1114P - Deciphering unresectable in-transit metastasis in melanoma: Multi-modal and longitudinal insights

Background

In-transit metastases (ITM) in melanoma occur between the primary tumor and the draining lymph node, indicating worse survival and poor systemic therapy response. However, some patients exhibit locoregional recurrences with durable distant progression-free survival, and the mechanisms underlying these heterogeneous outcomes are not understood.

Methods

We investigated melanoma patients with unresectable ITM using whole-exome sequencing (WES) and bulk RNA sequencing (RNAseq) to compare those who progressed to distant metastasis (n=21) against those who did not (n=19). We also characterized the tumor-immune dynamics from longitudinal samples of two patients (pt1: 28 samples; pt2: 24 samples) using WES, RNAseq, snRNAseq, and high-plex CyCIF imaging.

Results

ITM patients exhibited high genomic heterogeneity, partly due to Acral samples. We observed enrichment of aging signatures correlated with genomic heterogeneity and copy number signature 9 (diploid with chromosomal instability). Patients who progressed to distant metastasis tended to have higher genomic heterogeneity and lower tumor mutational burden (TMB). Bulk deconvolution showed low immune infiltrate with CD4 memory resting T cells and M2 macrophages. Pt1 (Acral) experienced progressive disease after treatment with CDK4/6 and MEK inhibitors, and ICB, exhibiting aggressive features, low TMB, and an NRAS mutation. Distant metastases arose from a lineage with high aneuploidy and a TET2 mutation. Brain metastasis diverged early but emerged late, with the highest TMB and aneuploidy. CyCIF analysis revealed NGFR+/AXL+ tumor cells, low and heterogeneous immune composition. Pt2 cutaneous melanoma with a BRAF V600E mutation had abundant immune infiltrates. After DTIC chemo and limb perfusion, Pt2 achieved complete response without systemic therapy. Increased TMB and TCR diversity post-DTIC and regression features with abundant CD8+ T cells led to complete remission.

Conclusions

This study maps evolutionary dynamics from primary to ITM and distant metastasis, highlighting features leading to progression and differences in tumor-immune interactions. Pt2's autonomous response post-chemo suggests potential for combined chemo+ICB therapy in ITM patients.

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Doris Duke foundation.

Disclosure

All authors have declared no conflicts of interest.