Advertisement

Economic Evaluation of Systemic Treatments for Advanced Melanoma: A Systematic Review

Open AccessPublished:August 29, 2019DOI:https://doi.org/10.1016/j.jval.2019.07.003

      Highlights

      • Many novel, high-cost treatments have come to market for the treatment of melanoma in recent years. There is disparity in patient access across Europe, and even the wealthiest countries have imposed restrictions on access.
      • The BRAF monotherapy (vemurafenib, dabrafenib) and BRAF/MEK combination therapy (BRAF monotherapy with cobimetinib or trametinib) have not been shown to be cost-effective in any jurisdiction.
      • The PD-1 inhibitors (pembrolizumab, nivolumab) are consistently found to be cost-effective compared to ipilimumab, although their cost-effectiveness relative to cytotoxic chemotherapy is not established. Nivolumab in combination with ipilimumab is unlikely to be cost effective in any setting where PD-1 inhibitors are standard of care.
      • Consideration could be given to divestment from BRAF-targeted treatment and ipilimumab to allow funding of more cost-effective PD-1 inhibitors.

      Abstract

      Background

      Many high cost treatments for advanced melanoma have become available in recent years. National health technology assessment agencies have raised concerns regarding uncertainty in their clinical and cost-effectiveness.

      Objective

      The aim of this systematic review is to identify economic evaluations of treatments for advanced melanoma and review model assumptions, outcomes, and quality as preparation for a health technology assessment.

      Methods

      A search of Embase, MEDLINE, EconLit, and the Cochrane Database was conducted. Only studies using decision-analytic models were included. Two authors independently completed full-text review and data extraction.

      Results

      Fifteen studies were identified. There were major differences in the structural assumptions underpinning the models. There was general agreement in study conclusions, although the predicted costs and quality-adjusted life years for each treatment varied. BRAF monotherapy (vemurafenib, dabrafenib) or BRAF/MEK combination therapy (BRAF monotherapy with cobimetinib or trametinib) has not been shown to be cost-effective in any jurisdiction. PD-1 inhibitors (pembrolizumab, nivolumab) are consistently found to be cost-effective compared with ipilimumab, although their cost-effectiveness compared with chemotherapy is not established. Combination therapy with nivolumab and ipilimumab is unlikely to be cost-effective in any setting. One study including all agents found that none of the new treatments were cost-effective relative to chemotherapy. Publication of the study in a health economics journal is associated with better reporting of and higher-quality assessment than those published in clinical journals.

      Conclusion

      Despite differences in model structures and assumptions, the conclusions of most included studies were consistent. Health technology assessment has a key role in maximizing value from high-cost innovative treatments. Consideration should be given to divestment from BRAF/MEK inhibitors and ipilimumab in favor of reimbursement of PD-1 inhibitors.

      Keywords

      Introduction

      Cutaneous melanoma is among the most aggressive of all skin cancers.
      • Garbe C.
      • Peris K.
      • Hauschild A.
      • et al.
      Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2016.
      Incidence is increasing worldwide, in particular in northern European populations.
      • Ferlay J.
      • Soerjomatarum I.
      • Dikshit R.
      • et al.
      Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
      The 5-year survival in metastatic melanoma (stage IV) disease ranges from 10% to 25%.
      • Balch C.M.
      • Gershenwald J.E.
      • Soong S.J.
      • et al.
      Final version of 2009 AJCC melanoma staging and classification.
      Cytotoxic chemotherapy (CC) was once the backbone of treatment for advanced or metastatic disease, exhibiting variable levels of disease response, but no impact on overall survival (OS).
      • Pasquali S.
      • Hadjinicolaou A.
      • Chiarion-Sileni V.
      • Rossi C.
      • Mocellin S.
      Systemic treatments for metastatic cutaneous melanoma.
      In 2010, ipilimumab became the first checkpoint inhibitor immunotherapy to demonstrate survival benefit in metastatic melanoma, with an increase of 3 months in median OS and evidence of durable responses in a small proportion of patients.
      • Hodi F.S.
      • O'Day S.J.
      • McDermott D.F.
      • et al.
      Improved survival with ipilimumab in patients with metastatic melanoma.
      • Schadendorf D.
      • Hodi F.S.
      • Robert C.
      • et al.
      Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma.
      In 2015, the PD-1 inhibitor immunotherapies pembrolizumab and nivolumab received regulatory approval, demonstrating improvement in progression-free survival (PFS) and OS compared with CC and ipilimumab.
      • Ribas A.
      • Puzanov I.
      • Dummer R.
      • et al.
      Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.
      • Weber J.S.
      • D'Angelo S.P.
      • Minor D.
      • et al.
      Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.
      • Schachter J.
      • Ribas A.
      • Long G.V.
      • et al.
      Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006).
      Concomitant administration of nivolumab and ipilimumab (NIVO-IPI) was subsequently approved, demonstrating gains in PFS and OS compared with ipilimumab.
      • Larkin J.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • et al.
      Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.
      Talimogene laherparepvec (T-VEC), an oncolytic viral immunotherapy associated with an increase in OS compared to granulocyte macrophage colony stimulating factor, received authorization in Europe in 2015.
      Committee for Medicinal Products for Human Use
      CHMP assessment report imlygic.
      The BRAF gene is mutated in approximately 50% of cutaneous melanomas; for this subgroup of patients, the BRAF inhibitor vemurafenib was authorized in 2011, and dabrafenib in 2013. The MEK inhibitors cobimetinib and trametinib were subsequently authorized for concomitant administration with BRAF inhibitors, overcoming acquired resistance,
      • Hauschild A.
      • Grob J.-J.
      • Demidov L.V.
      • et al.
      Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.
      • Chapman P.B.
      • Hauschild A.
      • Robert C.
      • et al.
      Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
      and prolonging PFS and OS with durable responses seen in some patients.
      • Long G.V.
      • Eroglu Z.
      • Infante J.
      • et al.
      Long-term outcomes in patients with BRAF V600–mutant metastatic melanoma who received dabrafenib combined with trametinib.
      • Robert C.
      • Karaszewska B.
      • Schachter J.
      • et al.
      Improved overall survival in melanoma with combined dabrafenib and trametinib.
      • Larkin J.
      • Ascierto P.A.
      • Dréno B.
      • et al.
      Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.
      Patients with a BRAF mutation are also eligible for treatment with immunotherapy agents.
      These new treatments have transformed the treatment landscape in melanoma, delivering meaningful improvements in survival with reduced toxicity compared to CC. Owing to the high costs of these treatments, there is large disparity in access across Europe.
      • Kandolf Sekulovic L.
      • Peris K.
      • Hauschild A.
      • et al.
      More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments.
      Many of these treatments received rapid regulatory approval, in some instances based on surrogate endpoints. National health technology assessment (HTA) agencies have raised concerns regarding uncertainty in clinical effectiveness and cost-effectiveness.
      Haute Autorite de Sante
      Transparency Committee Opinion, Yervoy 5mg/ml, concentrate for solution for infusion.
      Pan-Canadian Oncology Drug Review
      Pan-Canadian Oncology Drug Review Expert Review Committee Final Recommendation: Nivolumab for the treatment of patients with unresectable or metastatic melanoma, regardless of BRAF status.
      Institute for Quality and Efficiency in Health Care
      Ipilimumab (new therapeutic indication) – Benefit assessment according to §35a Social Code Book V 1.
      National Institute for Health and Care Excellence (NICE)
      Final appraisal determination: cobimetinib in combination with vemurafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma.
      National Centre for Pharmacoeconomics
      NCPE report on the cost-effectiveness of pembrolizumab (Keytruda®) for the first line treatment of unresectable or advanced metastatic melanoma in adults.
      The objective of this review is to identify published economic evaluations of treatments for melanoma. The purpose is to review the structural and methodological assumptions considered appropriate, the model outcomes, and the quality of published evaluations using a published appraisal checklist for economic evaluations.

