title: Ipilimumab for Previously Untreated Unresectable Malignant Melanoma: A Critique of the Evidence.
abstract: The National Institute for Health and Care Excellence (NICE) invited the manufacturer of ipilimumab (Bristol-Myers Squibb Pharmaceuticals Limited) to submit clinical and cost-effectiveness evidence for previously untreated advanced (unresectable or metastatic) melanoma as part of the Institute's Single Technology Appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article presents a summary of the manufacturer's submission of ipilimumab, the ERG review and the resulting NICE guidance TA319, issued in July 2014. Ipilimumab at a recommended dose of 3 mg/kg monotherapy was previously granted marketing authorisation by the European Medicines Agency in adult patients who had received prior therapy and was recommended by NICE in guidance TA268. In October 2013, the EMA approved the extension of this indication to previously untreated advanced melanoma patients. NICE decisions are bound by the marketing authorisation; therefore, the decision problem faced by the NICE Appraisal Committee was whether ipilimumab at a recommended dose of 3 mg/kg monotherapy was effective and cost effective compared with first-line standard of care involving dacarbazine (DTIC) and vemurafenib (for BRAF V600 mutation-positive patients). The CA184-024 trial was the primary source of clinical evidence for ipilimumab. However, this was based on a dose of 10 mg/kg with concomitant DTIC. The results over a 5-year period indicated that ipilimumab 10 mg/kg plus DTIC demonstrated a significant increase in median overall survival (OS) of 2.1 months compared with DTIC plus placebo (11.2 vs. 9.1 months). The BRIM-3 trial, which was an open-label randomised controlled trial (RCT) in BRAF V600 mutation-positive patients, was the primary source of evidence for an indirect comparison with vemurafenib. The results showed that vemurafenib increased median OS by 3.6 months compared with DTIC (13.2 vs. 9.6 months). The economic evaluation compared the costs and outcomes of ipilimumab by assuming that the 3 mg/kg dosing regimen was clinically equivalent in efficacy to an ipilimumab 10 mg/kg dosing regimen plus DTIC and by using a treatment sequencing approach that incorporated second-line active therapy and third-line best supportive care (BSC). In the first appraisal meeting, the committee recommended ipilimumab only in the context of research as part of a clinical study. This was primarily based on the lack of robust evidence to support the assumption of clinical equivalence between dosages and the absence of evidence available to inform the sequential use of treatments. Following the consultation, the manufacturer submitted additional analyses and evidence to support the cost effectiveness of ipilimumab at first line. The manufacturer's response was based on concerns relating to uncertainty surrounding the relative efficacy of ipilimumab 3 mg/kg monotherapy compared with DTIC and vemurafenib, comparability of the patient populations at first and second line, and the effects of concomitant DTIC. These additional analyses indicated that the incremental cost-effectiveness ratio (ICER) was £ 47,900 per quality-adjusted life-year (QALY) gained for ipilimumab compared with DTIC and £ 28,600 per QALY gained for ipilimumab compared with vemurafenib. Following consideration of the additional evidence and the responses from a large number of consultees and commentators, the committee recommended ipilimumab as an option for adults with previously untreated advanced melanoma.
authors.affiliation: Centre for Health Economics, Alcuin 'A' Block, University of York, Heslington, York, YO10 5DD, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Giannopoulou
authors.affiliation: Centre for Health Economics, Alcuin 'A' Block, University of York, Heslington, York, YO10 5DD, UK.
authors.forename: Eleftherios
authors.initials: E
authors.lastname: Sideris
authors.affiliation: Centre for Reviews and Dissemination, University of York, York, UK.
authors.forename: Ros
authors.initials: R
authors.lastname: Wade
authors.affiliation: Centre for Reviews and Dissemination, University of York, York, UK.
authors.forename: Thirimon
authors.initials: T
authors.lastname: Moe-Byrne
authors.affiliation: Centre for Reviews and Dissemination, University of York, York, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Eastwood
authors.affiliation: Centre for Health Economics, Alcuin 'A' Block, University of York, Heslington, York, YO10 5DD, UK. claire.mckenna@york.ac.uk.
authors.forename: Claire
authors.initials: C
authors.lastname: McKenna
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use*; D003362:Cost-Benefit Analysis; D003606:Dacarbazine / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use; D016527:Drug Costs; D006801:Humans; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D019057:Quality-Adjusted Life Years; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D013673:Technology Assessment, Biomedical / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D000074324:Ipilimumab; D003606:Dacarbazine