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Supplements The Role of Immuno-Oncology in the Treatment of Advanced Melanoma

Exploring the Economic Implications of Immuno-Therapy


The therapeutic armamentarium for melanoma has expanded in recent years with the introduction of promising novel immunotherapies and targeted therapies.1,2 The burden of melanoma, in terms of lives lost and economic losses, is substantial. In the United States, annual indirect costs due to premature mortality are estimated to range from $3.2 billion to $3.3 billion (2009 US$).3 Indirect costs attributable to melanoma morbidity are estimated at $18.5 million for lost workdays, $3.9 million for lost workdays of caregivers, and $7 million due to days of restricted activity.3 The results of a systematic review of literature on melanoma-related burden show that estimated years of potential life lost (YPLL) per death from melanoma range from 17 to 36 years in those younger than 65 years, while among those 65 years or older, the averages are 9.3 YPLL for men and 11.4 YPLL for women.3

Early detection of melanoma reduces the risk of developing more advanced disease,2 and study results suggest that screening for melanoma could be cost-effective when conducted in high-risk populations, including older men and those with a family history of melanoma.4 The present article focuses on the cost-effectiveness of immunotherapy in the treatment of melanoma, an important class of novel and emerging agents.

Treatment Costs and Cost-Effectiveness of Immunotherapies

Kohn and colleagues developed a Markov model to estimate US payer costs (2016 US$) and quality-adjusted life years (QALYs) for 3 immune checkpoint inhibitors, pembrolizumab, nivolumab, and ipilimumab, and combinations thereof, in treatment-naïve patients with BRAF wild-type advanced melanoma.5 Efficacy and adverse event (AE) data were derived from phase 3 clinical trials of the respective therapies, and the authors’ model employed a 6-week cycle period, which matched the assessment period used in the trials.5 Their model assessed 6 treatment options: (1) first-line nivolumab followed by second-line ipilimumab, (2) first-line nivolumab plus ipilimumab followed by second-line carboplatin plus paclitaxel, (3) first-line pembrolizumab every 2 weeks followed by second-line ipilimumab, (4) first-line pembrolizumab every 3 weeks followed by second-line ipilimumab, (5) first-line ipilimumab followed by second-line nivolumab, and (6) first-line dacarbazine followed by second-line ipilimumab and third-line nivolumab.5

Based on their model, the authors observed that pembrolizumab given every 3 weeks followed by ipilimumab as second-line therapy produced both greater efficacy and lower costs compared with treatments involving first-line ipilimumab, first-line pembrolizumab given every 2 weeks, and first-line dacarbazine. In comparison with this regimen, treatment with first-line nivolumab was the next best option, associated with incremental costs of $44,593 and 0.16 QALYs and resulting in an incremental cost-effectiveness ratio (ICER) of $278,706/QALY. First-line nivolumab plus ipilimumab was the least cost-effective, with $78,809 in incremental costs and 0.18 QALYs.5

Oh and colleagues employed a Markov model to compare the cost-effectiveness of combination nivolumab plus ipilimumab versus either treatment as monotherapy for first-line treatment of patients with metastatic (confirmed stage III or IV) melanoma, of whom 24% were programmed death-ligand (PD-L1) positive and 32% possessed the BRAF  V600 mutation.6,7 Their model, which drew data from the phase 3 CheckMate 067 clinical trial, defined cost-effectiveness below a willingness-to-pay (WTP) threshold of $100,000 and employed a 1-month cycle length and time horizon of 175 months, in light of the 10-year mortality rate for patients with metastatic melanoma.6 Nivolumab monotherapy proved to be the most cost-effective treatment, at an overall cost of $169,320 (2015 US$) (Table 1).6 Ipilimumab monotherapy although ranked second in total costs, had an incremental cost of $44,443 compared with nivolumab, and an incremental progression-free QALY (PFQALY) of –0.57. Combination nivolumab plus ipilimumab therapy had an incremental cost of $59,032 compared with nivolumab monotherapy, but also conferred an incremental PFQALY of 0.13. Compared with ipilimumab monotherapy, combination therapy had an incremental cost of $14,589 and incremental PFQALY of 0.69, making it the second most cost-effective option of the 3.6 Nevertheless, compared with nivolumab, combination therapy was not considered cost-effective because it was associated with an ICER of $454,092 per PFQALY gained, well above the WTP threshold. Yet, it was cost-effective when compared with ipilimumab, based on an ICER of $21,143 per PFQALY gained. Differences in cost-effectiveness were primarily driven by higher costs and shorter progression-free survival (PFS) observed with ipilimumab versus nivolumab.6

