Cost-effectiveness of treating advanced melanoma with tumor-infiltrating lymphocytes based on an international randomized phase 3 clinical trial

Abstract

Introduction: In a multicenter, open-label randomized phase 3 clinical trial conducted in the Netherlands and Denmark, treatment with ex vivo-expanded tumor-infiltrating lymphocytes (TIL-NKI/CCIT) from autologous melanoma tumor compared with ipilimumab improved progression-free survival in patients with unresectable stage IIIC-IV melanoma after failure of first-line or second-line treatment. Based on this trial, we conducted a cost-utility analysis.

Methods: A Markov decision model was constructed to estimate expected costs (expressed in 2021€) and outcomes (quality-adjusted life years (QALYs)) of TIL-NKI/CCIT versus ipilimumab in the Netherlands. The Danish setting was assessed in a scenario analysis. A modified societal perspective was applied over a lifetime horizon. TIL-NKI/CCIT production costs were estimated via activity-based costing. Through sensitivity analyses, uncertainties and their impact on the incremental cost-effectiveness ratio (ICER) were assessed.

Results: Mean total undiscounted lifetime benefits were 4.47 life years (LYs) and 3.52 QALYs for TIL-NKI/CCIT and 3.33 LYs and 2.46 QALYs for ipilimumab. Total lifetime undiscounted costs in the Netherlands were €347,168 for TIL-NKI/CCIT (including €67,547 for production costs) compared with €433,634 for ipilimumab. Undiscounted lifetime cost in the Danish scenario were €337,309 and €436,135, respectively. This resulted in a dominant situation for TIL-NKI/CCIT compared with ipilimumab in both countries, meaning incremental QALYs were gained at lower costs. Survival probabilities, and utility in progressive disease affected the ICER most.

Conclusion: Based on the data of a randomized phase 3 trial, treatment with TIL-NKI/CCIT in patients with unresectable stage IIIC-IV melanoma is cost-effective and cost-saving, both in the current Dutch and Danish setting. These findings led to inclusion of TIL-NKI/CCIT as insured care and treatment guidelines. Publicly funded development of the TIL-NKI/CCIT cell therapy shows realistic promise to further explore development of effective personalized treatment while warranting economic sustainability of healthcare systems.

Keywords: Healthcare Economics and Organizations; Ipilimumab; Melanoma.

Figure 1

Model structure. Structure of the decision tree presented as a flow-diagram of treatment with ex vivo-expanded tumor infiltrating lymphocytes from autologous melanoma tumor (TIL-NKI/CCIT) and ipilimimab-arm combined with the Markov decision-model with three mutually exclusive health states: progression-free survival (PFS), progressive disease (PD) and the absorbing state death.

Figure 2

Deterministic (univariate) sensitivity analysis. Results of the deterministic (univariate) sensitivity analysis visualized in a tornado diagram. The diagram shows the impact of discounted individual parameters on the incremental cost-effectiveness ratio by alternately varying input values one by one between pre-set minimum and maximum values (see table 1). BRAF/MEK, V-Raf murine sarcoma viral oncogene homolog B1/mitogen activated protein kinase; ipi, ipilimumab; OS, overall survival; PFS, progression-free survival; Prob, probability; QALY, quality-adjusted life year; TIL-NKI/CCIT, ex vivo-expanded tumor infiltrating lymphocytes from autologous melanoma tumor; Tx, treatment; #, number.

Figure 3

Probabilistic sensitivity analysis. Results of the probabilistic sensitivity analysis (PSA) visualized in cost-effectiveness plane. The PSA shows uncertainty of estimated discounted base case incremental cost-effectiveness ratio over a lifetime horizon by simultaneously sampling uncertainty across all parameters by 10,000 iterations. All model input parameters are sampled randomly, according to their individual appropriate distributions between pre-set minimum and maximum values (table 1). QALYs, quality-adjusted life years; WTP, willingness to pay.