A Phase 3 Trial of Fianlimab (anti-LAG-3) and Cemiplimab versus Pembrolizumab in the Adjuvant Setting in Patients with Completely Resected High-risk Melanoma

The primary objective of this Phase 3 trial is to demonstrate the **superiority** of the combination of fianlimab and cemiplimab compared to pembrolizumab, as measured by **relapse-free survival** (RFS) in patients with completely resected high-risk melanoma. This objective is clinically relevant as it aims to establish a more effective adjuvant treatment option that could potentially reduce the risk of melanoma recurrence, thereby improving patient outcomes.

Secondary objectives include:

• Evaluating whether post-operative adjuvant therapy improves **distant metastasis-free survival** (DMFS) in stage IIB, IIC, or III patients receiving fianlimab and cemiplimab compared to pembrolizumab.
• Assessing the **safety and tolerability** of fianlimab and cemiplimab compared to pembrolizumab.
• Characterizing the **pharmacokinetics** (PK) of fianlimab and cemiplimab using sparse PK sampling in patients aged 12 years and older.
• Assessing the **immunogenicity** of fianlimab and against cemiplimab.
• Demonstrating the superiority of fianlimab and cemiplimab compared to pembrolizumab, as measured by **overall survival** (OS).
• Assessing the impact of fianlimab and cemiplimab on **quality of life** compared to pembrolizumab in adults.

The clinical trial involves a total of **732 participants** diagnosed with **melanoma**. The study population includes both male and female subjects, encompassing a broad age range from young adults to older adults. Participants were selected based on specific criteria, including having stage IIB, IIC, III, or stage IV melanoma as per the American Joint Committee on Cancer (AJCC) 8th edition, with the condition that the melanoma must be completely surgically resected. The trial includes individuals who have undergone complete surgical resection within 12 weeks prior to randomization and have documented disease-free status through physical examination and imaging studies within four weeks before randomization. The trial population also considers vulnerable groups, ensuring a comprehensive representation of the affected demographic. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is a **Phase 3** study designed to evaluate the efficacy of **fianlimab** in combination with **cemiplimab** compared to **pembrolizumab** in patients with completely resected high-risk **melanoma**. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is approximately five years, with recruitment starting in April 2023 and expected completion by April 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as having stage IIB, IIC, III, or stage IV melanoma that has been completely surgically resected. The screening process will include a complete physical examination and imaging studies to document disease-free status. Following randomization, participants will receive intravenous administration of the study drugs according to their assigned group.

Throughout the trial, participants will attend regular follow-up visits to monitor their health status and assess the primary endpoint of relapse-free survival (RFS). Secondary endpoints include overall survival (OS), distant metastasis-free survival (DMFS), and the occurrence of treatment-emergent adverse events (TEAEs), among others. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to gather comprehensive data on the trial's outcomes.

The expected length of participant involvement is up to 51 weeks, with conditions for early termination including the occurrence of dose-limiting toxicity (DLT), serious adverse events (SAEs), or any adverse events of special interest (AESIs) that necessitate discontinuation of the study drug. Participants may also be withdrawn if they fail to comply with the study protocol or if the investigator deems it in their best interest to discontinue participation.

The clinical trial involves the administration of three distinct treatments, each with specific characteristics and administration protocols. **LIBTAYO** (cemiplimab) is a **concentrate for solution for infusion**. It is administered intravenously at a dosage of 350 mg. The treatment is of biological/biotechnological origin and is provided by Regeneron Ireland D.A.C. The maximum treatment period for LIBTAYO is 51 weeks, with a maximum daily and total dose of 350 mg. The product is specifically labeled and packaged for clinical use, with potential differences in pack, label, and QP release sites compared to the marketing authorization.

**KEYTRUDA** (pembrolizumab) is also a **concentrate for solution for infusion**. It is administered intravenously at a dosage of 200 mg. This treatment is provided by Merck Sharp & Dohme BV and is of biological/biotechnological origin. The maximum treatment period is 51 weeks, with a maximum daily and total dose of 200 mg. The product is study-specific in terms of labeling and packaging.

**FIANLIMAB** is a **solution for injection** administered intravenously. The dosage is 1600 mg, with a maximum treatment period of 51 weeks. The product is of biological/biotechnological origin and is provided by Regeneron Pharmaceuticals, Inc. The maximum daily and total dose is 1600 mg. Fianlimab is identified by the sponsor product code REGN3767 and is also known as an anti-LAG-3 monoclonal antibody.

All treatments are administered intravenously, and participant compliance is monitored throughout the trial. The trial aims to compare the efficacy of fianlimab and cemiplimab against pembrolizumab in patients with completely resected high-risk melanoma, focusing on relapse-free survival as the primary outcome measure.

Efficacy in this clinical trial will be assessed primarily through **relapse-free survival (RFS)**, which serves as the primary endpoint. Secondary endpoints include **overall survival (OS)**, **distant metastasis-free survival (DMFS)**, and various safety and patient-reported outcomes. The trial aims to demonstrate the superiority of the combination of fianlimab and cemiplimab compared to pembrolizumab in patients with completely resected high-risk melanoma.

Data collection will involve measuring the concentrations of fianlimab and cemiplimab in serum over time, as well as monitoring for the presence of anti-drug antibodies (ADA) and neutralizing antibodies. Patient-reported outcomes will be evaluated using validated instruments such as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-QLQ-C30), the European Quality of Life Dimension 5 (EQ-5D-5L), and the Functional Assessment of Cancer Therapy (FACT) - melanoma. Additional assessments will include the Patient Global Impressions Scale (PGIS) and the Patient Global Impressions of Change Scale (PGIC).

The occurrence of treatment-emergent adverse events (TEAEs), immune-mediated adverse events (im-EAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) will be systematically recorded. The trial will also track any TEAEs resulting in death, dose-limiting toxicity (DLT), and any interruptions or discontinuations of study drugs due to TEAEs. Laboratory abnormalities will be monitored throughout the study period.