AbstractBackgroundThe efficacy‐effectiveness gap between randomized trial and real‐world evidence regarding the clinical benefit of ipilimumab for metastatic melanoma (MM) has been well characterized by previous literature, consistent with initial concerns raised by health technology assessment agencies (HTAs). As these differences can significantly impact cost‐effectiveness, it is critical to assess the real‐world cost‐effectiveness of second‐line ipilimumab versus non‐ipilimumab treatments for MM.MethodsThis was a population‐based retrospective cohort study of patients who received second‐line non‐ipilimumab therapies between 2008 and 2012 versus ipilimumab treatment between 2012 and 2015 (after public reimbursement) for MM in Ontario. Using a 5‐year time horizon, censor‐adjusted and discounted (1.5%) costs (from the public payer's perspective in Canadian dollars) and effectiveness were used to calculate incremental cost‐effectiveness ratios (ICERs) in life‐years gained (LYGs) and quality‐adjusted life years (QALYs), with bootstrapping to capture uncertainty. Varying the discount rate and reducing the price of ipilimumab were done as sensitivity analyses.ResultsIn total, 329 MM were identified (Treated: 189; Controls: 140). Ipilimumab was associated with an incremental effectiveness of 0.59 LYG, incremental cost of $91,233, and ICER of $153,778/LYG. ICERs were not sensitive to discounting rate. Adjusting for quality of life using utility weights resulted in an ICER of $225,885/QALY, confirming the original HTA estimate prior to public reimbursement. Reducing the price of ipilimumab by 100% resulted in an ICER of $111,728/QALY.ConclusionDespite its clinical benefit, ipilimumab as second‐line monotherapy for MM patients is not cost‐effective in the real world as projected by HTA under conventional willingness‐to‐pay thresholds.