Quantifying the efficacy-effectiveness gap in first line treatment of metastatic melanoma

Abstract Purpose Pivotal phase III trials underpin regulatory approval of immunotherapy (IO) and BRAF/MEK inhibitors (BRAF/MEKi) in metastatic melanoma (MM). However, how trial-derived efficacy benchmarks translate into real-world effectiveness across eligibility strata remains insufficiently quantified. Methods We conducted a nationwide registry-based cohort study using the Danish Metastatic Melanoma Database, including patients with stage IV MM treated in first line with anti-PD-1 monotherapy, anti-PD-1/anti-CTLA-4, or BRAF/MEKi between 2014 and 2023. Real-world outcomes were compared with reconstructed pseudo-individual patient data from pivotal trials as regulatory efficacy benchmarks. Trial eligibility was defined using key exclusion criteria from pivotal studies. Overall survival (OS), progression-free survival (PFS), and melanoma-specific survival (MSS) were analyzed using Kaplan-Meier and Cox regression methods. Results Among 1909 patients, 41.7-44.9% of IO-treated and 74.3% of BRAF/MEKi-treated patients were trial-ineligible. In eligible populations, IO outcomes mirrored regulatory benchmarks. In contrast, trial-ineligible patients experienced substantial effectiveness deviations, with significantly higher mortality hazards for anti-PD-1 monotherapy (OS HR 1.61, 95% CI 1.39-1.86; p < 0.001) and nivolumab/ipilimumab (OS HR 1.30, 95% CI 1.02-1.66; p = 0.035) compared to their reference trials. For BRAF/MEKi, real-world outcomes were inferior to regulatory benchmarks even among trial-eligible patients and were markedly worse in trial-ineligible populations, with hazard ratios >2.5 across OS, MSS, and PFS (all p < 0.001). Conclusion Real-world effectiveness of first-line therapies in MM deviates from regulatory trial benchmarks in trial-ineligible populations, with larger discrepancies for BRAF/MEKi than IO. These findings support population-specific effectiveness evaluation to complement trial-based efficacy estimates and inform health-technology assessment and clinical decision-making.