Combining immune-related adverse events and inflammatory profiles enhances prognostic accuracy in metastatic melanoma under PD-1-based therapy

Dionysios Garmpis^1,2Guillermo Hidalgo-Gadea³Cornelia Mauch^1,4,5Julia Tietze⁶Cindy Franklin^1,2*

• ¹Department of Dermatology and Venereology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
• ²Center for Integrated Oncology (CIO) Aachen Bonn Cologne Düsseldorf, Cologne site, Cologne, Germany
• ³Department of Biopsychology, Faculty of Psychology, Ruhr University Bochum, Bochum, Germany
• ⁴Department of Dermatology and Venereology, Ruhr University Bochum, Bochum, Germany
• ⁵Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Cologne site, Cologne, Germany
• ⁶Department of Dermatology and Venereology, University Hospital Rostock, Rostock, Germany

Background Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced melanoma, yet predictive biomarkers for treatment response and survival remain limited. Immune-related adverse events (irAEs) are frequent during ICI therapy and have been associated with improved outcomes, while baseline inflammatory markers—such as C-Reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR)—often predict poor prognosis. However, no study to date has systematically integrated irAE characteristics and blood-based inflammation profiles to evaluate their combined prognostic value across different therapy lines. Methods We retrospectively analyzed 231 patients with unresectable stage IIIC–IV melanoma treated with PD-1-based ICIs at the University Hospital Cologne (2015–2021). Patients were stratified into first-line (n=149) and higher-line (n=82) groups. We assessed the occurrence, number, type, and severity of organ-specific and non-specific irAEs, and correlated these with progression-free survival (PFS) and overall survival (OS) alongside baseline hematological markers (CRP, neutrophils, lymphocytes, lymphocyte-to-monocyte ratio (LMR), NLR) using multivariate Cox regression. Results Across both therapy lines, the occurrence, higher number, and moderate severity (CTCAE I– III) of organ-specific irAEs independently predicted longer PFS and OS, whereas high-grade irAEs (≥IV) were associated with worse OS. In first-line therapy, ≥2 irAEs conferred markedly prolonged PFS (HR 0.49; p=0.007) and OS (HR 0.53; p=0.040). Elevated CRP and neutrophils predicted shorter survival, while higher lymphocyte counts and LMR were favorable; CRP emerged as the most consistent independent prognostic biomarker. Eosinophil counts predicted both irAE development and improved survival in univariate analyses only. Combining irAEs with CRP and lymphocyte-based markers improved PFS prediction, particularly in first-line therapy. Conclusion Integrating irAE characteristics with baseline inflammatory biomarkers enhances prognostic stratification in ICI-treated melanoma, especially in first-line settings. Moderate irAEs appear to reflect beneficial immune activation, whereas high-grade events may compromise outcomes. 3 CRP and lymphocyte-based indices provide additive value and should be considered in future biomarker-driven patient selection and monitoring strategies.