Randomized, Double-Blind, Placebo-Controlled Trial of Adjuvant Cemiplimab Post-Surgery and Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma

The primary objective of this study is to compare **disease-free survival** (DFS) in patients with high-risk **cutaneous squamous cell carcinoma** (CSCC) treated with adjuvant **cemiplimab** versus those treated with placebo, following surgery and radiation therapy (RT). This objective is clinically relevant as DFS is a critical endpoint in oncology trials, reflecting the time patients remain free from cancer recurrence, which is essential for assessing the efficacy of adjuvant therapies in improving patient outcomes.

Secondary objectives include:

• Comparing the overall survival (OS) of high-risk CSCC patients treated with adjuvant cemiplimab versus placebo after surgery and RT.
• Comparing the effect of adjuvant cemiplimab with placebo on patients' freedom from locoregional recurrence (FFLRR) after surgery and RT.
• Comparing the effect of adjuvant cemiplimab with placebo on patients' freedom from distant recurrence (FFDR) after surgery and RT.
• Comparing the effect of adjuvant cemiplimab with placebo on the cumulative incidence of second primary CSCC tumors (SPTs) after surgery and RT.
• Evaluating the safety of adjuvant cemiplimab and placebo in high-risk CSCC patients after surgery and RT.
• Assessing cemiplimab pharmacokinetics and immunogenicity in human serum.

The clinical trial involves a total of **279 participants** diagnosed with **cutaneous squamous cell carcinoma (CSCC)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including the resection of pathologically confirmed CSCC and completion of curative intent post-operative radiation therapy within 2 to 10 weeks of randomization. The trial includes individuals with high-risk CSCC who have an Eastern Cooperative Oncology Group performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have adequate hepatic, renal, and bone marrow function. The trial population also includes vulnerable groups, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographics. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy of adjuvant **cemiplimab** versus placebo in patients with high-risk **cutaneous squamous cell carcinoma** (CSCC) following surgery and radiation therapy. The primary objective is to compare disease-free survival (DFS) between the two groups. The trial is expected to run from June 2019 to March 2029, with participants involved for a maximum treatment period of 48 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as resection of pathologically confirmed CSCC, completion of post-operative radiation therapy, and adequate organ function. Following randomization, participants will receive either **LIBTAYO** (cemiplimab) or a matching placebo via **IV infusion**. Regular follow-up visits will be scheduled to monitor treatment response, safety, and any adverse events. The end-of-study visit will assess the final outcomes, including DFS and overall survival (OS).

Participant involvement is expected to last up to 48 weeks, with conditions for early termination including significant adverse events, withdrawal of consent, or disease progression. Secondary endpoints include overall survival, freedom from locoregional and distant recurrence, and the occurrence of second primary tumors. Safety will be evaluated through the incidence and severity of treatment-emergent adverse events, and **cemiplimab** concentrations in serum will be measured to assess immunogenicity.

The clinical trial involves the administration of **LIBTAYO** (cemiplimab), a **concentrate for solution for infusion**. Cemiplimab is a monoclonal antibody classified under the ATC code L01XC33. The pharmaceutical form is a concentrate that is prepared for intravenous (IV) infusion. The maximum daily dose is 700 mg, with a total maximum dose of 5600 mg over the treatment period. The treatment is administered every two weeks for a maximum duration of 48 weeks. The product is manufactured by Regeneron Ireland D.A.C. and is used as an adjuvant therapy in patients with high-risk cutaneous squamous cell carcinoma following surgery and radiation therapy.

The study also includes a **matching placebo** designed to mimic the administration of cemiplimab. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo is administered via the same route and schedule as the active treatment, which is through IV infusion every two weeks. This allows for a direct comparison of disease-free survival between the cemiplimab and placebo groups, providing a robust assessment of the treatment's efficacy.

Efficacy in this clinical trial will be assessed primarily through the evaluation of **disease-free survival (DFS)**. DFS is defined as the time from randomization to the first documented disease recurrence, which may be local, regional, or distant, or death due to any cause. This endpoint will provide a measure of the effectiveness of adjuvant cemiplimab compared to placebo in patients with high-risk cutaneous squamous cell carcinoma (CSCC) following surgery and radiation therapy.

Secondary efficacy endpoints include overall survival (OS), freedom from locoregional recurrence (FFLRR), and freedom from distant recurrence (FFDR). OS is defined as the time from randomization to the date of death. FFLRR measures the time from randomization to the date of first locoregional recurrence, while FFDR is defined as the time from randomization to the date of first distant recurrence. Additionally, the cumulative occurrence of second primary cutaneous squamous cell carcinoma tumors (SPTs) will be monitored from randomization to the occurrence of the first primary endpoint event or the end of the study.

Safety and other pharmacokinetic parameters will also be evaluated, including the incidence and severity of treatment-emergent adverse events (TEAEs), deaths, and laboratory abnormalities. Cemiplimab concentrations in serum and immunogenicity, as measured by anti-drug antibodies (ADA) in serum, will be assessed to further understand the treatment's impact. These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive data collection and analysis.