A Study of MK-1084 Plus Pembrolizumab (MK-3475) in Participants With KRAS G12C Mutant, Metastatic Non-small Cell Lung Cancer (NSCLC) With Programmed Cell Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥50% (MK-1084-004)

Merck Sharp & Dohme (MSD)

Status and phase: Enrolling; Phase 3

Conditions: Non-small Cell Lung Cancer

Treatments: Drug: MK-1084; Other: Placebo; Biological: Pembrolizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT06345729

MK-1084-004 (Other Identifier)

1084-004

2023-507776-42 (Registry Identifier)

U1111-1296-8093 (Other Identifier)

PHRR241128-007796 (Registry Identifier)

jRCT2031240213 (Registry Identifier)

Details and patient eligibility

About

This is a study evaluating the efficacy and safety of MK-1084 with pembrolizumab as first-line treatment in participants with metastatic non-small cell lung cancer (NSCLC) with identified Kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutation and programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. There are two primary study hypotheses:

Hypothesis 1: Combination of MK-1084 and pembrolizumab is superior to placebo plus pembrolizumab with respect to progression free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR).

Hypothesis 2: Combination of MK-1084 plus pembrolizumab is superior to placebo plus pembrolizumab with respect to overall survival (OS).

Enrollment: 600 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

• Has a histologically or cytologically confirmed diagnosis of NSCLC
• Has newly diagnosed Stage IV NSCLC by American Joint Committee on Cancer (AJCC) Staging Manual, Version 8
• Has measurable disease based on RECIST 1.1
• Has provided tumor tissue that demonstrates PD-L1 expression in ≥50% of tumor cells
• Has provided tumor tissue that demonstrates presence of KRAS G12C mutation
• Has life expectancy of at least 3 months
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days before randomization
• For participant assigned male sex at birth: If capable of producing sperm, participant must agree to the following during the study treatment period and for at least 10 days after the last dose of oral intervention: Either be abstinent or must agree to use male condom plus additional contraceptive method.
• For participant assigned female sex at birth: Either be a person of nonchildbearing potential (PONCBP) or must agree to follow contraceptive guidance during the study treatment period and for at least 10 days after the last dose of oral intervention and 120 days after the last dose of pembrolizumab. Must abstain from breastfeeding during the study intervention period and for at least 120 days after study intervention.
• Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART).
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load before randomization

Exclusion Criteria:

• Diagnosis of small cell lung cancer
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease
• Has a known history of, or active, neurologic paraneoplastic syndrome
• Has an active infection requiring systemic therapy
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QT interval corrected for heart rate by Fridericia's formula (QTcF) interval to >470 ms, and/or other serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention
• Is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease. Examples include, but are not limited to, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome.
• Has one or more of the following ophthalmological findings/conditions: intraocular diagnosis of central serous retinopathy, retinal vein occlusion, or retinal artery occlusion, diagnosis of retinal degenerative disease pressure >21 mm Hg and/or any diagnosis of glaucoma
• Is unable to swallow orally administered medication, or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, or malabsorption)
• Received prior systemic anticancer therapy for their metastatic NSCLC
• Received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor within 12 months before diagnosis of metastatic NSCLC
• Has received radiotherapy within 2 weeks of start of study intervention
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
• Active autoimmune disease that has required systemic treatment in the past 2 years
• History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
• History of allogeneic tissue/solid organ transplant
• Has not fully recovered from any effects of major surgical procedure. Surgical procedures that required general anesthesia must be completed at least 2 weeks before first study intervention administration.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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600 participants in 2 patient groups

MK-1084 with Pembrolizumab

Experimental group

Description:

Participants receive pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles and MK-1084 by oral tablets once daily until discontinuation criterion is met.

Treatment:

Biological: Pembrolizumab

Drug: MK-1084

Placebo with Pembrolizumab

Active Comparator group

Description:

Participants receive pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles and placebo by oral tablets once daily until discontinuation criterion is met.

Treatment:

Biological: Pembrolizumab

Other: Placebo