The most notable contributions to uncertainty in the Markov model developed by Oh et al were the influence of PD-L1 positive status, the use of nivolumab treatment in progressive disease adjusted for immune-related AEs (irAEs), the only AEs included in the model, and the use of combination therapy in progressive disease adjusted for irAEs. With regard to PD-L1 status, additional analyses revealed that nivolumab was still the preferred therapy of the 3 options, both for patients who were PD-L1 positive and those who were PD-L1 negative.6 Recognizing the potential influence in the variability and duration of observed irAEs among the 3 treatments, analyses were conducted based on alternative utility values—0.80 for stable disease and 0.26 for progressive disease or death—without adjustments for irAEs (Table 1).6 The results of these analyses indicated that nivolumab remained the preferred option over ipilimumab and combination nivolumab plus ipilimumab.6

Results observed in the Kohn and Oh studies were supported by results from an Australian study that employed a Markov model to estimate the cost-effectiveness of nivolumab versus ipilimumab as first-line therapy from the perspective of an Australian public healthcare population with BRAF wild-type advanced melanoma.8 This study, published in 2016, preceded the publication of CheckMate 067 and therefore depended on different sources for patient data.7,8 Nivolumab data were derived from the nivolumab arm of the CA209066 trial comparing nivolumab with dacarbazine, while ipilimumab data were derived from the MDX010-020 study comparing ipilimumab with gp100. The analysis was thus based on indirect comparisons. The authors considered both dacarbazine and gp100 relatively ineffective, therefore exerting comparable treatment efficacy or lack thereof.8 The model employed a 10-year time horizon, and cycle length was based on the Response Evaluation Criteria In Solid Tumors 1.1 treatment response assessment periods used in CA209066, which occurred at week 9, then every 6 weeks for the next 12 months, and then every 12 weeks thereafter.8 Drug costs were reported in 2015 US dollars.8 The base case analysis results again favored nivolumab, as patients receiving nivolumab were predicted to live 3.1 years and 2.5 QALYs, at a net cost of $178,612 per person. By contrast, those receiving ipilimumab were predicted to live 1.5 years and 1.2 QALYs at a net cost of $138,987 per person. This resulted in ICERs of $25,101 per life-year saved and $30,475 per QALY saved.8

A somewhat different conclusion was drawn via an analysis using 28-month overall survival (OS) and PFS data from CheckMate 067 to compare the cost-effectiveness of first-line treatment in patients with advanced melanoma with combination nivolumab plus ipilimumab versus nivolumab, ipilimumab, and pembrolizumab monotherapies; the BRAF-inhibitor/MEK-inhibitor combinations of dabrafenib plus trametinib and vemurafenib plus cobimetinib; dabrafenib and vemurafenib monotherapies; and dacarbazine. Cost and AE data were derived from the published literature, expert input, and other publicly available sources. The incremental analysis employed in the study was incremental cost-utility ratios (ICURs) for nivolumab plus ipilimumab.9 Based on a 30-year time horizon, nivolumab plus ipilimumab treatment was projected to have the highest accrued survival (6.015 LY and 4.979 QALY), as well as the highest costs: $291,096, inclusive of treatment, follow-up, AE management, and postprogression costs. ICURs for nivolumab plus ipilimumab, compared in a pairwise fashion, varied from $34,774/QALY versus dabrafenib plus trametinib to $92,647/QALY versus nivolumab. An extended dominance analysis showed that nivolumab plus ipilimumab, nivolumab, and dacarbazine represented the most cost-effective options at different WTP thresholds.9

Wang and colleagues undertook a cost-effectiveness analysis comparing pembrolizumab and ipilimumab in ipilimumab-naïve patients with advanced melanoma.10 Pembrolizumab, which was shown in the Kohn study to be the most cost-effective of that study’s comparator treatments when dosed every 3 weeks, is of particular interest in this context due its superior OS outcomes in the KEYNOTE-006 trial. KEYNOTE-006, a randomized, controlled, open-label study, compared pembrolizumab with ipilimumab in patients with advanced melanoma who had not previously been treated with ipilimumab,and of whom 35% in the pembrolizumab group and 39% in the ipilimumab group had BRAF mutations.11 Drawing data from KEYNOTE-006, the Wang study employed a partitioned survival model, dividing survival time into PFS and postprogression survival. For PFS, Kaplan-Meier estimates for the first 60 weeks (median follow-up period) were used.10 The authors used a 20-year time horizon and incorporated PFS, OS, quality of life, and AE data from KEYNOTE-006. Cost data included drug acquisition, drug administration, AE management, and disease management costs. Both pembrolizumab and ipilimumab were given every 3 weeks, the latter for a maximum of 4 doses.10

Results of the Wang study showed that treatment with pembrolizumab was associated with 1.68 years of PFS and 3.29 years of postprogression survival, for a total of 4.96 years of OS.10 Patients treated with ipilimumab experienced 0.84 years of PFS and 2.98 years of postprogression survival, for a total of 3.83 years of OS. This produced a mean OS difference of 1.14 years in favor of pembrolizumab, a substantial proportion of which was PFS. Pembrolizumab treatment conferred a QALY gain of 0.79 over ipilimumab; pembrolizumab total direct per-patient treatment costs were $63,680 higher, producing an ICER for pembrolizumab of $81,091 per QALY across the 20-year time horizon.10

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