Phase 3 Randomized Placebo‑Controlled Trial of Adjuvant mRNA‑4157 (Intismeran) Plus Pembrolizumab Combination Therapy in Completely Resected High‑Risk Stage I NSCLC

The primary objective is to evaluate whether the addition of disease-free survival benefit is observed with intismeran combined with pembrolizumab (MK-3475A) compared with placebo, as assessed by blinded independent central review in patients with completely resected high‑risk stage I nonsquamous non‑small cell lung cancer.

• Compare intismeran plus pembrolizumab or intismeran monotherapy with placebo regarding disease‑free survival assessed by blinded independent central review.
• Compare the same treatment arms with respect to distant metastasis‑free survival as assessed by blinded independent central review.
• Compare overall survival between the treatment groups and placebo.
• Assess the safety profile and tolerability of intismeran as monotherapy and in combination with pembrolizumab.
• Evaluate mean change from baseline in global health status/quality of life, physical functioning, and role functioning using the EORTC QLQ‑C30 questionnaire.

The trial enrolled 608 participants diagnosed with Stage I NSCLC. Eligible subjects were adults of both sexes, spanning the age categories defined by codes 3 and 4, corresponding to adult and older adult populations. Participants were selected on the basis of a histological confirmation of pathological Stage I (tumor ≤4 cm) non‑small cell lung cancer with at least one high‑risk pathologic feature (tumor size >2 cm, visceral pleural invasion, lymphovascular invasion, or high‑grade histology) as determined locally. All enrolled patients had undergone complete surgical resection of the primary tumor and had not received any systemic therapy, radiotherapy, or other definitive treatment for the current disease. Mandatory baseline requirements included provision of a recent surgical tissue sample and a corresponding blood specimen. Specific viral‑infection criteria allowed enrollment of individuals with well‑controlled HIV on antiretroviral therapy, hepatitis B surface antigen‑positive participants on antiviral therapy with undetectable viral load, and hepatitis C‑infected participants with undetectable viral load at screening. No additional lifestyle restrictions (e.g., diet or physical activity) were stipulated in the enrollment criteria.

The study is a Phase III, multi‑center, randomized, double‑blind, placebo‑controlled trial evaluating adjuvant intismeran autogene plus subcutaneous pembrolizumab (MK‑3475A) and intramuscular mRNA‑4157 versus placebo in participants with completely resected high‑risk Stage I non‑small cell lung cancer. Eligible individuals undergo a screening visit to confirm histologic stage, high‑risk pathology, and surgical completeness, and to collect required tissue and blood samples. Upon meeting inclusion criteria, participants are randomized in a 1:1 ratio to receive either the active combination therapy or matching placebo, with dosing administered according to the protocol schedule. Subsequent study visits occur at predefined intervals for safety assessments, administration of study drugs, and collection of efficacy data, including imaging for the primary endpoint of Disease-Free Survival evaluated by blinded independent central review. Follow‑up continues until disease recurrence, discontinuation, or the pre‑specified end‑of‑study visit, which marks the final assessment of survival outcomes and quality‑of‑life measures. Participant involvement is expected to span several years, encompassing the treatment period and longitudinal monitoring. Early termination may occur for reasons such as unacceptable toxicity, disease progression, withdrawal of consent, or major protocol deviations.

The investigational product identified as MK-3475A contains the active monoclonal antibody pembrolizumab and is supplied as a solution for injection. Each dose consists of 790 mg administered by subcutaneous injection; the dosing frequency follows the study‑specified schedule and is recorded in the participant’s dosing log.

The second investigational agent, mRNA‑4157, is provided as a dispersion for injection intended for intramuscular administration. Each dose contains 1 mg of the mRNA construct and is given according to the protocol‑defined interval, with administration details documented by the study staff.

The control arm receives a matching control designated as Placebo to V940. The placebo contains no active substance, is described as not applicable for pharmaceutical form, and is administered using the same route and schedule as the corresponding active comparator to maintain blinding.

All study medications are administered by qualified personnel at the study sites. Compliance is monitored through completed dosing records, verification of injection administration, and periodic review of protocol adherence by the clinical monitoring team.

The primary efficacy parameter is Disease-Free Survival (DFS) as assessed by Blinded Independent Central Review (BICR) in participants with nonsquamous non‑small cell lung cancer receiving the investigational combination in Arm A and Arm C. DFS will be determined by central imaging review according to protocol‑specified intervals throughout the treatment and follow‑up periods.

Secondary efficacy assessments include DFS by BICR, Distant metastasis‑free survival (DMFS), Overall Survival (OS), and patient‑reported outcomes measured with the EORTC QLQ‑C30 questionnaire. Changes from baseline will be evaluated for the combined Global Health Status/Quality of Life scale (items 29 & 30) and for Physical Functioning (items 1‑5) and Role Functioning (items 6‑7) scores. These questionnaires will be administered at baseline and at predefined study visits.

All efficacy data will be collected according to the study schedule, entered into the trial database, and analyzed using appropriate statistical methods for time‑to‑event and longitudinal questionnaire data.