KEYMAKER-U01 Substudy 01J: A Study of Pembrolizumab Plus MK-1084 in Participants With Non-Small Cell Lung Cancer (NSCLC) With Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) G12C Mutations (MK-3475-01J/KEYMAKER-U01J)

KEYMAKER-U01 Substudy 01J: A Randomized Phase 2 Umbrella Study With Rolling Arms of Investigational Agents for First-line Treatment of Participants With Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer (NSCLC) With KRAS G12C Mutations

Researchers want to learn if using a study medicine called MK-1084 can help treat NSCLC. MK-1084 is a type of treatment called targeted therapy for the Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C gene change. The goal of this study is to learn about the safety of MK-1084 and to learn how many people have the cancer get smaller or go away during the study treatment.

Study Overview

• Status: Recruiting
• Conditions: Malignant Neoplasm
• Intervention / Treatment: Drug: Carboplatin; Drug: MK-1084; Biological: Cetuximab; Biological: Pembrolizumab; Drug: Pemetrexed

• Study Type: Interventional
• Enrollment (Estimated): 130
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Toll Free Number; Phone Number: 1-888-577-8839; Email: Trialsites@msd.com

Study Locations

• Chile
  • Region M. de Santiago
    • Santiago, Region M. de Santiago, Chile, 7560908
      • Recruiting
      • Centro de Oncología de Precisión ( Site 0160)
      • Contact: Study Coordinator; Phone Number: +56978611788
• China
  • Sichuan
    • Chengdu, Sichuan, China, 610066
      • Recruiting
      • West China Hospital, Sichuan University ( Site 0315)
      • Contact: Study Coordinator; Phone Number: +8618980602252
• Finland
  • Northern Savonia
    • Kuopio, Northern Savonia, Finland, 70200
      • Recruiting
      • Kuopion Yliopistollinen Sairaala ( Site 0261)
      • Contact: Study Coordinator; Phone Number: +35817173311
  • Southwest Finland
    • Turku, Southwest Finland, Finland, 20520
      • Recruiting
      • Turku University Hospital ( Site 0262)
      • Contact: Study Coordinator; Phone Number: +35823138709
  • Uusimaa
    • Helsinki, Uusimaa, Finland, 00290
      • Recruiting
      • HYKS Syöpätautien klinikka ( Site 0260)
      • Contact: Study Coordinator; Phone Number: +358406682951
• Hong Kong
  • Kowloon, Hong Kong
    • Recruiting
    • Hong Kong United Oncology Centre ( Site 0231)
    • Contact: Study Coordinator; Phone Number: +852 2386 8002
  • Pokfulam, Hong Kong
    • Recruiting
    • Queen Mary Hospital ( Site 0230)
    • Contact: Study Coordinator; Phone Number: +85222551727
• Netherlands
  • Overijssel
    • Deventer, Overijssel, Netherlands, 7416 SE
      • Recruiting
      • Deventer Ziekenhuis ( Site 0272)
      • Contact: Study Coordinator; Phone Number: +31570536437
  • South Holland
    • Leiden, South Holland, Netherlands, 2333 ZA
      • Recruiting
      • Leids Universitair Medisch Centrum ( Site 0273)
      • Contact: Study Coordinator; Phone Number: +31715566376
• South Korea
  • Seoul, South Korea, 03722
    • Recruiting
    • Severance Hospital Yonsei University Health System ( Site 0080)
    • Contact: Study Coordinator; Phone Number: +82222280880
• Spain
  • Seville, Spain, 41009
    • Recruiting
    • Hospital Universitario Virgen de la Macarena ( Site 0093)
    • Contact: Study Coordinator; Phone Number: +34 671560092
• Turkey (Türkiye)
  • Adana, Turkey (Türkiye), 34010
    • Recruiting
    • Koç Üniversitesi Hastanesi ( Site 0142)
    • Contact: Study Coordinator; Phone Number: 08502508250-21251
  • Ankara, Turkey (Türkiye), 6230
    • Recruiting
    • Hacettepe Universite Hastaneleri ( Site 0140)
    • Contact: Study Coordinator; Phone Number: +90 312 305 50 00
