on 1L treatment and progression after 1L were adjusted based on the NMA results. OS and time to next treatment (TTNT) after first progression were considered the same for the three BTKIs. Costs of regimens (wholesale acquisition cost), adverse event (AE) management, and disease progression were incorporated into the appropriate health states. Utilities of PF1 (0.799), P1 (0.66), PF2 (0.55) and P2 (0.42) were obtained from literature. Annual discount rate of 3.0% was applied. Life years (LY), quality adjusted LY (QALY), and incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were estimated. Probabilistic sensitivity analyses (PSA; 10,000 iterations) were performed to obtain cost-effectiveness acceptability curves (CEAC).

Results. Compared with IBR, ACA (HR=0.54; 95%CI=0.41-0.72) but not ZAN (HR=1.03; 95%CI=0.80-1.34) was associated with a statistically significant lower HR of progression or death. At 10 years, 77% of ACA patients were in PF1 and 9% in PF2, compared to 49% and 28% of ZAN patients, and 50% and 27% of IBR patients. As shown in the table, in base case analyses, total costs of IBR treatment were higher by $104,331 over ACA and by $350,340 over ZAN; with ACA being higher by $246,009 over ZAN. Survival was estimated to be 6.83 LYs for IBR, 7.02 LYs for ACA (+0.19) and 6.82 LYs for ZAN (-0.01). QALYs were estimated to be 5.00 for IBR, 5.46 for ACA (+0.46) and 5.09 for ZAN (+0.09). This yielded negative (cost saving) ICER of $-549,110/LYg and ICUR of $-226,806/QALYg for ACA over IBR. The statistically non-significant survival benefit, the 0.01 LY lost but 0.09 QALY gained, and the lower cost of ZAN over IBR yielded an ICER of $35,034,000/LYg and a negative (cost saving) ICUR of $3,892,666/QALYg. Compared to ZAN, treatment with ACA was associated with incremental costs of $246,009, 0.20 LY and 0.37 QALY differentials, yielding ICER of $1,230,045/LYg yet ICUR of $664,889/QALYg. All estimates were confirmed with negligible differences in PSAs. In a scenario analysis for the PF1 state only, QALY gains were 5.25 for ACA, 4.40 for ZAN and 4.34 for IBR. Considering cost differentials of $-69,138 for ACA and $-352,297 for ZAN relative to IBR, the corresponding ICURs were $-75,975/QALYg and $-5,871,617/QALYg, resp.

Conclusion. Clinically over the course of 1L treatment with a BTKI followed by 2L treatment with VR, ACA in 1L is associated with greater reductions in the risk of progression or death compared to IBR and ZAN over 10 years. This benefit comes at lower cost than IBR, which resulted in cost-saving ICUR and ICER estimates; but at higher cost than ZAN, which resulted in an ICUR of ~$665,000 per QALY gained. Proportionately, QALY results came out more favorably than LY results. This rather unusual result is attributable to the better safety profiles and lower AE costs of ACA and ZAN, coupled with lower pricing.

McBride:Bristol-Myers Squibb: Current Employment.

Author notes


Asterisk with author names denotes non-ASH members.

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