Primary Tumor Histologic Regression and Immunotherapy Outcomes in Recurrent or Metastatic Melanoma

BACKGROUND: Histologic regression in primary cutaneous melanoma has shown inconsistent prognostic associations, and its relevance to immune checkpoint inhibitor (ICI) outcomes in patients who later develop recurrent or metastatic disease remains unclear. This study aimed to evaluate the association between primary tumor histologic regression and treatment response and survival outcomes in patients with recurrent or metastatic melanoma treated with ICIs. METHODS: This retrospective single-center cohort included 81 patients with resected stage I-III cutaneous melanoma who later developed recurrent or metastatic disease and received ICIs. Histologic regression was classified as present or absent based on primary pathology reports. Objective response rate (ORR) and disease control rate (DCR) were assessed according to RECIST v1.1. Progression-free survival (PFS) and overall survival (OS) from ICI initiation were estimated using Kaplan-Meier analysis and evaluated with prespecified multivariable Cox models. RESULTS: Histologic regression was identified in 24 patients (29.6%). Baseline characteristics were largely comparable between groups, although regression was more frequent in male patients (83.3% vs 59.6%; p = 0.039). ORR was numerically higher in the regression-present group (58.3% vs 43.9%; p = 0.330), and DCR was also higher (87.5% vs 66.7%; p = 0.061). Median PFS was significantly longer in patients with regression (39.3 vs 17.8 months; log-rank p = 0.044). In multivariable analysis, regression remained independently associated with longer PFS (adjusted HR, 0.43; 95% CI, 0.19-0.94; p = 0.035), whereas no independent association with OS was observed (adjusted HR, 0.54; 95% CI, 0.28-1.06; p = 0.071). CONCLUSIONS: In patients with recurrent or metastatic melanoma treated with ICIs, primary tumor histologic regression was independently associated with prolonged PFS but not OS. These findings suggest a potential link between regression and early immune-mediated disease control, while its impact on long-term survival remains uncertain.