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Exploring the Economic Implications of Immuno-Therapy
Introduction
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
Looking at a patient population composed exclusively of individuals with advanced melanoma who had the BRAF  V600 mutation, Jensen and colleagues performed a cost-effectiveness analysis comparing combination nivolumab plus ipilimumab with combination dabrafenib plus trametinib.12 It is important to note that about half of patients with advanced melanoma have a BRAF mutation.12 When comparing therapies, it is also worth noting that dabrafenib is indicated as monotherapy for the treatment of unresectable or metastatic melanoma in patients with the BRAF V600E mutation or in combination with trametinib for unresectable or metastatic melanoma in patients with the BRAF  V600E or BRAF  V600K mutation.13,14 Trametinib, alone or in combination with dabrafenib, is indicated for patients with either BRAF   V600E or BRAF  V600K mutation.14 Nivolumab, indicated as monotherapy or in combination with ipilimumab, is also indicated as monotherapy in patients with unresectable or metastatic melanoma with or without a BRAF mutation.15 Ipilimumab is indicated as monotherapy for patients with unresectable or metastatic melanoma and as adjuvant therapy in patients with cutaneous melanoma with pathologic involvement of regional lymph nodes (<1 mm) who have undergone complete resection, including total lymphadenectomy.16
The Jensen study employed a non-Markov, decision-analytic model that drew on published medical literature and assumptions when data were unavailable. Overall response rates (ORR), median PFS, AEs, healthcare resource utilization, and AE-related discontinuations were included, while postprogression costs were excluded.12 The model followed patients from the time they initiated treatment until disease progression or death. The basis of cost estimates assumed a hypothetical US payer with 1 million members, and within this model, the expected number of patients with advanced BRAF-positive melanoma was approximately 14.12 From a US payer perspective, the budget impact of dabrafenib plus trametinib, within a hypothesized 1-million member enrollment, would be a total cost burden of $2,674,321 compared with $3,558,329 for nivolumab plus ipilimumab.12 The breakdown of costs can be seen in Table 212. Key drivers of the greater costs associated with nivolumab plus ipilimumab therapy were drug acquisition, drug administration, and AE costs.12 The cost-benefit analysis showed that when PFS duration was incorporated, dabrafenib plus trametinib treatment conferred a cost of $17,716 per PFS month versus $22,162 for nivolumab plus ipilimumab. When ORR was incorporated into the analysis, dabrafenib plus trametinib therapy was associated with a cost of $282,429 per responder compared with $388,745 for nivolumab plus ipilimumab.12
Costs Associated With Treatment-Related AEs
AEs can exert significant influence on costs in the management of melanoma.1 At present, there is a paucity of data associating AE-related costs with specific immunotherapy agents. However, study data showing the cost of managing AEs commonly experienced by patients treated with immunotherapies do exist.1 Bilir and colleagues recently conducted a medical literature review and a series of interviews with experts in melanoma to develop a list of AEs most commonly associated with immunotherapies. Investigators calculated the estimated costs of managing those AEs in 2014 US dollars.1 Nivolumab and pembrolizumab had not yet been approved by the FDA when the Bilir study was completed, so immunotherapy data were restricted to ipilimumab. Nevertheless, the study results offer insights into the expected AE-related costs of other immunotherapy treatments for melanoma.1
The authors reported that the most common AEs associated with ipilimumab treatment were immune-related diarrhea/colitis, dyspnea, anemia, and vomiting, with hypophysitis being less commonly observed.1 The Bilir study found that on a per-event basis for grade 3 and 4 toxicities, the cost for managing anemia was $145; diarrhea, $131 ($110 for immune-related diarrhea); dyspnea, $227; elevated liver enzymes, $110; hypophysitis, $132; rash, $139; and vomiting, $184.1 Inpatient costs for common immunotherapy-related AEs are shown in Table 31.