      Methods

      A systematic review protocol was developed in line with the objectives of the review, with reference to published literature on systematic review of economic evaluations and the Guidelines for the Retrieval and Interpretation of Economic Evaluations of Health Technologies in Ireland.
      Health Information and Quality Authority
      Guidelines for the retrieval and interpretation of economic evaluations of health technologies in Ireland.
      The search strategy was derived based on published search filers for economic evaluations (see Appendix in Supplemental Materials found at https://doi.org/10.1016/j.jval.2019.07.003). We searched EconLit via EBSCOhost, Cochrane Library (restricted to NHS Economic Evaluation Database and HTA database), Embase, and MEDLINE via Ovid from inception. Searches were conducted on August 9, 2017 and updated on September 17, 2018.
      Decision analytic models examining the cost-effectiveness of pharmacologic treatments for patients with advanced (unresectable or metastatic) melanoma, irrespective of line of treatment, were included. All studies with an outcome of cost per quality-adjusted life year (QALY), cost per life year gained (LYG), or alternative measure of health outcome, and cost-minimization studies were included. Cost-of-illness and non-English-language studies were excluded. Conference abstracts were excluded owing to a lack of information to assess quality.
      Titles and abstracts were screened by 1 author (C.G.). The full texts of the remaining articles were reviewed by 2 reviewers independently (C.G, L.Mc.C.) in accordance with the eligibility criteria. Disagreements were resolved by discussion and arbitration (M.B.) where necessary.
      Study data were extracted using a data extraction form, which included the study title, author, country, perspective, model type, time horizon, discount rate, treatment(s), resource use, modeling of adverse events (AEs), survival extrapolation, utility, funding sources, and cost and effectiveness outcomes. Data extraction was conducted independently by 2 authors (C.G., L.McC.). Extracted total costs and incremental cost-effectiveness ratios (ICERs) were inflated to 2017 costs using the country-specific Consumer Price Index (CPI) for health (or overall CPI if CPI health not available), then converted to US dollars using the Organistion for Economic Cooperation and Developement Purchasing Price Parity index.
      Organistion for Economic Cooperation and Developement
      Prices and purchasing power parities.
      For studies where the cost year was not specified, it was assumed to be the year of publication.
      Completeness of reporting was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist, which provides 25 recommendations to optimize reporting of health economic evaluations.
      • Husereau D.
      • Drummond M.
      • Petrou S.
      • et al.
      Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.
      Quality of the evaluation was assessed using the Philips Quality Checklist, which is designed to inform critical appraisal of the methodological quality of economic modeling.
      • Philips Z.
      • Ginnelly L.
      • Sculpher M.
      • et al.
      Review of guidelines for good practice in decision-analytic modelling in health technology assessment.
      Both are qualitative instruments with no overall score produced. The number of compliances with the CHEERS checklist and positive assessments of quality for each field of the Philips checklist are reported. Checklists were completed independently by 2 authors (C.G. and L.McC.), and disagreements were resolved by discussion. Pearson's correlation coefficient was used to examine the relationship between completeness of reporting and study quality. Logistic regression models were used to investigate associations among journal type (health economics vs clinical), reporting, and study quality. Chi-square tests were performed to determine if there were relationships between study conclusions (cost-effective or not) and journal type or study sponsor (industry vs other). Statistical analysis was conducted in RStudio using R version 3.5.0.

      Results

      A total of 660 records were identified, and 636 were screened after duplicates were removed. Following title and abstract screening, 505 publications were excluded, and 131 underwent full text review. Most did not meet the eligibility criteria; 15 studies were included in the final review. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram is presented in Figure 1. Summary details of the included studies are provided in Table 1. Excluded studies and reasons for exclusion are provided (see Appendix in Supplemental Materials found at https://doi.org/10.1016/j.jval.2019.07.003).
      Figure thumbnail gr1
      Figure 1Preferred reporting items for systematic reviews and meta-analyses diagram for review.
      Table 1Summary of included economic evaluations.
      Author, year, countryInterventionComparatorPerspective, time horizonDiscount rateModel typeSponsorICER (cost/QALY), 2017 US$Conclusions
      Kohn, 2017, United States
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.
      Treatment sequences of immunotherapyTreatment sequences of immunotherapyThird-party payer, lifetime3%MMNational Cancer Institute, Wellcome1L Pembrolizumab: dominant

      1L Ipilimumab: $72 117

      1L Nivolumab: $93 154

      1L NIVO + IPI: $203 862
      PD-1 monotherapy followed by ipilimumab is the most cost-effective sequence in the United States. NIVO + IPI followed by chemo is not cost-effective.
      Oh, 2017, United States
      • Oh A.
      • Tran D.M.
      • McDowell L.C.
      • et al.
      Cost-effectiveness of nivolumab-ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States.
      NIVO + IPI(a) Nivolumab, (b) ipilimumabSocietal, 15 years3%
      Applied to costs only.
      MMNo fundingNS (cost/progression-free QALY)NIVO + IPI is not cost-effective compared to nivolumab; nivolumab is dominant over ipilimumab in the United States.
      Matter-Walstra, 2015, Switzerland
      • Matter-Walstra K.
      • Braun R.
      • Kolb C.
      • et al.
      A cost-effectiveness analysis of trametinib plus dabrafenib as first-line therapy for metastatic BRAF V600-mutated melanoma in the Swiss setting.
      Dabrafenib and trametinibVemurafenibPayer, lifetime3%,
      Applied to costs only.
      6%
      Applied to outcomes only.
      MMState secretariat for Education, Research, and Innovation$275 472Dabrafenib and trametinib are unlikely to be cost-effective in the Swiss setting.
      Barzey, 2013, United States
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
      IpilimumabBSCThird-party payer, lifetime3%MMBristol-Myers Squibb$157 434Ipilimumab is associated with an increase in costs and QALYs, likely to be cost-effective in the United States at a threshold of $200 000/QALY.
      Bohensky, 2016, Australia
      • Bohensky M.A.
      • Pasupathi K.
      • Gorelik A.
      • et al.
      A cost-effectiveness analysis of nivolumab compared with ipilimumab for the treatment of BRAF wild-type advanced melanoma in Australia.
      NivolumabIpilimumabPayer, 10 years5%MMBristol-Myers Squibb$32 424Nivolumab is cost-effective in the Australian setting.
      Curl, 2014, United States
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
      Vemurafenib(a) Dacarbazine, (b) vemurafenib followed by ipilimumabSocietal, lifetime3%Decision treeNo funding$395 782 vs dacarbazineVemurafenib and subsequent ipilimumab are associated with an increase in QALYs, but likely in excess of accepted WTP thresholds.
      Delea, 2015, Canada
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      Dabrafenib(a) Dacarbazine, (b) vemurafenibPayer, 5 years5%PSMGlaxo SmithKline$311 028 vs dacarbazine.

      Dabrafenib dominant over vemurafenib.
      Dabrafenib is not cost-effective at common WTP thresholds. Likely to be cost saving vs vemurafenib, with similar QALYs.
      De Francesco, 2016, Italy
      • De Francesco M.
      • Lamotte M.
      • Ascierto P.
      • Di Rienzo P.
      • Asukai Y.
      Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
      Ipilimumab(a) Dacarbazine, (b) vemurafenibPayer, 15 years3%PSMBristol Myers Squibb$66 691
      Based on discount prices.
      vs dacarbazine.

