Phase 3 Randomized Study of Adjuvant Pembrolizumab With or Without mRNA-4157 in Resectable Stage II-IIIB (N2) Non-Small Cell Lung Cancer Not Achieving pCR

The primary objective of this study is to compare **adjuvant** V940 plus pembrolizumab to placebo plus pembrolizumab with respect to disease-free survival (DFS) as assessed by the investigator in patients with resectable Stage II to IIIB (N2) **Non-Small Cell Lung Cancer** (NSCLC) who have not achieved a pathological complete response (pCR) after receiving neoadjuvant pembrolizumab with platinum-based doublet chemotherapy. This objective is clinically relevant as it aims to determine the efficacy of the combination therapy in prolonging DFS, which is a critical endpoint in cancer treatment, reflecting the time patients remain free from disease recurrence.

Secondary objectives include:

• Comparing adjuvant V940 plus pembrolizumab to placebo plus pembrolizumab with respect to overall survival (OS).
• Evaluating the treatments with respect to distant-metastasis free survival (DMFS) and DFS2 as assessed by the investigator.
• Assessing lung cancer-specific survival (LCSS) and 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 adjuvant V940 plus pembrolizumab.

The clinical trial involves a total of **422 participants** diagnosed with **Non-Small Cell Lung Cancer** (NSCLC). 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 a histologically or cytologically confirmed diagnosis of previously untreated and pathologically confirmed resectable Stage II, IIIA, or IIIB (N2) NSCLC, as per the American Joint Committee on Cancer (AJCC) 8th Edition. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days before the first dose of study intervention. Lifestyle considerations such as diet and physical activity are not specified. The trial includes individuals with well-controlled HIV on anti-retroviral therapy, those with hepatitis B who have received antiviral therapy and have an undetectable viral load, and those with a history of hepatitis C with an undetectable viral load at screening. The selection process ensures that participants have not achieved a pathological complete response (pCR) following neoadjuvant chemotherapy and pembrolizumab followed by surgery, and that EGFR-directed therapy is not indicated as primary therapy, confirmed by the absence of tumor-activating EGFR mutations.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of adjuvant pembrolizumab with or without V940 in participants with resectable Stage II to IIIB (N2) **non-small cell lung cancer** (NSCLC) who have not achieved a pathological complete response (pCR) after neoadjuvant pembrolizumab with platinum-based doublet chemotherapy. The trial aims to compare disease-free survival (DFS) as the primary endpoint, with secondary endpoints including overall survival (OS), distant metastasis-free survival (DMFS), and lung cancer-specific survival (LCSS), among others. The estimated duration of the trial extends until January 26, 2038, with recruitment anticipated to start on October 30, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of resectable NSCLC, an ECOG performance status of 0 or 1, and the absence of tumor-activating EGFR mutations. Following the screening, participants will be randomized to receive either the investigational treatment or placebo. The study involves regular follow-up visits to monitor treatment response and safety, with assessments including imaging studies and laboratory tests. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement in the study is determined by the treatment period, which may vary depending on the specific regimen assigned. Conditions that may lead to early termination from the study include the occurrence of adverse events, disease progression, or withdrawal of consent by the participant. The trial is structured to ensure rigorous monitoring and data collection to support the evaluation of the investigational treatment's efficacy and safety in the target population.

The clinical trial involves the administration of several treatments, including **mRNA-4157**, which is an experimental medication. **mRNA-4157** is provided as a **dispersion for injection** and is administered via the **intramuscular** route. The maximum daily dose is 1 mg, with a total maximum dose of 9 mg over a treatment period of 27 weeks. This investigational product is classified as an Advanced Therapy Medicinal Product (ATMP) and is developed by MODERNATX, INC. The active substance is derived from nucleic acid.

Another key treatment in the trial is **KEYTRUDA** (pembrolizumab), a biological product provided as a **concentrate for solution for infusion**. It is administered through **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 3600 mg over a treatment period of 42 weeks. Pembrolizumab is a protein-based therapeutic developed by MERCK SHARP & DOHME B.V.

**Paclitaxel** is included as a non-experimental treatment, provided in the form of **PHF00230MIG** for **intravenous infusion**. The maximum daily dose is 200 mg/m², with a total maximum dose of 800 mg/m² over 12 weeks. This chemical-based treatment is used as part of the standard chemotherapy regimen.

**Gemcitabine hydrochloride** is also administered as a **PHF00230MIG** for **intravenous infusion**. The maximum daily dose is 1000 mg/m², with a total maximum dose of 4000 mg/m² over 12 weeks. This chemical agent is part of the chemotherapy protocol.

**Cisplatin** is provided in the form of **PHF00015MIG** for **intravenous infusion**. The maximum daily dose is 75 mg/m², with a total maximum dose of 300 mg/m² over 12 weeks. This chemical compound is utilized in the chemotherapy regimen.

**Pemetrexed disodium** is administered as **PHF00200MIG** for **intravenous infusion**. The maximum daily dose is 500 mg/m², with a total maximum dose of 2000 mg/m² over 12 weeks. This chemical-based treatment is part of the chemotherapy protocol.

**Carboplatin** is included as a **PHF00230MIG** for **intravenous infusion**. The maximum daily dose is 6 mg/mL, with a total maximum dose of 24 mg/mL over 12 weeks. This chemical agent is part of the standard chemotherapy regimen.

A **placebo for mRNA-4157** is also utilized in the study, serving as a control to compare the effects of the experimental treatment. The placebo is administered in a manner consistent with the experimental product, although specific details regarding its form and administration route are not provided.

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 evaluated by the investigator. Secondary endpoints include Overall Survival (OS), Distant Metastasis-Free Survival (DMFS), Disease-Free Survival 2 (DFS2), and Lung Cancer Specific Survival (LCSS). Additionally, changes from baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) will be measured, focusing on Global Health Status/Quality of Life, Physical Functioning, and Role Functioning. The number of participants experiencing at least one adverse event (AE) and those discontinuing study therapy due to AEs will also be recorded.