Phase 2 Study of Pembrolizumab, MK-1084, and Combination Therapy in Patients With Advanced or Metastatic KRAS G12C-Mutant Nonsquamous Non-Small Cell Lung Cancer

The primary objectives of this study are to evaluate the safety and tolerability of investigational agent combinations and to assess the objective response rate (ORR) as determined by RECIST 1.1 and blinded independent central review (BICR) in participants with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) harboring KRAS G12C mutations. Secondary objectives include the evaluation of:

• duration of response (DOR) per RECIST 1.1 as assessed by BICR;
• progression-free survival (PFS) per RECIST 1.1 as assessed by BICR;
• overall survival (OS);
• pharmacokinetics (PK) of the investigational agent combinations.

This clinical trial involves 85 participants diagnosed with advanced or metastatic nonsquamous non-small cell lung cancer. The study population includes both male and female individuals within specific age ranges. Eligible participants must demonstrate the presence of KRAS G12C mutations through histological examination of tumor tissue or circulating tumor DNA. Requirements for inclusion involve the provision of archival or newly obtained tumor samples and recovery from previous adverse events to a baseline or low grade. Additionally, participants must have stable management of certain viral infections, such as human immunodeficiency virus, hepatitis B, or hepatitis C, if applicable. The primary objectives are:

• To evaluate the safety and tolerability of investigational agent combinations
• To evaluate objective response rate as assessed by blinded independent central review

This Phase 2, randomized, umbrella study evaluates investigational agent combinations for the first-line treatment of participants with advanced or metastatic nonsquamous non-small cell lung cancer harboring KRAS G12C mutations. The research methodology utilizes a rolling arms design to assess the safety, tolerability, and efficacy of various therapeutic regimens. Investigational products include cetuximab, pembrolizumab, and MK-1084, which are compared against carboplatin and pemetrexed. The primary objectives are to determine the objective response rate as assessed by blinded independent central review and to monitor safety through the evaluation of dose limiting toxicity and adverse events. Secondary endpoints include progression free survival, overall survival, and duration of response, as well as pharmacokinetic parameters for MK-1084 such as maximum concentration and area under the concentration-time curve. Study involvement begins with a screening visit to confirm histological diagnosis and the presence of specific genetic mutations via tumor tissue or circulating tumor DNA. Following successful screening, participants receive study interventions, with subsequent monitoring to evaluate clinical outcomes. Participation may be discontinued if required clinical conditions or safety criteria are met.

Cetuximab is an investigational agent administered via intravenous infusion at a dose of 1250 mg using the pharmaceutical form PHF00230MIG.

MK-1084 is an investigational agent provided as a film-coated tablet or tablet for oral administration.

Pembrolizumab, provided as Keytruda 25 mg/mL concentrate for solution for infusion, is an investigational agent administered via intravenous infusion at a dose of 400 mg.

Carboplatin is a comparator treatment administered via intravenous infusion at a dose of 750 mg using the pharmaceutical form PHF00230MIG.

Pemetrexed disodium, referred to as pemetrexed, is a comparator treatment administered via intravenous infusion at a dose of 1250 mg using the pharmaceutical form PHF00230MIG.

Efficacy assessment in this study of participants with advanced or metastatic nonsquamous non-small cell lung cancer involves several parameters. The primary efficacy endpoint is the objective response rate (ORR) evaluated according to RECIST 1.1 and assessed by blinded independent central review (BICR). Secondary efficacy parameters include duration of response (DOR), progression-free survival (PFS), and overall survival (OS), all determined in accordance with RECIST 1.1 and BICR.