Phase 3 Randomized Study of Adjuvant mRNA-4157 and Pembrolizumab Versus Placebo and Pembrolizumab in Resected Stage II-IIIB Non-Small Cell Lung Cancer

The primary objective of this Phase 3 clinical study is to compare **V940** plus **pembrolizumab** to placebo plus pembrolizumab with respect to **disease-free survival (DFS)** in participants with resected Stage II, IIIA, IIIB (N2) non-small cell lung cancer. This objective is clinically relevant as DFS is a critical endpoint in evaluating the efficacy of adjuvant therapies in prolonging the time patients remain free from cancer recurrence following surgical resection.

Secondary objectives include:

• Comparing V940 plus pembrolizumab to placebo plus pembrolizumab with respect to **overall survival (OS)**.
• Evaluating V940 plus pembrolizumab to placebo plus pembrolizumab with respect to **distant metastasis-free survival (DMFS)** as assessed by the investigator.
• Evaluating V940 plus pembrolizumab to placebo plus pembrolizumab with respect to **lung cancer-specific survival (LCSS)**.
• Evaluating V940 plus pembrolizumab to placebo plus pembrolizumab with respect to mean change from baseline in global health status/quality of life (QoL), physical functioning, and role functioning using the EORTC QLQ-C30 and EORTC QLQ-LC24.
• Evaluating the **safety and tolerability** of V940 plus pembrolizumab.

The clinical trial involves a total of **618 participants** diagnosed with **Stage II, IIIA, IIIB (N2) Non-small Cell Lung Cancer**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including having undergone margin-negative, completely resected non-small cell lung cancer, and having no evidence of disease before randomization. All participants have received at least one dose of adjuvant treatment with standard of care platinum doublet chemotherapy, and no more than 24 weeks have elapsed between surgical resection and the first dose of pembrolizumab. The trial does not include a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria allow for participants with controlled hepatitis B, hepatitis C, and HIV, provided certain medical conditions are met. The trial aims to compare V940 plus pembrolizumab to placebo plus pembrolizumab with respect to disease-free survival (DFS).

The clinical trial is a **Phase 3**, randomized, double-blind, placebo- and active-comparator-controlled study designed to evaluate the efficacy and safety of adjuvant **V940 (mRNA-4157)** plus **pembrolizumab** versus adjuvant placebo plus pembrolizumab in participants with resected Stage II, IIIA, IIIB (N2) **non-small cell lung cancer** (NSCLC). The primary objective is to compare the two treatment regimens with respect to disease-free survival (DFS). Secondary endpoints include overall survival (OS), distant metastasis-free survival (DMFS), lung cancer-specific survival (LCSS), and various quality of life measures.

The trial is expected to commence recruitment on April 5, 2024, and is estimated to conclude by December 21, 2035. Participants will be involved in the study for a maximum treatment period of 52 weeks. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as complete resection of NSCLC and no evidence of disease, followed by randomization. Participants will then receive either the investigational product or placebo in combination with pembrolizumab. Follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the integrity of the data and the safety of the participants. The study will utilize **intramuscular injection** for mRNA-4157 and **intravenous infusion** for pembrolizumab, with the placebo administered as a saline solution. The trial's design and methodology aim to provide robust data on the potential benefits of the investigational treatment in improving outcomes for patients with resected NSCLC.

The clinical trial involves the administration of **mRNA-4157**, an investigational medicinal product developed by MODERNATX, INC. This product is formulated as a **dispersion for injection** and is administered via **intramuscular injection**. The active substance, mRNA-4157, is a synthetic, non-heritable mRNA encapsulated in a synthetic lipid nanoparticle. It is designed to deliver a patient-specific mRNA sequence without integrating into the host genome. The maximum daily dose is 1 mg, with a total maximum dose of 9 mg over a treatment period of 27 weeks. The mRNA-4157 is classified as an Advanced Therapy Medicinal Product (ATMP).

The trial also includes a **placebo** group, which receives a saline solution as a comparator to the mRNA-4157. The saline solution is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo is not associated with any active pharmaceutical ingredient and serves as a control to evaluate the efficacy and safety of the mRNA-4157 in combination with pembrolizumab.

**Pembrolizumab**, marketed as KEYTRUDA by MERCK SHARP & DOHME B.V., is used as a standard-of-care therapy in this trial. It is provided as a **25 mg/mL concentrate for solution for infusion** and is administered via **intravenous infusion**. Pembrolizumab is a monoclonal antibody that targets the PD-1 receptor, enhancing the immune system's ability to detect and fight cancer cells. The maximum daily dose is 400 mg, with a total maximum dose of 3600 mg over a treatment period of 52 weeks. Pembrolizumab is classified as a biological medicinal product.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Disease-Free Survival (DFS)**, which will be used to compare the efficacy of V940 (mRNA-4157) plus pembrolizumab versus placebo plus pembrolizumab in participants with resected Stage II, IIIA, IIIB (N2) non-small cell lung cancer. Secondary endpoints include Overall Survival (OS), Distant Metastasis-Free Survival (DMFS), and Lung Cancer Specific Survival (LCSS). Additionally, changes from baseline in quality of life and functioning scores will be evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and the EORTC QLQ-Lung Cancer Questionnaire (LC24). These assessments will include global health status, physical functioning, role functioning, dyspnea, coughing, and chest pain scores. The number of participants experiencing adverse events and those who discontinue study treatment due to adverse events will also be recorded.

The efficacy parameters will be measured and collected at specified timepoints throughout the trial. Validated scales such as the EORTC QLQ-C30 and QLQ-LC24 will be utilized to ensure reliable and consistent data collection. The analysis of these parameters will be conducted to determine the comparative efficacy of the treatment regimens. The trial is designed to provide robust data on the efficacy of the investigational product in the specified patient population.