Phase 3 Randomized Study of MK-1084 and Pembrolizumab vs. Pembrolizumab and Placebo in First-Line KRAS G12C-Mutant Metastatic NSCLC with PD-L1 ≥50%

The primary objective of this study is to compare the efficacy of **MK-1084** in combination with **pembrolizumab** versus pembrolizumab plus placebo in participants with KRAS G12C-mutant, metastatic non-small cell lung cancer (NSCLC) with PD-L1 TPS ≥50%. The primary endpoints are progression-free survival (PFS) and overall survival (OS), both assessed according to RECIST 1.1 by blinded independent central review (BICR). These endpoints are clinically relevant as they provide critical insights into the potential of MK-1084 to improve survival outcomes in this patient population, which is characterized by a specific genetic mutation and high PD-L1 expression.

Secondary objectives include:

• Evaluating the objective response rate (ORR) and duration of response (DOR) per RECIST 1.1 as assessed by BICR.
• Assessing the safety and tolerability of MK-1084 plus pembrolizumab compared to placebo plus pembrolizumab.
• Evaluating the mean change from baseline in global health status/quality of life (QoL), physical functioning, role functioning, dyspnea, cough, and chest pain.
• Determining the time to deterioration in global health status/QoL, physical functioning, role functioning, dyspnea, cough, and chest pain.

The clinical trial involves a total of **415 participants** diagnosed with **non-small cell lung cancer** (NSCLC). The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific inclusion criteria, such as a histologically or cytologically confirmed diagnosis of NSCLC, newly diagnosed Stage IV disease, and the presence of certain genetic markers like the KRAS G12C mutation. The trial does not include a vulnerable population. Participants' general health status allows for the inclusion of individuals with controlled HIV, Hepatitis B, and Hepatitis C, provided certain conditions are met. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to compare the efficacy of MK-1084 plus pembrolizumab versus placebo plus pembrolizumab in terms of progression-free survival (PFS) and overall survival (OS).

The clinical trial is a **randomized, double-blind, controlled** study designed to evaluate the efficacy and safety of MK-1084 in combination with **pembrolizumab** compared to pembrolizumab plus placebo in participants with KRAS G12C-mutant, metastatic **non-small cell lung cancer** (NSCLC) with PD-L1 TPS ≥50%. The trial is a Phase III study, aiming to confirm the safety and efficacy of the treatment regimen in the target population. The primary objectives are to assess progression-free survival (PFS) and overall survival (OS), with secondary endpoints including objective response rate (ORR), duration of response (DOR), and quality of life measures.

The trial is expected to commence recruitment on May 17, 2024, and conclude by February 18, 2031. Participants will be involved in the study for a maximum treatment period of 36 months. The study includes several key visits: an initial **screening visit** to confirm eligibility based on criteria such as histologically confirmed NSCLC, presence of KRAS G12C mutation, and PD-L1 expression, followed by regular **follow-up visits** to monitor treatment response and adverse events. 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 early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it in the participant's best interest. The study will utilize a double-blind design to ensure unbiased results, with neither participants nor investigators aware of the treatment assignments. The trial will be conducted across multiple centers, adhering to rigorous ethical and scientific standards to ensure the validity and reliability of the findings.

The clinical trial involves the administration of **pembrolizumab**, marketed under the name Keytruda, which is a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 25 mg/mL and is administered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 10,400 mg over a treatment period of up to 36 months. Pembrolizumab is a biological product, specifically a protein of other origin, and is manufactured by Merck Sharp & Dohme B.V. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.

Another experimental treatment in the study is **MK-1084**, which is provided in **tablet** form. This chemical compound is administered orally. The trial includes two variations of MK-1084, both produced by Merck & Co. Inc. The dosing schedule for MK-1084 is determined based on the study protocol, and participant compliance is closely monitored to ensure accurate data collection and analysis.

The study also includes a **placebo** component, which is used as a comparator treatment. The placebo is designed to match the MK-1084 tablets in appearance but does not contain the active substance. The placebo is administered orally, and its use is integral to maintaining the double-blind nature of the trial. Compliance with placebo administration is monitored to maintain the integrity of the study results.

The efficacy of the clinical trial will be assessed using the primary endpoints of **Progression-Free Survival (PFS)** and **Overall Survival (OS)**. These endpoints will be evaluated to compare the combination of MK-1084 and pembrolizumab against pembrolizumab plus placebo in participants with KRAS G12C-mutant, metastatic non-small cell lung cancer (NSCLC) with PD-L1 TPS ≥50%. PFS will be assessed according to RECIST 1.1 criteria by Blinded Independent Central Review (BICR).

Secondary endpoints include the Objective Response Rate (ORR), Duration of Response (DOR), and the number of participants experiencing one or more Adverse Events (AEs) or discontinuing study treatment due to an AE. Additionally, changes from baseline in global health status/quality of life, physical functioning, role functioning, dyspnea, cough, and chest pain scores will be measured using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) and the Lung Cancer version (LC13). Time to deterioration (TTD) in these scores will also be evaluated.