A Phase 2 Peri-operative Trial of Fianlimab and Cemiplimab Compared with Anti-PD1 Alone in Patients with Resectable Stage III and IV Melanoma

The primary objective of this study is to evaluate the treatment effect of the combination of **fianlimab** and **cemiplimab** compared to **cemiplimab** alone as peri-operative therapy in patients with resectable **melanoma**. This is measured by the pathological complete response (pCR) rate assessed by local pathological review in Phase 2. The findings will inform the appropriate dose of **fianlimab** to be used in combination with **cemiplimab** for the Phase 3 part of the study. In Phase 3, the primary objective is to assess the event-free survival (EFS) for the combination of **fianlimab** and **cemiplimab** versus **pembrolizumab** alone as peri-operative therapy in patients with resectable **melanoma**. These objectives are clinically relevant as they aim to improve treatment outcomes and inform dosing strategies for patients with resectable **melanoma**.

Secondary objectives include:

• Phase 2: Assess pCR by Blinded Independent Pathological Review (BIPR), event-free survival (EFS), distant metastasis-free survival (DMFS) in stage III patients, overall survival (OS), the rate of major pathological response (MPR) by local pathological review and BIPR, objective response rate (ORR) to neo-adjuvant treatment by investigator and Blinded Independent Central Review (BICR), time to recurrence of disease as measured by relapse-free survival (RFS), safety and tolerability of neoadjuvant and adjuvant therapy, concentration and immunogenicity of **fianlimab** and **cemiplimab**, and the impact of treatment on functioning, symptoms, and quality of life using FACT-M, EORTC-QLQ-C30, and EQ-5D-5L.
• Phase 3: Assess OS, DMFS in stage III patients, pCR rate by local pathological review and BIPR, the rate of MPR by local pathological review and BIPR, ORR to neo-adjuvant treatment by investigator and BICR, time to recurrence of disease as measured by RFS, safety and tolerability of neo-adjuvant and adjuvant therapy, concentration and immunogenicity of **fianlimab** and **cemiplimab**, and the impact of treatment on functioning, symptoms, and quality of life using FACT-M Melanoma subscale, EORTC QLQ-C30, and EQ-5D-5L.

The clinical trial involves a total of **266 participants** diagnosed with **melanoma**, specifically targeting individuals with resectable stages III (IIIB, IIIC, IIID) or stage IV (M1a, M1b, M1c) melanoma, as per the American Joint Committee on Cancer (AJCC) 8th edition. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on their ability to undergo full disease staging and surgical resection with curative intent, confirmed by a pathology report. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population also considers vulnerable groups, ensuring comprehensive representation. Lifestyle factors such as diet and physical activity are not specified, focusing instead on the medical and surgical eligibility of the participants.

The clinical trial is designed to evaluate the efficacy and safety of **fianlimab** and **cemiplimab** in comparison to anti-PD1 therapy alone in patients with resectable Stage III and IV **melanoma**. This study is structured as a randomized, double-blind, controlled trial, encompassing both Phase 2 and Phase 3 components. The trial is expected to commence recruitment in January 2025 and conclude by June 2033, with a maximum treatment period of 52 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed cutaneous melanoma and the ability to undergo complete surgical resection. Following randomization, participants will receive either the combination therapy or the comparator treatment. The trial includes regular follow-up visits to monitor treatment response and safety, with assessments such as pathological complete response (pCR) and event-free survival (EFS) being primary endpoints. Secondary endpoints include overall survival (OS), disease-free survival (DFS), and the occurrence of treatment-emergent adverse events (TEAEs).

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events, disease progression, or withdrawal of consent. Participants are expected to be involved in the study for the duration of the treatment period and follow-up assessments, unless early termination criteria are met. The trial aims to provide comprehensive data to inform the optimal dosing strategy for the combination therapy in the Phase 3 component.

The clinical trial involves the administration of several treatments, including **Fianlimab**, which is provided as a **solution for injection**. Fianlimab is of biological/biotechnological origin and is administered via **IV infusion**. The maximum treatment period for Fianlimab is 52 weeks. The specific dosage details for Fianlimab are not provided in the data.

**Cemiplimab**, marketed as LIBTAYO, is another experimental medication used in the trial. It is a **concentrate for solution for infusion** and is also of biological/biotechnological origin. Cemiplimab is administered through **IV infusion** with a maximum daily dose of 350 mg and a total dose of 6067 mg over the treatment period. The treatment duration is up to 52 weeks.

**Pembrolizumab** is used as a comparator treatment in the study. It is provided as a **solution for infusion** and is administered via **intravenous use**. Pembrolizumab is of biological/biotechnological origin, with a maximum daily dose of 200 mg and a total dose of 3467 mg over a 52-week period.

The trial also includes a **placebo** for Fianlimab, which is a saline/dextrose formulation sourced locally by investigational sites. The placebo is used to maintain blinding in the study and is administered in a manner consistent with the active treatment to ensure participant compliance and study integrity.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. In Phase 2, the primary endpoint is the **pathological complete response (pCR) rate** as assessed by local pathological review. For Phase 3, the primary endpoint is **Event-free survival (EFS)**. Secondary endpoints for both phases include pCR rate as assessed by BIPR, **distant metastasis-free survival (DMFS)**, **overall survival (OS)**, and **major pathological response (MPR)** as assessed by both BIPR and local pathological review. Additionally, the **objective response rate (ORR)** will be evaluated by investigators and BICR per RECIST 1.1 criteria, along with **recurrence-free survival (RFS)**.

Further secondary endpoints involve the occurrence of treatment-emergent adverse events (TEAEs), immune-mediated adverse events (imAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs). The study will also monitor the occurrence of TEAEs resulting in death, interruption or discontinuation of study drugs due to TEAEs, and cancellation or delay of surgery due to TEAEs. Laboratory abnormalities, concentrations of fianlimab and cemiplimab in serum, and anti-drug antibodies (ADA) in serum to both fianlimab and cemiplimab will be measured.

Patient-reported outcomes will be assessed through changes from baseline in disease-related symptoms per FACT-M subscale, functioning per EORTC QLQ-C30, global health status/QoL per EORTC QLQ-C30, and overall health state per EQ-5D-5L. These assessments will be conducted at specified timepoints throughout the trial to ensure comprehensive evaluation of the treatment's efficacy.