      Ipilimumab dominant over vemurafenib.
      Ipilimumab is associated with increase in costs and QALYs, ICER similar to other countries; likely to be dominant over vemurafenib at discounted price in Italy.
      Miguel, 2017, Portugal
      • Miguel L.S.
      • Lopes F.V.
      • Pinheiro B.
      • et al.
      Cost-effectiveness of pembrolizumab for advanced melanoma treatment in Portugal.
      PembrolizumabIpilimumabPayer, 40 years5%PSMMerck, Sharpe & Dohme$63 286Pembrolizumab cost-effective at a WTP threshold of €50 000/QALY ($84 459/QALY) in Portugal.
      Shih, 2015, United States
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      Dabrafenib, vemurafenibDacarbazineSocietal, lifetimeNAMMNSDabrafenib vs

      Dacarbazine: $166 636

      Vemurafenib: Dominated

      Vemurafenib vs

      Dacarbazine: $357 745
      Dabrafenib is associated with an increase in QALYs but not cost-effective at a threshold of $100 000/QALY in United States. Dabrafenib is dominant over vemurafenib.
      Wang, 2017, United States
      • Wang J.
      • Chmielowski B.
      • Pellissier J.
      • et al.
      Cost-effectiveness of pembrozilumab versus ipilimumab in ipilimumab-naive patients with advanced melanoma in the United States.
      PembrolizumabIpilimumabPayer, 20 years3%PSMMerck, Sharpe and Dohme$86 277Pembrolizumab is cost-effective at a WTP threshold of $100 000-$150 000/QALY in United States.
      Jensen, 2016, United States
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      NIVO + IPIDabrafenib in combination with trametinibPayer and societal, NSNSNSNovartisNSDabrafenib and trametinib are associated with lower total costs, lower total costs, cost/month PFS, cost/responder in United States.
      Pike, 2015, Norway
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      All licensed treatmentsDacarbazinePayer, 10 years4%MMNOKCVs Dacarbazine:

      NIVO-IPI: $172 031

      Nivo: $113 925

      Pembro: $119 381

      Ipi: $172 444

      Dab + Tram: $292 176

      Vem + Cobi: $268 800

      Vem: $264 057

      Dab: $229 126
      None of the treatments are cost-effective compared to dacarbazine in Norway.
      Hillner, 2000, United States
      • Hillner B.E.
      • Agarwala S.
      • Middleton M.R.
      Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.
      TemozolomideDacarbazineSocietal, 1 yearNANSSchering PloughNSThere is a trend toward greater survival with temozolomide at an acceptable cost/LYG.
      Meng, 2018, England
      • Meng Y.
      • Hertel N.
      • Ellis J.
      • et al.
      The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
      Nivolumab(a) Ipilimumab, (b) dacarbazine, (c) vemurafenib, (d) dabrafenibPayer, 40 years3.5%MMBristol-Myers SquibbNivolumab vs

      Ipilimumab (BRAF negative): $34 338
      Based on discount prices.


      Ipilimumab (BRAF positive): $24 351
      Based on discount prices.


      Vemurafenib: Dominant
      Based on discount prices.


      Dabrafenib: Dominant
      Based on discount prices.
      Nivolumab is cost-effective at discounted price compared to ipilimumab and BRAF monotherapy, in both BRAF positive and negative patients, in UK.
      BSC indicates best supportive care; NS, not specified; NA, not applicable; MM, Markov model; PSM, partitioned survival model; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; LYG, life year gained; WTP, willingness to pay.
      Applied to costs only.
      Applied to outcomes only.
      Based on discount prices.

