Phase 3 Evaluation of Fianlimab and Cemiplimab Versus Pembrolizumab in Treatment-Naïve Unresectable Locally Advanced or Metastatic Melanoma

The primary objective of this Phase 3 trial is to demonstrate the superiority of **fianlimab** combined with **cemiplimab** compared to **pembrolizumab**, as measured by **progression-free survival (PFS)** in patients with previously untreated unresectable locally advanced or metastatic **melanoma**. This is clinically relevant as PFS is a critical endpoint in oncology trials, indicating the length of time during and after treatment that a patient lives with the disease without it worsening.

Secondary objectives include:

• Demonstrating superiority of fianlimab + cemiplimab compared to pembrolizumab, as measured by overall survival (OS).
• Demonstrating superiority in objective response rate (ORR) with fianlimab + cemiplimab compared to pembrolizumab.
• Assessing ORR, PFS, and OS with fianlimab + cemiplimab compared to cemiplimab to inform the contribution of each component.
• Assessing immunogenicity of fianlimab and cemiplimab.
• Assessing the impact of fianlimab + cemiplimab on physical functioning, role functioning, and global health status/quality of life, as compared to pembrolizumab in adults.
• Assessing safety and tolerability of treatment in patients aged 12 to <18 years.
• Assessing ORR, PFS, and OS with treatment in patients aged 12 to <18 years.
• Assessing the safety and tolerability of fianlimab + cemiplimab compared to pembrolizumab and to cemiplimab.
• Characterizing pharmacokinetics (PK) of fianlimab and cemiplimab using sparse PK sampling in patients aged ≥12 years.
• Assessing the duration of response (DoR) with fianlimab + cemiplimab compared to pembrolizumab.

The clinical trial involves a total of **1028 participants** diagnosed with **melanoma**, specifically targeting individuals with histologically confirmed unresectable Stage III and Stage IV (metastatic) melanoma. The study population includes both male and female subjects, with an age range starting from 12 years and above. Participants were selected based on specific inclusion criteria, such as having a measurable disease per RECIST v1.1 and a performance status of 0 or 1 for adults, or a Karnofsky or Lansky performance status of at least 70 for pediatric patients. The trial also considers individuals with acral and mucosal melanomas, although their accrual is limited to approximately 10% of the total population. Participants are required to have an anticipated life expectancy of at least 3 months. The trial population includes vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **fianlimab** in combination with **cemiplimab** compared to **pembrolizumab** in patients with previously untreated unresectable locally advanced or metastatic **melanoma**. This is a Phase III, randomized, double-blind, controlled trial. The primary objective is to demonstrate the superiority of the combination therapy in terms of progression-free survival (PFS). Secondary endpoints include overall survival (OS), objective response rate (ORR), disease control rate (DCR), and duration of response (DoR), among others. The trial is expected to conclude by April 20, 2031, with recruitment having started on July 14, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease stage, and performance status. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, including assessments of adverse events and laboratory abnormalities. The end-of-study visit will occur after the completion of the treatment period or upon early termination. The expected length of participant involvement is up to 24 months, although this may vary depending on individual response and tolerability.

Conditions that may lead to early termination from the study include the occurrence of unmanageable adverse events, disease progression, or withdrawal of consent. The trial employs a double-blind design to ensure unbiased results, with neither participants nor investigators aware of the treatment allocation. The study drugs, including **fianlimab**, **cemiplimab**, and **pembrolizumab**, are administered via intravenous infusion, with dosing and administration schedules tailored to each participant's needs. The trial aims to provide comprehensive data on the safety and efficacy of the investigational combination therapy in a diverse patient population.

The clinical trial involves the administration of several treatments, including **Fianlimab**, **Cemiplimab**, **Pembrolizumab**, and a placebo. **Fianlimab** is a solution for injection, with the active substance being fianlimab, also known as ANTI-LAG-3 MONOCLONAL ANTIBODY REGN3767. It is of biological/biotechnological origin and is administered via intravenous use. The maximum treatment period for Fianlimab is set at 9999 time units, with no specified maximum daily or total dose amount. The product is manufactured by Regeneron Pharmaceuticals, Inc.

**Cemiplimab**, marketed as LIBTAYO, is a concentrate for solution for infusion. The active substance is cemiplimab, and it is also of biological/biotechnological origin. This treatment is administered intravenously, with a maximum treatment period of 9999 time units. Similar to Fianlimab, there is no specified maximum daily or total dose amount. The product is produced by Regeneron Ireland D.A.C.

**Pembrolizumab**, marketed as KEYTRUDA, is a 25 mg/mL concentrate for solution for infusion. The active substance is pembrolizumab, and it is of biological/biotechnological origin. This treatment is administered intravenously, with a maximum daily dose of 200 mg and a maximum total dose of 7000 mg over a treatment period of 24 time units. The product is manufactured by Merck Sharp & Dohme B.V.

The placebo used in the trial is a saline/dextrose formulation sourced locally by investigational sites. It is intended to serve as a control for the Fianlimab treatment. The placebo is administered intravenously, mirroring the administration route of the active treatments, to maintain blinding in the study.

Efficacy in this clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**. This endpoint is designed to evaluate the time from randomization until disease progression or death from any cause, whichever occurs first. Secondary efficacy endpoints include overall survival (OS), objective response rate (ORR), disease control rate (DCR), and duration of response (DoR). These parameters will provide a comprehensive assessment of the treatment's impact on disease progression and patient outcomes.

Additional secondary endpoints involve the evaluation of patient-reported outcomes (PROs) using validated instruments such as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), EQ-5D-5L, and Functional Assessment of Cancer Therapy (FACT)-melanoma. These tools will assess changes in physical functioning, role functioning, and global health status/quality of life (GHS/QoL) over the course of the trial. The incidence of adverse events (AEs), including treatment-emergent adverse events (TEAEs) leading to death, and laboratory abnormalities will also be monitored to ensure a comprehensive safety profile of the investigational treatments.

Biomarker analysis will include the measurement of concentrations of cemiplimab and fianlimab in serum, as well as the incidence and titer of anti-drug antibodies (ADA) and neutralizing antibodies (NAb) to both fianlimab and cemiplimab over time. These assessments will be conducted at specified intervals throughout the trial to evaluate the immunogenicity and pharmacokinetics of the investigational drugs. The trial is structured to provide a robust evaluation of the efficacy and safety of fianlimab in combination with cemiplimab compared to pembrolizumab in patients with previously untreated unresectable locally advanced or metastatic melanoma.