Evaluation of MK-1084 with Pembrolizumab and Berahyaluronidase Alfa versus MK-3475A with Pemetrexed/Platinum in KRAS G12C-Mutant Advanced NSCLC

The primary objective of this study is to compare the progression-free survival (PFS) of MK-1084 in combination with MK-3475A against MK-3475A combined with platinum-doublet chemotherapy in participants with non-small cell lung cancer (NSCLC) who are PD-L1 positive with a tumor proportion score (TPS) ≥1%. This assessment is conducted using RECIST 1.1 criteria via blinded independent central review (BICR). Secondary objectives include:

• Evaluation of PFS in the total participant population.
• Comparison of overall survival (OS) in both the PD-L1 positive (TPS ≥1%) and total participant populations.
• Assessment of the objective response rate (ORR) and duration of response (DOR) in all participants and in the PD-L1 positive subgroup.
• Analysis of the safety and tolerability of the MK-1084 and MK-3475A combination.
• Evaluation of quality of life (QoL), specifically measuring mean changes and time to deterioration in global health status, dyspnea, cough, and chest pain.

This clinical trial involves 510 participants diagnosed with nonsquamous non-small cell lung cancer (NSCLC). The study population consists of individuals with advanced or metastatic disease, specifically involving KRAS G12C mutations. Eligible stages include Stage IIIB, Stage IIIC, or Stage IV (M1a, M1b, or M1c). Participants must have tumors that are PD-L1 positive with a tumor proportion score (TPS) of ≥1%. The cohort includes both male and female subjects. Regarding human immunodeficiency virus (HIV) status, individuals who are positive must be well controlled on antiretroviral therapy (ART).

This Phase 3, randomized, open-label, multicenter clinical study is designed to evaluate the safety and efficacy of MK-1084 in combination with subcutaneous pembrolizumab and berahyaluronidase alfa (MK-3475A) compared to pembrolizumab in combination with platinum-doublet chemotherapy, consisting of pemetrexed and either cisplatin or carboplatin. The investigation targets participants with KRAS G12C-mutant, advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) as a first-line treatment. The primary objective is to compare progression-free survival (PFS) as assessed by independent central review in participants whose tumors exhibit programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of ≥1%. Secondary endpoints include overall survival (OS), overall response rate (ORR), duration of response (DOR), and various health-related quality of life assessments. The study is estimated to occur between November 2025 and August 2032.

The experimental treatment consists of pembrolizumab (MK-3475A), provided as a solution for injection via subcutaneous administration.

The experimental treatment also includes MK-1084, which is administered as an oral film-coated tablet or tablet.

The comparator therapy involves pemetrexed disodium, administered via intravenous infusion at a dose of 500 mg/m2. This is used in combination with a platinum agent, specifically cisplatin administered at 75 mg/m2 via intravenous infusion or carboplatin administered via intravenous infusion.

The primary efficacy endpoint is progression-free survival (PFS) in participants with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%, as assessed by blinded independent central review (BICR) according to RECIST 1.1. Secondary efficacy parameters include PFS in all participants, overall survival (OS) in both the total population and participants with PD-L1 TPS ≥1%, overall response rate (ORR) in all participants and those with PD-L1 TPS ≥1%, and duration of response (DOR).

Efficacy assessment also involves evaluating changes from baseline and time to deterioration (TTD) for various patient-reported outcomes. These assessments utilize the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the European Organization for Research and Treatment of Cancer Quality of Life Lung Cancer-Specific Questionnaire (EORTC QLQ-LC13). Specific metrics include global health status/quality of life (GHS/QoL), dyspnea score, cough score, and chest pain score.