An earlier analysis of costs associated with AEs related to therapies for metastatic melanoma sought to determine the incremental costs for patients experiencing an AE, stratified by category (eg, cardiovascular, central nervous system, gastrointestinal, metabolic, skin and subcutaneous, etc) during a 30-day period based on overall treatment costs, not including the costs of study drugs. Because only ipilimumab was available at the time, the study focuses almost entirely on nonimmunotherapy agents, making it difficult to extrapolate to immunotherapy.17 It is worth noting, however, that adjusted incremental costs for patients with AEs (adjusted for age, sex, and insurance status) ranged from approximately $6500 to $9100 per individual for the 30-day period. The exception was for skin and subcutaneous AEs, as adjusted incremental costs were reduced by $900 for patients not experiencing these types of AEs.17
Conclusions
In the management of advanced melanoma, outcomes from cost-effectiveness analyses vary based on the comparator agents, study model design, BRAF mutation status of patients, influence of AEs, and WTP thresholds. Two
immunotherapy agents for advanced melanoma, nivolumab and pembrolizumab, have been available for a relatively short period of time, suggesting that relevant data are somewhat limited. Nevertheless, 2 studies comparing immunotherapies, either as monotherapy or in combination, identified pembrolizumab given every 3 weeks as the most cost-effective regimen, while immunotherapy studies in which pembrolizumab was not included found nivolumab monotherapy was the most cost-effective.1. Bilir SP, Ma Q, Zhao Z, Wehler E, Munakata J, Barber B. Economic burden of toxicities associated with treating metastatic melanoma in the United States. Am Health Drug Benefits. 2016;9(4):203-213.
2. National Cancer Institute. SEER cancer stat facts: melanoma of the skin. seer.cancer.gov/statfacts/html/melan.html. Published April 2017. Accessed November 5, 2017.
3. Guy GP, Ekwueme DU. Years of potential life lost and indirect costs of melanoma and non-melanoma skin cancer: a systematic review of the literature. Pharmacoeconomics. 2011;29(10):863-874. doi: 10.1016/j.amepre.2012.07.031.
4. Gordon LG, Rowell D. Health system costs of skin cancer and cost-effectiveness of skin cancer prevention and screening: a systematic review. Eur J Cancer Prev. 2015;24(2):141-149.
doi: 10.1097/CEJ.0000000000000056.
5. Kohn CG, Zeichner SB, Chen Q, Montero AJ, Goldstein DA, Flowers CR. Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma. J Clin Oncol. 2017;35(11):1194-1202. doi: 10.1200/JCO.2016.69.6336.
6. Oh A, Tran DM, McDowell LC, et al. Cost-effectiveness of nivolumab-ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States. J Manag Care Spec Pharm. 2017;23(6):653-664.
doi: 10.18553/jmcp.2017.23.6.653.
7. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-1356.
doi: 10.1056/NEJMoa1709684.
8. Bohensky MA, Pasupathi K, Gorelik A, Kim H, Harrison JP, Liew D. A cost-effectiveness analysis of nivolumab compared with ipilimumab for the treatment of BRAF wild-type advanced melanoma in Australia. Value Health. 2016;19(8):1009-1015. doi: 10.1016/j.jval.2016.05.013.
9. Sabater J, Baker T, Paly V, et al. Cost-effectiveness of nivolumab+ipilimumab in first-line treatment of advanced melanoma: analysis using 28-month overall survival from CheckMate 067. In: Proceedings from the 42nd European Society for Medical Oncology Conference; September 8-12, 2017; Madrid, Spain. Abstract 1115P. oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/Cost-effectiveness-of-nivolumab-ipilimumab-in-first-line-treatment-of-advanced-melanoma-Analysis-using-28-month-overall-survival-from-CheckMate-067.
10. Wang J, Chmielowski B, Pellissier J, Xu R, Stevinson K, Liu FX. Cost-effectiveness of pembrolizumab versus ipilimumab in ipilimumab-naïve patients with advanced melanoma in the United States. J Manag Care Spec Pharm. 2017;23(2):184-194. doi: 10.18553/jmcp.2017.23.2.184.
11. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521-2532. doi: 10.1056/NEJMoa1503093.
12. Jensen IS, Zacherle E, Blanchette CM, Zhang J, Yin W. Evaluating cost benefits of combination therapies for advanced melanoma. Drugs Context. 2016;5:1-14. doi: 10.7573/dic.212297.
13. Tafinlar [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017.
14. Mekinist [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017.
15. Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2017.
16. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2017.
17. Arondekar B, Curkendall S, Monberg M, et al. Economic burden associated with adverse events in patients with metastatic melanoma. J Manag Care Spec Pharm. 2015;21(2):158-164. doi: 10.18553/jmcp.2015.21.2.158.
