Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans, it exhibits a high tumor mutational burden and is more common in immunocompromised patients, which aimed to explore the impact of immunotherapy in this cancer. CSCC shows good response to anti-PD1 immunotherapy, and cemiplimab is the first FDA-approved and the only EMA-approved treatment for this tumor. However, 50% of patients won't respond to anti-PD1 and to date there is little evidence on the reasons for such a lack of effectiveness. Also, anti-PD1 immunotherapy is very safe, but some patients will develop adverse events, and anticipating severe adverse events might help in patients' management. The NGF-GRACE project aims to find biomarkers of response and toxicity, both in the blood and the tumor, using advanced technologies. The goal is to move towards more personalized treatments, better select patients, predict side effects, and improve our understanding of the immune system in CSCC.
Total bilirubin ≤1.5x upper limit of normal (ULN) (or ≤3x ULN, if liver metastases).
Patients with Gilbert's Disease and total bilirubin up to 3x ULN may be eligible after communication with and approval from the medical monitor
Transaminases ≤3x ULN (or ≤5x ULN, if liver metastases)
Alkaline phosphatase (ALP) ≤2.5x ULN (or ≤5x ULN, if liver or bone metastases) Renal function: Serum creatinine ≤2x ULN or estimated creatinine clearance >35 mL/min (according the method of Cockcroft and Gault) Creatine phosphokinase (CPK) (also known as CK [creatine kinase]) elevation ≤ grade 2
- Patient who refuses to participate in the study.
Being unsuitable for cemiplimab treatment
Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for immune-related adverse events (irAEs). The following are not exclusionary: vitiligo, childhood asthma that has resolved, type 1 diabetes, residual hypothyroidism requiring only hormone replacement, or psoriasis that does not require systemic treatment.
Untreated brain metastasis(es) that may be considered active.
Every patient who is going to be treated with cemiplimab is a potential candidate for this study considering the inclusion and exclusion criteria of the registry study, included in SmPC.
Cohort
Prospective
Cemiplimab
Drug350 mg IV every 3 weeks as per standard of care. Patients are observed prospectively for biomarkers of response and toxicity during cemiplimab treatment.
Biomarker signature associated with cemiplimab response
Identification of peripheral blood and tumor immune biomarkers (cellular and soluble) that correlate with objective response to cemiplimab. Immune biomarkers to be reported include: 1. Peripheral blood biomarkers (cellular and soluble): * Cellular biomarkers include: CD4⁺, CD8⁺ and T cells, B and plasma cells, NK cells, monocytes, dendritic cells and other myeloid populations, functional and checkpoint markers (e.g. PD-1, HLA-DR). * Soluble biomarkers (cytokines and chemokines): IL-2, IL-6, IL-10, IFN-γ, TNF-α, Chemokines (CXCL9, CXCL10, CCL2, and CCL5). 2. Tumor tissue biomarkers (single-cell multi-omics): * Cellular biomarkers: CD3, CD4, CD8, CD11c, CD14, CD16, CD19, CD25, CD27, CD28, CD45RA, CD56, CD62L, CD127, CD134, CD137, CD161, CD183, CD185, CD186, CD196, CD197, CD272, CD278, CD279, CD357, CD366, HLA-DR, IgD and IdM. * Transcriptomic biomarkers: Single-cell transcriptome data (WTA library) will be generated to explore gene expression profiles associated with immune response.
Best Overall Response (BOR)
Proportion of patients with complete response (CR) or partial response (PR) according to RECIST v1.1 criteria, as assessed during cemiplimab treatment.
Immune-related toxicity rate
Descripción: Incidence and severity of immune-related adverse events (irAEs) according to CTCAE v5.0, and their association with baseline immune profiles.
Progression-Free Survival (PFS)
Time from cemiplimab initiation to disease progression or death from any cause.
Overall Survival (OS)
Time from cemiplimab initiation to death from any cause.
Analysis of transcriptomic and proteomic immune profiling of tumor-infiltrating cells
Single-cell analysis of tumor samples before and during treatment, identifying profiles associated with response or resistance.
Correlation between tumor and blood immune biomarkers
Association between immune signatures in peripheral blood and those found in the tumor microenvironment. Immune biomarkers to be reported include: 1. Peripheral blood biomarkers (cellular and soluble): - Cellular biomarkers include: CD4⁺, CD8⁺ and T cells, B and plasma cells, NK cells, monocytes, dendritic cells and other myeloid populations, functional and checkpoint markers (e.g. PD-1, HLA-DR). - Soluble biomarkers (cytokines and chemokines): IL-2, IL-6, IL-10, IFN-γ, TNF-α, Chemokines (CXCL9, CXCL10, CCL2, and CCL5). 2. Tumor tissue biomarkers (single-cell multi-omics): - Cellular biomarkers: CD3, CD4, CD8, CD11c, CD14, CD16, CD19, CD25, CD27, CD28, CD45RA, CD56, CD62L, CD127, CD134, CD137, CD161, CD183, CD185, CD186, CD196, CD197, CD272, CD278, CD279, CD357, CD366, HLA-DR, IgD and IdM. - Transcriptomic biomarkers: Single-cell transcriptome data (WTA library) will be generated to explore gene expression profiles associated with immune response.
Change in immune cell subpopulations over time
Longitudinal changes in peripheral immune cell subpopulations measured by spectral flow cytometry (NGF).
Change in soluble immune markers over time
Longitudinal variation of cytokines and chemokines in serum analyzed by Luminex.
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Instituto de Investigación Biomédica de Salamanca
Lead sponsor
Regeneron Pharmaceuticals
Collaborator
Carlos III Health Institute
Collaborator
University of Salamanca
Collaborator
