Neoadjuvant immunotherapy for resectable stage III cutaneous melanoma—comparison between patients with lymph node and in-transit metastases
Ellen Krabbe, Anne Huibers, Ana Carneiro, Karolin Isaksson, Karl Björkström, Braslav Jovanovic, Antonios Valachis, Gustav J Ullenhag, Hildur Helgadottir, Lars Ny, Axel Nelson, Roger Olofsson BaggeAbstract
Introduction
Randomized trials have demonstrated superior event-free survival (EFS) with neoadjuvant immunotherapy compared with adjuvant therapy alone in patients with resectable stage III melanoma, establishing this as the preferred treatment strategy. However, most trial participants had lymph node (LN) metastases only, and data on patients with in-transit metastases (ITM) remain limited. This study evaluated outcomes of neoadjuvant immunotherapy in a population-based cohort, focusing on ITM.
Methods
We included all patients with macroscopic stage III cutaneous melanoma treated with neoadjuvant immune checkpoint inhibitors (ICIs) at five Swedish academic centers (2022–2025). Patients were stratified into three groups LN metastases only, ITM only, and combined LN and ITM. The primary endpoint was major pathological response (MPR); secondary endpoints were EFS, distant metastasis-free survival (DMFS), and locoregional recurrence-free interval (LRFI).
Results
Among 243 patients, 47 had ITM only and 21 had both LN and ITM. MPR was significantly higher in patients with LN metastases (50%) than in those with ITM (23%) or combined disease (33%) (P = 0.003). In multivariable analyses, ITM was associated with significantly increased risk of events for LRFI (HR 3.80; 95% c.i. 1.58–9.14; P = 0.003). Although EFS differed significantly in unadjusted analyses, this was not significant after adjustment (HR 1.76; 95% c.i. 0.97–3,21; P = 0.065). There was no significant difference between ITM and LN in DMFS in unadjusted or multivariable analysis.
Discussion
Patients with ITM had an increased risk of locoregional recurrence following neoadjuvant immunotherapy, with no difference in DMFS, suggesting a biologically distinct disease phenotype but with similar long term benefit as LN disease.