      Study Design and Structural Assumptions

      The identified studies were published between 2000 and 2018. Nine studies were sponsored by the pharmaceutical industry, 5 were funded independently, and 1 did not include declarations of funding.
      Most studies (n = 8) used a Markov modeling approach. One study used a decision tree model,
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
      4 used a partitioned survival model,
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      • De Francesco M.
      • Lamotte M.
      • Ascierto P.
      • Di Rienzo P.
      • Asukai Y.
      Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
      • Wang J.
      • Chmielowski B.
      • Pellissier J.
      • et al.
      Cost-effectiveness of pembrozilumab versus ipilimumab in ipilimumab-naive patients with advanced melanoma in the United States.
      • Miguel L.S.
      • Lopes F.V.
      • Pinheiro B.
      • et al.
      Cost-effectiveness of pembrolizumab for advanced melanoma treatment in Portugal.
      and the modeling approach was not described in 2 studies.
      • Hillner B.E.
      • Agarwala S.
      • Middleton M.R.
      Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      Most studies used the conventional 3-health state model of PFS, progressive disease, and death (n = 10). Health state descriptions were not specified in 2 studies.
      • Hillner B.E.
      • Agarwala S.
      • Middleton M.R.
      Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      One study examining the effects of treatment sequencing modeled 7 health states incorporating various progression states, and a response state with or without AEs.
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.
      One model had 2 substates in the PFS state, defined according to PD-L1 status.
      • Oh A.
      • Tran D.M.
      • McDowell L.C.
      • et al.
      Cost-effectiveness of nivolumab-ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States.
      Time horizons varied from 1 year to 40 years, were not always clearly specified or justified, and were specifically mentioned as drivers of uncertainty in 3 studies.
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      • Bohensky M.A.
      • Pasupathi K.
      • Gorelik A.
      • et al.
      A cost-effectiveness analysis of nivolumab compared with ipilimumab for the treatment of BRAF wild-type advanced melanoma in Australia.
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
      Cycle length varied from 1 week to 9 weeks, and was not reported in 5 studies.
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
      • Hillner B.E.
      • Agarwala S.
      • Middleton M.R.
      Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
      • Meng Y.
      • Hertel N.
      • Ellis J.
      • et al.
      The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
      The most common cycle length was 1 month (n = 4); half cycle correction was the exception rather than the rule (n = 1). Most studies were set in the United States (n = 8), with 5 from European countries, and 1 each from Canada and Australia. The payer perspective was most common (n = 13). Two studies provided the societal perspective,
      • Hillner B.E.
      • Agarwala S.
      • Middleton M.R.
      Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      whereas 2 stated a societal perspective was taken but did not document the inclusion of indirect costs and were classified as payer perspective.
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      Three studies did not apply or specify a discount rate.
      • Hillner B.E.
      • Agarwala S.
      • Middleton M.R.
      Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      One study applied a different discount rate to costs (3%) and outcomes (6%)
      • Matter-Walstra K.
      • Braun R.
      • Kolb C.
      • et al.
      A cost-effectiveness analysis of trametinib plus dabrafenib as first-line therapy for metastatic BRAF V600-mutated melanoma in the Swiss setting.
      ; the remaining studies applied the same rate to both costs and outcomes. Discount rates applied varied from 3% to 6%. Nine studies estimated model costs in USD, with the cost year ranging from 1999 to 2016. Cost year was not stated in 3 studies.
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
      • Meng Y.
      • Hertel N.
      • Ellis J.
      • et al.
      The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
      • Matter-Walstra K.
      • Braun R.
      • Kolb C.
      • et al.
      A cost-effectiveness analysis of trametinib plus dabrafenib as first-line therapy for metastatic BRAF V600-mutated melanoma in the Swiss setting.
      One study obtained evidence for clinical inputs through a de novo systematic review and evidence synthesis process
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      ; 1 identified clinical evidence inputs through published systematic reviews.
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      For all remaining studies, no evidence of a systematic approach to the identification of clinical inputs was presented. Only one study performed a quality assessment of the included studies.
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      Six studies included only 1 comparator, using evidence from a single phase III clinical trial.
      • Wang J.
      • Chmielowski B.
      • Pellissier J.
      • et al.
      Cost-effectiveness of pembrozilumab versus ipilimumab in ipilimumab-naive patients with advanced melanoma in the United States.
      • Miguel L.S.
      • Lopes F.V.
      • Pinheiro B.
      • et al.
      Cost-effectiveness of pembrolizumab for advanced melanoma treatment in Portugal.
      • Hillner B.E.
      • Agarwala S.
      • Middleton M.R.
      Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.
      • Oh A.
      • Tran D.M.
      • McDowell L.C.
      • et al.
      Cost-effectiveness of nivolumab-ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States.
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
      • Matter-Walstra K.
      • Braun R.
      • Kolb C.
      • et al.
      A cost-effectiveness analysis of trametinib plus dabrafenib as first-line therapy for metastatic BRAF V600-mutated melanoma in the Swiss setting.
      For the remaining studies, approaches to evidence synthesis were varied and sometimes unclear,
      • De Francesco M.
      • Lamotte M.
      • Ascierto P.
      • Di Rienzo P.
      • Asukai Y.
      Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
      and included naïve comparison,
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.
      • Bohensky M.A.
      • Pasupathi K.
      • Gorelik A.
      • et al.
      A cost-effectiveness analysis of nivolumab compared with ipilimumab for the treatment of BRAF wild-type advanced melanoma in Australia.
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      Bucher indirect comparison,
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      mixed covariate adjusted indirect comparisons using individual patient data,
      • Meng Y.
      • Hertel N.
      • Ellis J.
      • et al.
      The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
      and network meta-analysis.
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      Most commonly, PFS and OS outcomes from clinical trials were the source of treatment effects in the studies (n = 13). Two studies incorporated response rates into the modeling of treatment effects, using mean and median times to response from the pivotal trials.
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      In most cases, it was necessary to extrapolate the data to the time horizon of the model; parametric extrapolation methods were the most common (n = 9). One study carried forward the last observed transition probability,
      • Oh A.
      • Tran D.M.
      • McDowell L.C.
      • et al.
      Cost-effectiveness of nivolumab-ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States.
      1 assumed constant hazard,
      • Matter-Walstra K.
      • Braun R.
      • Kolb C.
      • et al.
      A cost-effectiveness analysis of trametinib plus dabrafenib as first-line therapy for metastatic BRAF V600-mutated melanoma in the Swiss setting.
      and another used the declining exponential approximation of life expectancy (approximation of survival by a simple exponential function) method.
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      No data extrapolation was required in 1 study because the data were relatively mature at the model time horizon.
      • Hillner B.E.
      • Agarwala S.
      • Middleton M.R.
      Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.
      Extrapolation of OS curves used external data sources (eg, cancer registries, long-term follow-up of ipilimumab trials) in a number of the studies to capture the natural history of the disease.
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      • Wang J.
      • Chmielowski B.
      • Pellissier J.
      • et al.
      Cost-effectiveness of pembrozilumab versus ipilimumab in ipilimumab-naive patients with advanced melanoma in the United States.
      • Miguel L.S.
      • Lopes F.V.
      • Pinheiro B.
      • et al.
      Cost-effectiveness of pembrolizumab for advanced melanoma treatment in Portugal.
      • Meng Y.
      • Hertel N.
      • Ellis J.
      • et al.
      The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
      Only 1 study reported adjusting the OS data for treatment crossover.
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      With 1 exception,
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
      studies did not consider the suitability of parametric modeling or explore alternative options.
      Thirteen cost-utility analyses were identified. Utility values were sourced from the literature derived using standard gamble methods (n = 6), or from pivotal clinical trials (n = 7) using the EuroQol-5D-3L. Three studies adopted a time to death approach to modeling utility in the base case
      • Wang J.
      • Chmielowski B.
      • Pellissier J.
      • et al.
      Cost-effectiveness of pembrozilumab versus ipilimumab in ipilimumab-naive patients with advanced melanoma in the United States.
      • Miguel L.S.
      • Lopes F.V.
      • Pinheiro B.
      • et al.
      Cost-effectiveness of pembrolizumab for advanced melanoma treatment in Portugal.
      • Meng Y.
      • Hertel N.
      • Ellis J.
      • et al.
      The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
      ; 2 used a response-based approach,
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
      and the remainder (n = 8) modeled utility based on progression status. Five studies applied a utility decrement for AEs.
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
      • Wang J.
      • Chmielowski B.
      • Pellissier J.
      • et al.
      Cost-effectiveness of pembrozilumab versus ipilimumab in ipilimumab-naive patients with advanced melanoma in the United States.
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.
      • Oh A.
      • Tran D.M.
      • McDowell L.C.
      • et al.
      Cost-effectiveness of nivolumab-ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States.
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
      The value set used to generate the utility values was stated in only 2 studies.
      • Miguel L.S.
      • Lopes F.V.
      • Pinheiro B.
      • et al.
      Cost-effectiveness of pembrolizumab for advanced melanoma treatment in Portugal.
      • Bohensky M.A.
      • Pasupathi K.
      • Gorelik A.
      • et al.
      A cost-effectiveness analysis of nivolumab compared with ipilimumab for the treatment of BRAF wild-type advanced melanoma in Australia.
      Estimated total QALYs with each treatment are shown in Table 2.
      Table 2Extracted total costs and QALYs from each study, 2017 US$. Figures given are the total predicted costs and QALYs, rather than incremental values.
      Drug TreatmentUSAUK
      • Meng Y.
      • Hertel N.
      • Ellis J.
      • et al.
      The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
      Norway
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      Italy
      • De Francesco M.
      • Lamotte M.
      • Ascierto P.
      • Di Rienzo P.
      • Asukai Y.
      Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
      Portugal
      • Miguel L.S.
      • Lopes F.V.
      • Pinheiro B.
      • et al.
      Cost-effectiveness of pembrolizumab for advanced melanoma treatment in Portugal.
      Australia
      • Bohensky M.A.
      • Pasupathi K.
      • Gorelik A.
      • et al.
      A cost-effectiveness analysis of nivolumab compared with ipilimumab for the treatment of BRAF wild-type advanced melanoma in Australia.
      Canada
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      Switzerland
      • Matter-Walstra K.
      • Braun R.
      • Kolb C.
      • et al.
      A cost-effectiveness analysis of trametinib plus dabrafenib as first-line therapy for metastatic BRAF V600-mutated melanoma in the Swiss setting.
      Cytotoxic chemotherapyDacarbazine
      No QALYs reported.
      $7013, temozolomide
      No QALYs reported.
      $13 092
      • Hillner B.E.
      • Agarwala S.
      • Middleton M.R.
      Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.


      $17 018, 0.18 QALYs
      Undiscounted QALYs
      ,
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.


      $9382, 0.3 QALYs
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.


      $150 462, 0.26 QALYs
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.


      $26 782, 0.62 QALYs
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
      $35 383,
      Based on discount prices.
      1.23 QALYs
      $16 714, 0.88 QALYs$23 785,
      Based on discount prices.
      0.65 QALYS
      --$31 328, 1.32 QALYs-
      Ipilimumab$227 433,
      Based on discount prices.
      3.68 PFQALYs
      • Oh A.
      • Tran D.M.
      • McDowell L.C.
      • et al.
      Cost-effectiveness of nivolumab-ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States.


      $156 231, 0.34 QALYs
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.


      $206 315, 1.76 QALYs
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.


      $255 163, 2.67 QALYs
      • Wang J.
      • Chmielowski B.
      • Pellissier J.
      • et al.
      Cost-effectiveness of pembrozilumab versus ipilimumab in ipilimumab-naive patients with advanced melanoma in the United States.
      $80 165,
      Based on discount prices.
      3.66 QALYs
      $99 189, 1.36 QALYs$107 124,
      Based on discount prices.
      1.9 QALYs
      $147 467, 2.33 QALYs$147 875, 1.2 QALYs--
      Nivolumab$180 148,
      Based on discount prices.
      4.24 PFQALYs
      • Oh A.
      • Tran D.M.
      • McDowell L.C.
      • et al.
      Cost-effectiveness of nivolumab-ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States.


      $176 545, 0.54 QALYs
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.
      $137 304,
      Based on discount prices.
      4.31 QALYs
      $110 340, 1.7 QALYs--$190 034, 2.5 QALYs--
      Pembrolizumab$130 832, 0.38 QALYs
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.


      $322 914, 3.45 QALYs
      • Wang J.
      • Chmielowski B.
      • Pellissier J.
      • et al.
      Cost-effectiveness of pembrozilumab versus ipilimumab in ipilimumab-naive patients with advanced melanoma in the United States.
      -$112 692, 1.68 QALYs-$209 430, 3.31 QALYs---
      Nivolumab with ipilimumab$242 955,
      Based on discount prices.
      4.37 QALYs
      • Oh A.
      • Tran D.M.
      • McDowell L.C.
      • et al.
      Cost-effectiveness of nivolumab-ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States.


