Opdualag vs. Cemiplimab/Fianlimab in Relation to the Immunological Response in Tumor and Peripheral Blood in Unresectable or Metastatic Melanoma

Cutaneous melanoma is an aggressive skin cancer which, in the metastatic setting, has a historic 5-year survival rate of <30%. In 2023, about 97,610 new cases of melanoma were estimated to occur in the US, with about 7,990 deaths. GLOBACON reported 324,635 cases of melanoma globally in 2020, which constituted about 1.7% of all cancers and 57,043 melanoma-associated deaths.

The parent trial of this corollary study is a randomized, open-label, multicenter phase 3 study comparing the anti-tumor activity of fixed-dose combination (FDC) of fianlimab + cemiplimab versus the FDC of relatlimab + nivolumab (referred to as Opdualag™) in participants with unresectable or metastatic melanoma (stage III-IV). This corollary study will explore the immunological response of CD8, CD4, and other immune cells in the blood and tumor microenvironment of patients in response to the provided treatments.

• Fianlimab + Cemiplimab (Drug): Patients treated with Fianlimab 1600 mg + Cemiplimab 350 mg under protocol NCT06246916
• Relatlimab + Nivolumab (Drug), also known as Opdualag: Patients treated with Relatlimab 160 mg + Nivolumab 480 mg under protocol NCT06246916

Primary outcomes

• Single-cell analysis of CD4+ T cells [Up to 39 months]: Single-cell RNAseq analysis of CD8+ T cells and other immune cells in blood and tumor biopsies.

Secondary outcomes

• Immunological response of CD4+ T cells [Up to 39 months]: Single-cell analysis of CD4+ T cell (frequency) and other immune cells in blood and tumor biopsies. Analysis of single-cell RNA-seq data to obtain gene module scores for each CD4+ T cell or myeloid cell in whole blood and tumor biopsies will be classified as binary: 1 (co-expressing cytotoxic and exhaustion gene modules) or 0 (no co-expression).
• Multiplexed immunofluorescence [Up to 39 months]: Degree of immune infiltration major immune subsets in the tumor microenvironment. The density of immune cells relative to the total number of cells in the tumor tissue will be calculated for each patient.
• Multiplexed immunofluorescence [Up to 39 months]: Frequencies of major immune subsets in the tumor microenvironment. The density of immune cells relative to the total number of cells in the tumor tissue will be calculated for each patient.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Study participants who meet inclusion criteria for the HCC 24-056 study will be eligible for this study.
2. Participants must be willing to provide additional samples beyond what is required of them in HCC 24-056. These include:

   1. 3 additional tumor biopsies
   2. 3 additional blood draws
3. Participants must have biopsiable non-target disease amenable to at least 3 biopsies.
4. Must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1\. Study participants who do not qualify to enroll in the HCC 24-056 study will not be eligible for this study.

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• John M Kirkwood, MD, Principal investigator, UPMC Hillman Cancer Center