Evaluation of Neoadjuvant and Adjuvant mRNA-4157 with Pembrolizumab Versus Standard of Care in Resectable Locally Advanced Cutaneous Squamous Cell Carcinoma

The primary objective of this clinical study is to compare **V940** plus **pembrolizumab** with the standard of care (SOC) in terms of event-free survival (EFS) in participants with resectable locally advanced cutaneous squamous cell carcinoma (LA cSCC). This objective is clinically relevant as it aims to determine the efficacy of the combination therapy in preventing disease progression or recurrence, which is crucial for improving patient outcomes in this population.

Secondary objectives include:

• Evaluating V940 plus pembrolizumab and SOC with respect to objective response (OR) prior to surgery, as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Assessing freedom from surgery (FFS) as evaluated by the investigator.
• Comparing V940 plus pembrolizumab with SOC regarding pathological complete response (pCR).
• Evaluating major pathological response (mPR) as assessed by blinded independent central review (BICR).
• Assessing disease-free survival (DFS) and disease-specific survival (DSS) as evaluated by the investigator.
• Comparing overall survival (OS) between V940 plus pembrolizumab and SOC.
• Evaluating the safety and tolerability of V940 plus pembrolizumab and SOC.
• Assessing the mean change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Score (GHS), Physical function, and Role function.

The clinical trial involves a total of **365 participants** diagnosed with resectable cutaneous squamous cell carcinoma (**cSCC**). The study population includes individuals of any gender, aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are in relatively good health. Participants were selected based on their confirmed diagnosis of resectable cSCC, with the disease being amenable to complete oncologic resection without resulting in significant functional loss or severe disfigurement. The trial does not include a vulnerable population. Participants are required to have adequate organ function and a life expectancy of more than three months. Those with controlled HIV, undetectable hepatitis C viral load, or hepatitis B under antiviral therapy are eligible. Lifestyle considerations such as diet and physical activity are not specified. The trial includes both male and female participants, with specific contraceptive requirements for those of childbearing potential. The study aims to compare the efficacy of V940 plus pembrolizumab against the standard of care in terms of event-free survival.

The clinical trial is designed as a **randomized**, open-label, Phase 2/3 study to evaluate the efficacy of V940 (mRNA-4157) in combination with **pembrolizumab** versus standard of care and pembrolizumab monotherapy in participants with resectable locally advanced cutaneous squamous cell carcinoma (cSCC). The primary objective is to compare the combination therapy with standard care in terms of event-free survival. The trial is expected to commence recruitment in June 2024 and conclude by May 2033, with a maximum treatment period of 66 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 a histologically confirmed diagnosis of resectable cSCC, adequate organ function, and a life expectancy of more than three months. Following randomization, participants will receive either the investigational combination therapy or the control treatment. Study visits will include regular assessments to monitor safety, efficacy, and any adverse events. Follow-up visits will be scheduled to evaluate secondary endpoints, including objective response, disease-free survival, and overall survival. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participant involvement is expected to last up to 66 weeks, with conditions for early termination including significant adverse events or disease progression. The trial employs a robust methodology to ensure the collection of reliable data, with the primary endpoint being event-free survival and secondary endpoints encompassing a range of clinical outcomes. The study is not classified as low intervention, reflecting its comprehensive approach to evaluating the investigational therapies.

The clinical trial involves the administration of **mRNA-4157**, an investigational medicinal product formulated as a **dispersion for injection**. This product is developed by MODERNATX, INC. and is designed for **intramuscular injection**. The active substance, mRNA-4157, is a synthetic, non-heritable mRNA encapsulated in a synthetic lipid nanoparticle. It is not intended to regulate, replace, or add a genetic sequence with a view to edit the host genome. The mRNA-4157 codes for a patient-specific mRNA sequence and a lipid mixture, which is consistent across patients. The maximum daily dose is 1 mg, with a total maximum dose of 9 mg over a treatment period of 66 days. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.

In addition to mRNA-4157, the trial also includes the administration of **KEYTRUDA** (pembrolizumab), a **concentrate for solution for infusion**. This product is manufactured by MERCK SHARP & DOHME B.V. and is administered via **intravenous infusion**. Pembrolizumab is a protein-based therapeutic agent, specifically a monoclonal antibody, with a maximum daily dose of 400 mg and a total maximum dose of 4400 mg over the same 66-day treatment period. The trial aims to evaluate the efficacy of the combination of mRNA-4157 and pembrolizumab compared to standard-of-care therapy in participants with resectable locally advanced cutaneous squamous cell carcinoma. Compliance with the dosing schedule is closely monitored to ensure the integrity of the trial results.

Efficacy in this clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is **Event-Free Survival (EFS)**, which will be used to compare the efficacy of V940 (mRNA-4157) in combination with pembrolizumab against the standard of care in participants with resectable locally advanced cutaneous squamous cell carcinoma (LA cSCC). Secondary endpoints include Objective Response, Freedom from Surgery, Pathological Complete Response, Major Pathological Response, Disease-Free Survival, Disease-Specific Survival, Overall Survival, and the percentage of participants experiencing adverse events (AEs) or discontinuing study treatment due to AEs. Additionally, changes in scores from baseline will be evaluated using the Global Health Status/Quality of Life (QoL) score, Physical Functioning score, and Role Functioning score, as measured by the QLQ-C30 instrument.

The trial will employ a randomized, open-label design to facilitate the collection and analysis of these efficacy parameters. The schedule for measuring and collecting data will be aligned with the trial's adaptive design, although specific timepoints are not detailed in the provided information. The use of validated scales and patient-reported outcomes will be integral to the assessment of changes in quality of life and functional scores. The trial aims to provide a comprehensive evaluation of the therapeutic impact of the investigational products on the targeted patient population.