      $211 620, 0.56 QALYs
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.


      $275 875
      No QALYs reported.
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      -$156 539, 1.69 QALYs-----
      Vemurafenib$175 345, 0.72 QALYs
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.


      $55 833, 0.29
      Undiscounted QALYs
      QALYs
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      $103 788,
      Based on discount prices.
      1.7 QALYs
      $97 894, 1.19 QALYs$151 612,
      Based on discount prices.
      1.66 QALYs
      --$128 823, 1.48 QALYs$74 040, 0.99 QALYs
      Dabrafenib$43 097, 0.34
      Undiscounted QALYs
      QALYs
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      $100 296
      Based on discount prices.
      , 1.69 QALYs
      $97 834, 1.23 QALYs---$95 242, 1.53 QALYs-
      Vemurafenib with cobimetinib--$256 784, 1.77 QALYs-----
      Dabrafenib with trametinib$207 338
      No QALYs reported.
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      -$257 892, 1.71 QALYs----$200 869, 1.45 QALYs
      BSC indicates best supportive care; Dab, dabrafenib; Dab + Tram, dabrafenib and trametinib; DTIC, dacarbazine; PFQALYs, progression-free quality-adjusted life years; Tem, temozolomide; Vem, vemurafenib; Vem + Cobi, vemurafenib and cobimetinib.
      Undiscounted QALYs
      No QALYs reported.
      Based on discount prices.
      The estimation of costs varied in the studies. Treatment acquisition costs were commonly based on the publicly available price, with 3 exceptions where confidential discount prices were used.
      • De Francesco M.
      • Lamotte M.
      • Ascierto P.
      • Di Rienzo P.
      • Asukai Y.
      Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
      • Oh A.
      • Tran D.M.
      • McDowell L.C.
      • et al.
      Cost-effectiveness of nivolumab-ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States.
      • Meng Y.
      • Hertel N.
      • Ellis J.
      • et al.
      The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
      Administration and monitoring costs were excluded from 2 studies,
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      • Matter-Walstra K.
      • Braun R.
      • Kolb C.
      • et al.
      A cost-effectiveness analysis of trametinib plus dabrafenib as first-line therapy for metastatic BRAF V600-mutated melanoma in the Swiss setting.
      whereas the approach was not clearly described in 3 studies.
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
      • Wang J.
      • Chmielowski B.
      • Pellissier J.
      • et al.
      Cost-effectiveness of pembrozilumab versus ipilimumab in ipilimumab-naive patients with advanced melanoma in the United States.
      • Miguel L.S.
      • Lopes F.V.
      • Pinheiro B.
      • et al.
      Cost-effectiveness of pembrolizumab for advanced melanoma treatment in Portugal.
      Most studies included costs for AEs (n = 13), while the application of costs for subsequent treatments was variable.

      Model Outcomes

      Immunotherapies

      Ipilimumab was compared with CC in 2 studies, in first-line and second-line treatment populations, respectively.
      • De Francesco M.
      • Lamotte M.
      • Ascierto P.
      • Di Rienzo P.
      • Asukai Y.
      Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
      Ipilimumab was associated with an increase in costs and QALYs compared to CC in both studies. The predicted QALYs associated with ipilimumab varied from 1.76 (second line)
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
      to 1.9 (first line).
      • De Francesco M.
      • Lamotte M.
      • Ascierto P.
      • Di Rienzo P.
      • Asukai Y.
      Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
      The predicted total costs ranged from $107 124 (first line) to $206 315 (second line)
      • Barzey V.
      • Atkins M.B.
      • Garrison L.P.
      • et al.
      Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
      ; drug acquisition cost in first line included a confidential discount available to the Italian health service.
      • De Francesco M.
      • Lamotte M.
      • Ascierto P.
      • Di Rienzo P.
      • Asukai Y.
      Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
      Incremental treatment cost was the driver of the increased cost in both models. It was concluded that ipilimumab was likely to be cost-effective as a second-line treatment at a willingness-to-pay (WTP) threshold of $200 000/QALY in the United States. No clear conclusion on cost-effectiveness was presented for the first-line indication, but the ICER was in line with that in other countries such as the UK and Sweden. In a comparison with vemurafenib as first-line treatment for BRAF-positive patients, ipilimumab was dominant, with some uncertainty noted in the probabilistic sensitivity analysis where 24% of the iterations were in the southwest quadrant.
      • De Francesco M.
      • Lamotte M.
      • Ascierto P.
      • Di Rienzo P.
      • Asukai Y.
      Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
      Nivolumab and pembrolizumab were compared with ipilimumab in 4 studies. All models predicted that the PD-1 inhibitors were associated with an increase in costs and QALYs and were likely to be cost-effective at the national WTP thresholds. They were associated with costs ranging from $110 340
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      to $322 914
      • Wang J.
      • Chmielowski B.
      • Pellissier J.
      • et al.
      Cost-effectiveness of pembrozilumab versus ipilimumab in ipilimumab-naive patients with advanced melanoma in the United States.
      and QALYs ranging from 0.38
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.
      to 4.31.
      • Meng Y.
      • Hertel N.
      • Ellis J.
      • et al.
      The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
      Discounted prices were used in 1 study and so generalizability is questionable.
      • Meng Y.
      • Hertel N.
      • Ellis J.
      • et al.
      The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
      All studies were from a payer perspective, and spanned a range of continents including the United States, Australia, and Europe.
      One study compared NIVO-IPI to monotherapy with nivolumab or ipilimumab, based on PFS results from CheckMate 067.
      • Oh A.
      • Tran D.M.
      • McDowell L.C.
      • et al.
      Cost-effectiveness of nivolumab-ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States.
      This study found that NIVO-IPI was associated with the highest costs and QALYs of the 3 interventions; nivolumab was dominant of ipilimumab, and NIVO-IPI was associated with an ICER of $483 131 versus nivolumab monotherapy (incremental costs $62 807, incremental progression-free QALYs 0.13). It concluded that at a threshold of $100 000/QALY, nivolumab was cost-effective, and NIVO-IPI was not cost-effective even in PD-1-negative patients where relative efficacy is greatest.
      • Larkin J.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • et al.
      Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.
      These conclusions were robust to sensitivity analysis, including higher WTP thresholds.
      Two studies compared all 4 immunotherapy regimens with conflicting findings.
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      One study examining sequences of immunotherapy and chemotherapy treatments found first-line pembrolizumab to be associated with the lowest costs, and it was dominant of CC and ipilimumab; the ICER for nivolumab versus pembrolizumab was $304 755/QALY ($45 713 incremental costs, 0.16 incremental QALYs).
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.
      The NIVO-IPI regimen was associated with an incremental QALY gain of 0.02 versus nivolumab and an ICER of $1 753 774. By contrast, pembrolizumab was dominated by nivolumab (higher costs and lower QALYs) in a separate study that found that none of the new treatments were cost-effective in the Norwegian setting relative to CC, with an ICER of $92 113 for nivolumab versus CC.
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.

