Economic Evaluation for the US of Ibrutinib Versus Acalabrutinib for Patients with Relapsed or Refractory Mantle Cell Lymphoma
Authors: Alrawashdh Neda , Alkhatib Nimer , McBride Ali , Persky Daniel , Abraham Ivo 
Published: October 2019

Abstract
Introduction . Mantle cell lymphoma (MCL) is a rare subtype of Non-Hodgkin lymphoma (NHL) with a poor prognosis. Ibrutinib is an oral Bruton's tyrosine kinase inhibitor (BTKi) approved in the US in 2013 for, among other indications, MCL patients with at least one prior therapy (i.e., relapsed/refractory [R/R] MCL). The BTKi acalabrutinib was approved in late 2017 specifically for this same indication. No studies have assessed the comparative efficacy and cost-effectiveness and cost-utility of both agents in the management of R/R MCL. We performed an indirect comparison of both agents in terms of progression-free survival (PFS) and overall survival (OS) to subsequently evaluate the relative cost-effectiveness and cost-utility of both treatment options of R/R MCL from a USA payer perspective.
Methods. A life time horizon Markov model with 3 health states was specified: PFS, progression, and death. Trials to simulate these health outcomes under the respective treatment regimens included Dreyling et al (Lancet 2016) for ibrutinib and Wang et al (Lancet 2018) for acalabrutinib. Kaplan-Meier PFS and OS curves were digitized, PFS and OS data extracted, Weibull distributions fitted to these data, and extrapolations to the life time horizon estimated for both acalabrutinib and ibrutinib to estimate the life time efficacy of each treatment. Naïve patient simulation was performed to indirectly estimate and compare the OS and PFS estimates of the two agents. Wholesale acquisition costs (WAC) were obtained from RedBook (average sales price not yet available for acalabrutinib): $12,180 for ibrutinib and $14,064 for acalabrutinib. Costs of managing side effects and EQ-5D utility values were sourced from published literature. Costs were inflated based on the medical consumer price index to the first quarter of 2018. Disutility values for side effects were assumed the same for both interventions. A discount rate of 3% was applied when survival exceeded one year. The life years (LY) and quality adjusted LY (QALY) for each treatment, the incremental LY and QALY gained with acalabrutinib over ibrutinib, and the incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were estimated in both base and probabilistic sensitivity analyses (PSA; 2000 simulations). The cost-effectiveness plane (CEP) and cost-effectiveness acceptability curves (CEAC) were plotted.
Results. In the naïve patient simulation median PFS and OS were estimated to be 14.6 months and 25.1 months for ibrutinib, and 27.6 months and 168 months for acalabrutinib. As shown in the table below, in the life time horizon Markov model acalabrutinib showed incremental cost of $259,200/LY (PSA: $258,780/LY) and incremental gains of 0.48 LY (PSA: 0.48 LY) and 0.36 QALY (PSA: 0.36 QALY) over ibrutinib. This yielded an ICER of $540,000 per LY gained (PSA: $539,125 per LY gained) and an ICUR of $720,000 per QALY gained (PSA: $718,833 per QALY gained). In the CEP scatter plot, all estimates were in the upper-right quadrant indicating greater incremental QALY at higher incremental cost. Per the CEAC plot, the probability that acalabrutinib would be considered cost-effective was 50% at a willingness to pay threshold (WTP) of $718,833 per QALY and 70% at a WTP threshold of $748,000 per QALY.
Conclusions. Clinically, treating patients with R/R MCL with acalabrutinib was associated with an absolute survival gain of 0.48 years (~6 months) and a quality-adjusted survival gain of 0.36 years (~4 months) over treatment with ibrutinib but at an additional cost of nearly $260,000 per year of treatment. Treating patients with RR/MCL acalabrutinib requires high WTP thresholds to be considered cost-effective to US payers.

Disclosures
Persky: Genentech: Honoraria; Spectrum: Research Funding; Merck: Research Funding; Morphosys (IDMC): Consultancy. Abraham:Sandoz: Consultancy.