Neoadjuvant Immunotherapy Using PD-1 Inhibitors for Resectable Stage III Cutaneous Melanoma - Different Outcomes Between Patients With Lymph Node and In-transit Metastases.

Abstract

Background and aims: Neoadjuvant immunotherapy has emerged as the preferred treatment strategy for patients with resectable stage III melanoma. However, real-world data remain limited, especially regarding patients with in-transit metastasis (ITM). The aim of this study was to evaluate neoadjuvant immunotherapy in a population-based cohort of patients with stage III melanoma with a specific focus on patients with ITM.

Study design: This population-based multicenter observational study included all patients with macroscopic stage III cutaneous melanoma treated with neoadjuvant PD-1 inhibitors at 5 academic cancer centers in Sweden from 2022 to 2025. Patients were stratified into 3 groups, LN metastasis only, ITM only, and concurrent LN and ITM involvement. The primary endpoint was major pathological response (MPR). Secondary endpoints included event-free survival (EFS), distant metastasis-free survival (DMFS), locoregional recurrence-free interval (LRFI), and safety outcomes.

Results: A total of 212 patients with a median follow-up of 14.7 months were included, of whom 41 had ITM only and 12 had both LN and ITM. The MPR rate was significantly higher in patients with LN metastases (52%) compared with ITM (22%) or concurrent LN and ITM (25%) ( P <0.001). EFS and LRFI were significantly inferior in patients with ITM compared with LN metastases. In multivariable Cox regression analyses, ITM was associated with a higher risk of events for EFS (HR 2.00; 95% CI: 1.08-3.71; P =0.028) and LRFI (HR 4.41; 95% CI: 1.76-11.02; P =0.002). Although DMFS differed between groups in unadjusted analyses, no association was observed after multivariable adjustment (HR 1.04; 95% CI: 0.46-2.33; P =0.925).

Discussion: This study represents the largest real-world cohort specifically evaluating patients with ITM treated with neoadjuvant immunotherapy. The lower pathological response rate and inferior EFS observed in patients with ITM compared with LN metastases, together with an increased risk of locoregional recurrence, but no difference in DMFS, suggest that ITM may represent a biologically distinct disease phenotype with a higher propensity for locoregional treatment failure.