      BRAF targeted treatment

      Three models examined the cost-effectiveness of BRAF inhibitor monotherapy compared with CC for the treatment of BRAF V600 mutant melanoma.
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      All concluded that BRAF inhibitor monotherapy was associated with an increase in QALYs (ranging from 0.29 to 1.66) and costs, and was unlikely to be cost-effective at national WTP thresholds.
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      Two models compared dabrafenib to vemurafenib, and both concluded that dabrafenib was dominant.
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      One study compared the cost-effectiveness of combination BRAF/MEK therapy to BRAF inhibitor monotherapy.
      • Matter-Walstra K.
      • Braun R.
      • Kolb C.
      • et al.
      A cost-effectiveness analysis of trametinib plus dabrafenib as first-line therapy for metastatic BRAF V600-mutated melanoma in the Swiss setting.
      It found that combination therapy was associated with an increase in QALYs and a significant increase in costs, producing an ICER far in excess of the national WTP. In a study comparing all the melanoma treatments, BRAF inhibitor monotherapy and dabrafenib and trametinib combination therapy were excluded due to dominance, and vemurafenib with cobimetinib was associated with an ICER in excess of $2 million versus nivolumab.
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      Finally, a study (with outcomes in cost/month PFS)
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      compared dabrafenib and trametinib combination therapy versus NIVO-IPI. Dabrafenib and trametinib combination therapy was associated with a lower per-patient treatment cost ($207 338 vs $275 875), a lower cost per month PFS ($18 849 vs $23 578), and a lower cost per responder ($300 490 vs $413 605).

      Cytotoxic chemotherapy

      One study compared the cost-effectiveness of temozolomide, an oral form of the CC dacarbazine, to intravenous dacarbazine using results from the Schering I95-018 clinical trial.
      • Hillner B.E.
      • Agarwala S.
      • Middleton M.R.
      Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.
      The outcome was cost/LYG. The ICER for temozolomide versus dacarbazine was $70 165/LYG; there was a 60% chance of cost-effectiveness at a threshold of $50 000/LYG.

      Reporting and Quality Assessment

      The CHEERS checklist was used to review completeness of reporting of the evaluation. Compliance with the CHEERS checklist was variable. No studies were found to have perfect compliance with the CHEERS reporting requirements; 3 studies were assessed as having only 1 noncompliance.
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      • De Francesco M.
      • Lamotte M.
      • Ascierto P.
      • Di Rienzo P.
      • Asukai Y.
      Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      One study was judged to have 13 of a possible 25 noncompliances,
      • Curl P.
      • Vujic I.
      • Van 't Veer L.J.
      • Ortiz-Urda S.
      • Kahn J.G.
      Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
      1 had 12,
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      and 2 were judged to have 11.
      • Hillner B.E.
      • Agarwala S.
      • Middleton M.R.
      Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      Almost all studies did not provide reasons for the type of decision model used (n = 11), even when a detailed description of the model was provided. Most (n = 11) did not report differences in costs and outcomes in subgroups and failed to report on all relevant aspects of the setting and location (n = 8). The descriptions of structural assumptions underlying the model were poorly reported in many studies (n = 8), with some providing inadequate discussion of uncertainty on inputs, structure, and assumptions (n = 5). Many studies did not report the dates of estimated resource use and unit costs (n = 7), although they did provide some description of the method for converting costs.
      The Philips checklist was used to perform an assessment of the quality of the economic evaluation. No study was considered to have a positive quality assessment for each field of the Philips checklist. No study considered competing theories about model structure or provided evidence of testing the mathematical logic of the model. No study considered all feasible options (talimogene laherparepvec was not included in any study), but 3 did provide justification.
      • De Francesco M.
      • Lamotte M.
      • Ascierto P.
      • Di Rienzo P.
      • Asukai Y.
      Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
      • Hillner B.E.
      • Agarwala S.
      • Middleton M.R.
      Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.
      • Kohn C.G.
      • Zeichner S.B.
      • Chen Q.
      • et al.
      Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.
      Only 1 study provided adequate assessment of the 4 principal types of uncertainty
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      ; 2 other studies did address methodological uncertainty.
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      • Miguel L.S.
      • Lopes F.V.
      • Pinheiro B.
      • et al.
      Cost-effectiveness of pembrolizumab for advanced melanoma treatment in Portugal.
      All studies provided clear statements of the decision problem. Only 1 study described and justified the choices made between data sources.
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      This study was also the only study preforming a quality assessment of the included studies. Three studies were deemed to have performed appropriate synthesis of evidence
      • Delea T.E.
      • Amdahl J.
      • Wang A.
      • Amonkar M.M.
      • Thabane M.
      Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
      • Bohensky M.A.
      • Pasupathi K.
      • Gorelik A.
      • et al.
      A cost-effectiveness analysis of nivolumab compared with ipilimumab for the treatment of BRAF wild-type advanced melanoma in Australia.
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      ; for 1 study the outcome was unclear,
      • Meng Y.
      • Hertel N.
      • Ellis J.
      • et al.
      The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
      whereas the remainder were considered not to meet best-practice standards.
      The relationships between reporting and study quality, and among study conclusion, sponsor, and journal type, were examined. A data table was constructed with the numbers of compliances with CHEERS and positive Philips assessments (higher numbers indicating better reporting or quality) for each study. The relationship between reporting compliance and a positive assessment of study quality was examined using Pearson's correlation coefficient. There was a strong positive correlation between CHEERS reporting compliances and positive assessments on the Philips quality checklist (P = .72), showing a strong relationship between reporting and quality assessment.
      Logistic regression models were used to investigate the relationship between the CHEERS and Philips assessments and journal type. Publication in an economics journal was associated with better compliance with the CHEERS checklist (P = .002) and a greater number of positive assessments on the Philips checklist (P = .01). Pharmaceutical industry sponsorship was not associated with better reporting (P = .385) or higher quality (P = .247).
      Chi-square tests were used to investigate the relationship between journal type or study sponsor and studies producing positive conclusions regarding cost-effectiveness. Two studies were excluded from these analyses: no conclusions regarding cost-effectiveness were advanced in one of the studies,
      • Jensen I.S.
      • Zacherle E.
      • Blanchette C.M.
      • Zhang J.
      • Yin W.
      Evaluating cost benefits of combination therapies for advanced melanoma.
      and no funding declaration was available in the other.
      • Shih V.
      • ten Ham R.M.
      • Bui C.T.
      • et al.
      Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
      For both comparisons, the P value was >.05, suggesting that the null hypothesis of independence could not be rejected (Table 3). Nevertheless, there is a clear trend that industry-sponsored studies are likely to find that the treatments are cost-effective compared with standard of care (7 of 8 studies had this conclusion, compared with one of five for independently funded studies).
      Table 3Outcome of chi-square tests investigating the relationship between journal type or study sponsor, and a positive assessment of cost-effectiveness.
      Study outcomeStudy sponsorJournal type
      AcademicIndustryClinical journalEconomics journal
      Cost-effective1735
      Not cost-effective4142
      χ23.41450.29167
      P value.0646.5892

