Lars Bastholt

Background: Adjuvant anti‐PD‐1 therapy improves recurrence‐free survival in resected stage III melanoma, but its impact on survival remains uncertain. Objective: To evaluate the association of adjuvant anti‐PD‐1 therapy with overall survival (OS) and melanoma‐specific mortality (MSM) in patients with stage III melanoma. Methods: Five‐year OS and MSM were compared between stage III melanoma patients diagnosed before (pre‐cohort: June 2016–May 2018, n = 450) and after (post‐cohort: January 2019–December 2020, n = 552) implementation of adjuvant anti‐PD‐1 in Denmark. Post‐cohort patients receiving adjuvant anti‐PD‐1 were propensity score‐matched to pre‐cohort patients. Results: Median follow‐up exceeded 5 years in both cohorts. At the population level, no difference in 5‐year OS or MSM was demonstrated between the total cohorts. In the post‐cohort, 297 patients (53.8%) received adjuvant anti‐PD‐1. After matching ( n = 279 per group), adjuvant anti‐PD‐1 was associated with higher 5‐year OS (80.3% vs. 71.7%; HR 0.67, 95% CI 0.47–0.95; p = 0.022). 5‐year MSM estimates were inconclusive (16.6% vs. 20.8%, HR 0.77, 95% CI 0.52–1.14; p = 0.24). Among matched patients with occult nodal disease, results were also inconclusive (OS HR 0.70, 95% CI 0.46–1.06). Sensitivity power analyses indicated that only large effects were detectable given the available events. Conclusions: We were unable to demonstrate an improved survival at the population level after adjuvant anti‐PD‐1 introduction, but matched analysis showed higher OS in treated patients. However, uncertainty in disease‐specific outcomes and limited power preclude firm conclusions. Mature trial data are essential for defining the role of adjuvant therapy alongside emerging neoadjuvant strategies. Until then, carefully individualized adjuvant treatment decisions are of particular importance.

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.

Background: Encorafenib is a BRAF inhibitor with a pharmacodynamic profile distinct from that of dabrafenib, including a longer dissociation half-life that may enable more sustained BRAF inhibition. It has been hypothesized that this could translate into superior clinical efficacy. We aimed to determine whether encorafenib plus binimetinib is superior to dabrafenib plus trametinib in terms of clinical activity and outcomes. Methods: Patients were identified through the Danish Metastatic Melanoma Database, a national registry collecting prospective data on systemic treatments. We retrospectively retrieved baseline, treatment, and outcome data for patients with metastatic BRAF-mutant melanoma treated with encorafenib plus binimetinib or dabrafenib plus trametinib from 2017 to 2024. Both unmatched and propensity score–matched analyses were conducted to mitigate potential confounding. Results: A total of 751 patients were included (422 dabrafenib plus trametinib, 329 encorafenib plus binimetinib). Baseline characteristics were balanced between groups. In the unmatched cohort, no statistically differences were observed between dabrafenib plus trametinib and encorafenib plus binimetinib in progression-free survival (PFS; median = 7.9 vs 8.0 months; hazard ratio [HR] = 0.99, P = .90), overall survival (median = 15.5 vs 15.4 months; HR = 0.91, P = .30), or melanoma-specific survival (median = 16.2 vs 15.7 months; HR = 0.94, P = .50). Propensity score–matched analyses confirmed these findings (PFS: HR = 1.05, P = .60; overall survival: HR = 0.922, P = .41; melanoma-specific survival: HR = 0.97, P = .74). Post hoc power analysis for detecting a 3-month survival difference was adequate for PFS (97.5%) but limited for overall survival (56.3%) and melanoma-specific survival (52.1%). Conclusions: We found no evidence that encorafenib plus binimetinib is superior to dabrafenib plus trametinib in metastatic melanoma. These findings suggest that the choice between these combinations should be guided by tolerability profiles and economic considerations rather than efficacy.