Malignant Melanoma, Metastatic Melanoma, Skin Cancer
Conditions
Keywords
Immunotherapy, Immune Checkpoint Inhibitors
Brief summary
This study evaluates whether interferon-gamma (IFN-γ) expression in tumor tissue and peripheral blood can serve as a predictive biomarker of response to immune checkpoint inhibitors in the first-line treatment of metastatic melanoma. Although immune checkpoint inhibitors have substantially improved outcomes in metastatic melanoma, not all patients respond to therapy. Reliable biomarkers that could help identify patients most likely to benefit from treatment are still lacking. This study investigates the association between IFN-γ expression levels and objective treatment response. In addition, the study explores whether characteristics of the gut microbiome are associated with immunotherapy outcomes. The results may contribute to improved patient stratification and personalized treatment approaches in metastatic melanoma.
Detailed description
Immune checkpoint inhibitors have significantly improved survival in patients with metastatic melanoma. However, treatment response varies considerably, and a substantial proportion of patients do not achieve durable benefit. The identification of predictive biomarkers remains an important unmet clinical need. This prospective, single-arm interventional study evaluates biological markers in patients receiving first-line immune checkpoint inhibitor therapy for metastatic melanoma. The primary objective is to assess whether interferon-gamma (IFN-γ) expression in tumor tissue and peripheral blood is associated with objective response to treatment. Tumor IFN-γ expression is assessed using immunohistochemistry, and peripheral blood IFN-γ concentration is measured using enzyme-linked immunosorbent assay (ELISA). The study also evaluates additional biomarkers, including PD-L1 expression, to explore their potential predictive value. Furthermore, the study investigates the relationship between gut microbiome composition and treatment outcomes. Microbiome diversity and bacterial taxonomic profiles are analyzed from stool samples to determine whether microbial characteristics are associated with response to immunotherapy. The study is conducted at a single tertiary oncology center and includes adult patients with metastatic melanoma receiving standard-of-care first-line immune checkpoint inhibitor therapy. The findings aim to support improved risk stratification and biomarker-guided therapeutic decision-making.
Interventions
DRUGPembrolizumab
PD-1 inhibitor used as first-line immunotherapy in patients with metastatic malignant melanoma.
DRUGNivolumab
PD-1 inhibitor used as first-line immunotherapy in patients with metastatic malignant melanoma.
DRUGIpilimumab/Nivolumab
Combination immunotherapy with PD-1 inhibitor (nivolumab) and CTLA-4 inhibitor (ipilimumab) used as first-line treatment in metastatic malignant melanoma.
Sponsors
Institute of Oncology Ljubljana
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Intervention model description
Single-arm interventional study in which all enrolled participants receive standard-of-care first-line immune checkpoint inhibitor therapy for metastatic melanoma. The study evaluates biomarker expression and its association with treatment response without randomization or treatment allocation.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age over 18 years * Cytologically or histologically verified malignant melanoma * Stage IIID unresectable/IV according to AJCC classification (8th edition, 2018) * Performance status WHO 0-2 (ECOG criteria) * First-line systemic immunotherapy treatment (nivolumab, ipilimumab/nivolumab combination, pembrolizumab) * CT triple scan/PET CT performed within 4 weeks prior to the first administration * Signed informed consent for participation in the clinical study
Exclusion criteria
* Previous systemic therapy for melanoma * Performance status WHO 3-4 (ECOG criteria) * Contraindications for immunotherapy (known immune deficiency, active immunosuppressive treatment, or active autoimmune disease requiring treatment) * Other malignant diseases (except cured basal cell carcinoma, squamous cell carcinoma, and other cured solid tumors without recurrence more than three years after treatment)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Assessed by Immune-Related RECIST (irRECIST) | Up to 28 weeks after treatment initiation | Objective response rate defined as the proportion of participants achieving complete response (CR) or partial response (PR) according to immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), based on CT or PET/CT imaging assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Tissue IFN-Gamma Expression Assessed by Immunohistochemistry (IHC) | Baseline (within 4 weeks before treatment initiation) | Interferon-gamma (IFN-γ) expression in tumor tissue measured using immunohistochemistry (IHC). Expression will be quantified using the Histochemical Score (H-score), a semi-quantitative scoring system ranging from 0 to 300. Higher H-scores indicate higher IFN-γ expression levels in tumor tissue. |
| Peripheral Blood IFN-Gamma Concentration Measured by ELISA | Baseline and up to 28 weeks after treatment initiation | Interferon-gamma (IFN-γ) concentration in peripheral blood measured using enzyme-linked immunosorbent assay (ELISA) and reported in picograms per milliliter (pg/mL). |
| Gut Microbiome Alpha Diversity Index Assessed by 16S rRNA Sequencing | Baseline (up to 4 weeks before treatment initiation) | Gut microbiome diversity assessed from stool samples using 16S rRNA sequencing. Alpha diversity will be quantified using the Shannon diversity index. |
| Relative Abundance of Bacterial Taxa in Stool Samples Assessed by 16S rRNA Sequencing | Baseline (up to 4 weeks before treatment initiation) | Relative abundance (%) of bacterial taxa assessed from stool samples using 16S rRNA sequencing. |
Countries
Slovenia
Outcome results
None listed