      Discussion

      Our systematic review identified 15 economic evaluations of the cost-effectiveness of treatments for advanced melanoma, published between 2000 and 2018. These new drug treatments are associated with significant clinical benefits in some patients and a high cost per patient, posing challenges to cost-effectiveness and affordability. Public health systems have struggled to make these drugs available to all eligible patients, and they are subject to prescribing restrictions even in Europe's wealthiest countries.
      • Kandolf Sekulovic L.
      • Guo J.
      • Agarwala S.
      • et al.
      Access to innovative medicines for metastatic melanoma worldwide: Melanoma World Society and European Association of Dermato-oncology survey in 34 countries.
      Although most studies used a simplified 3-health-state model, there were major differences in the structural assumptions underpinning the included models, including in the modeled time horizons, model type, application of discounting, estimation of utility, and extrapolation of survival. There were large variations in the predicted costs and QALYs associated with each treatment, for example, the predicted QALY gains with pembrolizumab and nivolumab varied from 0.38 to 4.31. Some of the variation in total costs is likely to be explained by different healthcare resource use and costs across jurisdictions. It may also be accounted for by differing approaches to capturing treatment options post-progression, where some studies assumed no post-progression drug costs were incurred while others included these costs. Variations in QALY gains are at least partially explained by the use of utility values derived by different methods, differing time horizons, and alternative approaches to survival extrapolation. Despite these variations, there was consistency in the conclusions across most of the studies.
      Six industry-sponsored studies evaluated the cost-effectiveness of immunotherapies. Ipilimumab was associated with an increase in costs and QALYs compared with CC, and PD-1 inhibitors were associated with an increase in cost and QALYs compared with ipilimumab. All studies had positive conclusions regarding the cost-effectiveness of the interventions. Nevertheless, many national HTA bodies cast doubt on the cost-effectiveness of ipilimumab at the time of marketing authorization.
      Pharmaceutical Benefits Advisory Committee
      Public Summary Document: Ipilimumab for the treamtent of patients with unresectable stage III or stage IV malignant melanoma who have not responded to or were intolerant to prior systemic therapy for metastatic disease.
      National Centre for Pharmacoeconomics
      Pharmacoeconomic evaluation of ipilimumab (Yervoy®) for the treatment of advanced (unresectable or metastatic) melanoma in adult patients who have received prior therapy.
      Pan-Canadian Oncology
      Drug Review. Pan-Canadian Oncology Drug Review Expert Review Committee Final Recommendation: ipilimumab for the treatment of advanced melanoma in patients who have received prior systemic therapy.
      National Institute for Health and Care Excellence (NICE)
      Final Appraisal Determination: ipilimumab for previously treated advanced (unresectable or metastatic) melanoma.
      Since ipilimumab may not have been cost-effective in the first incidence compared with CC, assessing new treatments such as PD-1 inhibitors versus ipilimumab may be inappropriate where it has been reimbursed at prices higher than the national WTP threshold. The consequences of this are illustrated by the Norwegian study, which found that all treatments are not cost-effective relative to CC, the original comparator in this new era of treatment.
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      All publications agree that PD-1 agents are associated with higher QALYs than ipilimumab, and in many instances are dominant, and that NIVO-IPI is unlikely to be cost-effective even in biomarker-enriched populations. Because ipilimumab is excluded from all cost-effective treatment options and is associated with a lower QALY gain than other immunotherapies, we suggest that divestment opportunities could be considered and pursued by healthcare systems.
      All studies found that BRAF monotherapy is associated with an increase in QALYs compared with CC, but the increase in costs is such that the treatment is unlikely to be cost-effective. Similarly, BRAF/MEK therapy is associated with an increase in QALYs compared with BRAF monotherapy but is considered unlikely to be cost-effective at national WTP thresholds. Three studies include a comparison between immunotherapies and BRAF monotherapy; immunotherapy was likely dominant over BRAF monotherapy in 2 studies, and the estimated ICER for vemurafenib and cobimetinib versus nivolumab was $2 053 845/QALY in the third.
      • De Francesco M.
      • Lamotte M.
      • Ascierto P.
      • Di Rienzo P.
      • Asukai Y.
      Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
      • Meng Y.
      • Hertel N.
      • Ellis J.
      • et al.
      The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      Any form of BRAF targeted therapy is unlikely to be cost-effective regardless of comparator or the national WTP threshold, and divestment from these costly therapies could allow reimbursement of PD-1 inhibitors.
      All identified models derived estimates of relative treatment effects from randomized controlled trials. Recently it has been highlighted that approximately 50% patients with metastatic melanoma do not meet the eligibility criteria for treatment within these randomized controlled trials, raising concerns regarding the generalizability of the results to the real-world population.
      • Donia M.
      • Kimper-Karl M.L.
      • Lundby Høyer K.
      • et al.
      The majority of patients with metastatic melanoma are not represented in pivotal phase III immunotherapy trials.
      • Davis S.
      • Gresham G.
      • Abdel-Rahman O.
      • Cheung W.
      Generalizability of clinical trials of advanced melanoma in the real-world, population-based setting.
      Cost-effectiveness in the real-world population is not established.
      No paper was found to have perfect compliance with the CHEERS reporting requirements, but publication in an economics journal was associated with fewer noncompliances (P = .002). The CHEERS statement is an assessment of reporting, not methodological quality, and failure to follow all the requirements in the CHEERS statement is not indicative of a poor-quality study. Poor reporting can make assessment of quality difficult.
      • Mathes T.
      • Walgenbach M.
      • Antoine S.-L.
      • Pieper D.
      • Eikermann M.
      Methods for systematic reviews of health economic evaluations: a systematic review, comparison, and synthesis of method literature.
      The strong correlation between CHEERS compliances and Philips quality assessment in our study supports the finding that their assessment is interdependent.
      Quality assessment of the studies highlighted significant deficiencies, mainly in the areas of identifying the evidence and the synthesis of relative treatment effects, with only 1 study describing and justifying the choices made between data sources.
      • Pike E.
      • Torkilseng E.B.
      • Sæterdal I.
      • et al.
      A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
      The exploration of uncertainty in the models was also of a poor standard.
      In our sample, publication in a health economics journal was associated with better reporting and higher-quality assessment. Studies with industry sponsors were more likely to conclude positively on cost-effectiveness relative to standard-of-care therapy, although this finding did not demonstrate statistical significance at the P < .05 level. Pharmaceutical industry sponsorship was not associated with higher quality of economic evaluation.
      We developed and executed a comprehensive search strategy in line with best-practice recommendations; we recently updated the search to ensure completeness. Both quality of reporting and study quality were assessed, recognizing the distinction and dependence between both. The quality assessment conducted is subjective in that it is framed by the Irish national reference case and therefore may not be directly applicable to other jurisdictions. Our study excluded 1 non-English publication and 3 studies where the full text could not be accessed.

      Conclusion

      BRAF monotherapy or BRAF/MEK combination therapy have not been shown to be cost -effective in any jurisdiction. PD-1 inhibitors are consistently found to be cost-effective compared with ipilimumab, although their cost-effectiveness relative to CC is not widely assessed. The NIVO-IPI regimen is unlikely to be cost-effective in any setting where PD-1 inhibitors are standard of care. Consideration could be given to pursuing divestment strategies from older, less effective treatments in favor of more cost-effective treatment with PD-1 inhibitors.

      Acknowledgments

      No funding was received for the conduct of this study or production of this manuscript.

      Supplemental Material

      References

        • Garbe C.
        • Peris K.
        • Hauschild A.
        • et al.
        Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2016.
        Eur J Cancer. 2016; 63: 201-217
        • Ferlay J.
        • Soerjomatarum I.
        • Dikshit R.
        • et al.
        Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
        Int J Cancer. 2015; 136: E359-E386
        • Balch C.M.
        • Gershenwald J.E.
        • Soong S.J.
        • et al.
        Final version of 2009 AJCC melanoma staging and classification.
        J Clin Oncol. 2009; 27: 6199-6206
        • Pasquali S.
        • Hadjinicolaou A.
        • Chiarion-Sileni V.
        • Rossi C.
        • Mocellin S.
        Systemic treatments for metastatic cutaneous melanoma.
        Cochrane Database Syst Rev. 2018; : CD011123
        • Hodi F.S.
        • O'Day S.J.
        • McDermott D.F.
        • et al.
        Improved survival with ipilimumab in patients with metastatic melanoma.
        N Engl J Med. 2010; 363: 711-723
        • Schadendorf D.
        • Hodi F.S.
        • Robert C.
        • et al.
        Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma.
        J Clin Oncol. 2015; 33: 1889-1894
        • Ribas A.
        • Puzanov I.
        • Dummer R.
        • et al.
        Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.
        Lancet Oncol. 2015; 16: 908-918
        • Weber J.S.
        • D'Angelo S.P.
        • Minor D.
        • et al.
        Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.
        Lancet Oncol. 2015; 16: 375-384
        • Schachter J.
        • Ribas A.
        • Long G.V.
        • et al.
        Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006).
        Lancet. 2017; 390: 1853-1862
        • Larkin J.
        • Chiarion-Sileni V.
        • Gonzalez R.
        • et al.
        Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.
        N Engl J Med. 2015; 373: 23-34
        • Committee for Medicinal Products for Human Use
        CHMP assessment report imlygic.
        www.ema.europa.eu/contact
        Date accessed: October 8, 2018
        • Hauschild A.
        • Grob J.-J.
        • Demidov L.V.
        • et al.
        Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.
        Lancet. 2012; 380: 358-365
        • Chapman P.B.
        • Hauschild A.
        • Robert C.
        • et al.
        Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
        N Engl J Med. 2011; 364: 2507-2516
        • Long G.V.
        • Eroglu Z.
        • Infante J.
        • et al.
        Long-term outcomes in patients with BRAF V600–mutant metastatic melanoma who received dabrafenib combined with trametinib.
        J Clin Oncol. 2018; 36: 667-673
        • Robert C.
        • Karaszewska B.
        • Schachter J.
        • et al.
        Improved overall survival in melanoma with combined dabrafenib and trametinib.
        N Engl J Med. 2015; 372: 30-39
        • Larkin J.
        • Ascierto P.A.
        • Dréno B.
        • et al.
        Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.
        N Engl J Med. 2014; 371: 1867-1876
        • Kandolf Sekulovic L.
        • Peris K.
        • Hauschild A.
        • et al.
        More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments.
        Eur J Cancer. 2017; 75: 313-322
        • Haute Autorite de Sante
        Transparency Committee Opinion, Yervoy 5mg/ml, concentrate for solution for infusion.
        • Pan-Canadian Oncology Drug Review
        Pan-Canadian Oncology Drug Review Expert Review Committee Final Recommendation: Nivolumab for the treatment of patients with unresectable or metastatic melanoma, regardless of BRAF status.
        • Institute for Quality and Efficiency in Health Care
        Ipilimumab (new therapeutic indication) – Benefit assessment according to §35a Social Code Book V 1.
        • National Institute for Health and Care Excellence (NICE)
        Final appraisal determination: cobimetinib in combination with vemurafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma.
        • National Centre for Pharmacoeconomics
        NCPE report on the cost-effectiveness of pembrolizumab (Keytruda®) for the first line treatment of unresectable or advanced metastatic melanoma in adults.
        • Health Information and Quality Authority
        Guidelines for the retrieval and interpretation of economic evaluations of health technologies in Ireland.
        • Organistion for Economic Cooperation and Developement
        Prices and purchasing power parities.
        http://www.oecd.org/sdd/prices-ppp/
        Date accessed: November 16, 2018
        • Husereau D.
        • Drummond M.
        • Petrou S.
        • et al.
        Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.
        BMJ. 2013; 346: f1049
        • Philips Z.
        • Ginnelly L.
        • Sculpher M.
        • et al.
        Review of guidelines for good practice in decision-analytic modelling in health technology assessment.
        Health Technol Assess. 2004; 8 (iii-iv, ix-xi, 1-158)
        • Curl P.
        • Vujic I.
        • Van 't Veer L.J.
        • Ortiz-Urda S.
        • Kahn J.G.
        Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
        PLoS One. 2014; 9: 1-9
        • Delea T.E.
        • Amdahl J.
        • Wang A.
        • Amonkar M.M.
        • Thabane M.
        Cost-effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada.
        Pharmacoeconomics. 2015; 33: 367-380
        • De Francesco M.
        • Lamotte M.
        • Ascierto P.
        • Di Rienzo P.
        • Asukai Y.
        Economic evaluation of ipilimumab in first line treatment of advanced melanoma in Italy.
        Glob Reg Heal Technol Assess. 2016; 3: 67-79
        • Wang J.
        • Chmielowski B.
        • Pellissier J.
        • et al.
        Cost-effectiveness of pembrozilumab versus ipilimumab in ipilimumab-naive patients with advanced melanoma in the United States.
        J Manag Care Spec Pharm. 2017; 23: 184-194
        • Miguel L.S.
        • Lopes F.V.
        • Pinheiro B.
        • et al.
        Cost-effectiveness of pembrolizumab for advanced melanoma treatment in Portugal.
        Value Health. 2017; 20: 1065-1073
        • Hillner B.E.
        • Agarwala S.
        • Middleton M.R.
        Post hoc economic analysis of temozolomide versus dacarbazine in the treatment of advanced metastatic melanoma.
        J Clin Oncol. 2000; 18: 1474-1480
        • Jensen I.S.
        • Zacherle E.
        • Blanchette C.M.
        • Zhang J.
        • Yin W.
        Evaluating cost benefits of combination therapies for advanced melanoma.
        Drugs Context. 2016; 5: 1-14
        • Kohn C.G.
        • Zeichner S.B.
        • Chen Q.
        • et al.
        Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma.
        J Clin Oncol. 2017; 35: 1194-1202
        • Oh A.
        • Tran D.M.
        • McDowell L.C.
        • 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: 653-664
        • Bohensky M.A.
        • Pasupathi K.
        • Gorelik A.
        • et al.
        A cost-effectiveness analysis of nivolumab compared with ipilimumab for the treatment of BRAF wild-type advanced melanoma in Australia.
        Value Health. 2016; 19: 1009-1015
        • Barzey V.
        • Atkins M.B.
        • Garrison L.P.
        • et al.
        Ipilimumab in second line treatment of patients with advanced melanoma: a cost-effectiveness analysis.
        J Med Econ. 2013; 16: 202-212
        • Meng Y.
        • Hertel N.
        • Ellis J.
        • et al.
        The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.
        Eur J Heal Econ. 2018; 19: 1163-1172
        • Shih V.
        • ten Ham R.M.
        • Bui C.T.
        • et al.
        Targeted therapies compared to dacarbazine for treatment of BRAF v600e metastatic melanoma: a cost effectiveness analysis.
        J Skin Cancer. 2015; 2015: 1-8
        • Matter-Walstra K.
        • Braun R.
        • Kolb C.
        • et al.
        A cost-effectiveness analysis of trametinib plus dabrafenib as first-line therapy for metastatic BRAF V600-mutated melanoma in the Swiss setting.
        Br J Dermatol. 2015; 173: 1462-1470
        • Pike E.
        • Torkilseng E.B.
        • Sæterdal I.
        • et al.
        A health technology assessment of the new drugs for inoperable or metastatic malignant melanoma.
        • Kandolf Sekulovic L.
        • Guo J.
        • Agarwala S.
        • et al.
        Access to innovative medicines for metastatic melanoma worldwide: Melanoma World Society and European Association of Dermato-oncology survey in 34 countries.
        Eur J Cancer. 2018; 104: 201-209
        • Pharmaceutical Benefits Advisory Committee
        Public Summary Document: Ipilimumab for the treamtent of patients with unresectable stage III or stage IV malignant melanoma who have not responded to or were intolerant to prior systemic therapy for metastatic disease.
        • National Centre for Pharmacoeconomics
        Pharmacoeconomic evaluation of ipilimumab (Yervoy®) for the treatment of advanced (unresectable or metastatic) melanoma in adult patients who have received prior therapy.
        • Pan-Canadian Oncology
        Drug Review. Pan-Canadian Oncology Drug Review Expert Review Committee Final Recommendation: ipilimumab for the treatment of advanced melanoma in patients who have received prior systemic therapy.
        • National Institute for Health and Care Excellence (NICE)
        Final Appraisal Determination: ipilimumab for previously treated advanced (unresectable or metastatic) melanoma.
        • Donia M.
        • Kimper-Karl M.L.
        • Lundby Høyer K.
        • et al.
        The majority of patients with metastatic melanoma are not represented in pivotal phase III immunotherapy trials.
        Eur J Cancer. 2017; 74: 89-95
        • Davis S.
        • Gresham G.
        • Abdel-Rahman O.
        • Cheung W.
        Generalizability of clinical trials of advanced melanoma in the real-world, population-based setting.
        Med Oncol. 2018; 35: 110
        • Mathes T.
        • Walgenbach M.
        • Antoine S.-L.
        • Pieper D.
        • Eikermann M.
        Methods for systematic reviews of health economic evaluations: a systematic review, comparison, and synthesis of method literature.
        Med Care. 2014; 34: 826-840