  • Ankara, Turkey (Türkiye), 06680
    • Recruiting
    • Liv Hospital Ankara ( Site 0146)
    • Contact: Study Coordinator; Phone Number: 905469299990
• Ukraine
  • Kyiv, Ukraine, 03022
    • Recruiting
    • VISION PARTNER Medical Centre ( Site 0135)
    • Contact: Study Coordinator; Phone Number: 380989648486
  • Kyiv, Ukraine, 03151
    • Recruiting
    • LIMITED LIABILITY COMPANY "MEDICAL CENTER "DOBROBUT-CLINIC" ( Site 0138)
    • Contact: Study Coordinator; Phone Number: +380671502987
  • Cherkasy Oblast
    • Cherkasy, Cherkasy Oblast, Ukraine, 18009
      • Recruiting
      • COMMUNAL NONPROFIT ENTERPRISE CLINICAL CENTER OF ONCOLOGY, HEMATOLOGY, TRANSPLANTOLOGY AND PALLIATI ( Site 0139)
      • Contact: Study Coordinator; Phone Number: +380472370123
  • Dnipropetrovsk Oblast
    • Kryvyi Rih, Dnipropetrovsk Oblast, Ukraine, 50000
      • Recruiting
      • Medical Center "Mriya Med-Service"-Clinical Research Department ( Site 0465)
      • Contact: Study Coordinator; Phone Number: +380677490687
  • Ivano-Frankivsk Oblast
    • Ivano-Frankivsk, Ivano-Frankivsk Oblast, Ukraine, 76018
      • Recruiting
      • Communal Non-Commercial Enterprise "Prykarpatski Clinical On-Surgery department #2 ( Site 0132)
      • Contact: Study Coordinator; Phone Number: 380978411455
  • Kirovohrad Oblast
    • Kropyvnytskyi, Kirovohrad Oblast, Ukraine, 25011
      • Recruiting
      • Limited Liability Company Ukrainian Center of Tomotherapy-Department of Chemotherapy ( Site 0467)
      • Contact: Study Coordinator; Phone Number: +380958718674
  • Lviv Oblast
    • Lviv, Lviv Oblast, Ukraine, 79059
      • Recruiting
      • Lviv Territorial Medical Union Multidisciplinary Clinical Hospital ( Site 0133)
      • Contact: Study Coordinator; Phone Number: +380677724757
  • Vinnytsia Oblast
    • Vinnitsya, Vinnytsia Oblast, Ukraine, 21029
      • Recruiting
      • Communal Noncommercial Enterprise "Podillia Regional Oncolog-Cardiothoracic department ( Site 0131)
      • Contact: Study Coordinator; Phone Number: 380953105783
  • Zakarpattia Oblast
    • Uzhhorod, Zakarpattia Oblast, Ukraine, 88000
      • Recruiting
      • Uzhhorod Municipal Multidisciplinary Clinical Hospital of Uzhhorod City Council ( Site 0137)
      • Contact: Study Coordinator; Phone Number: +380506847086
• United States
  • Florida
    • Clermont, Florida, United States, 34711
      • Recruiting
      • Clermont Oncology Center ( Site 0041)
      • Contact: Study Coordinator; Phone Number: 386-538-3169
  • North Dakota
    • Fargo, North Dakota, United States, 58102
      • Recruiting
      • Sanford Health Roger Maris Cancer Center ( Site 0039)
      • Contact: Study Coordinator; Phone Number: 701-234-2000
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Recruiting
      • Sanford Cancer Center Oncology Clinic ( Site 0038)
      • Contact: Study Coordinator; Phone Number: 605-328-8000

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

• Has histologically or cytologically confirmed diagnosis of advanced or metastatic nonsquamous Non-Small Cell Lung Cancer (NSCLC)
• Has tumor tissue or circulating tumor deoxyribonucleic acid (ctDNA) that demonstrates the presence of Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutations
• Can provide an archival tumor tissue sample or newly obtained core, incisional, excisional biopsy of a tumor lesion not previously irradiated
• Has recovered to ≤Grade 1 or baseline from any Adverse events (AEs) due to previous anticancer therapies and/or ≤Grade 2 neuropathy and/or endocrine-related AEs adequately treated with hormone replacement
• Has well controlled human immunodeficiency virus (HIV) on antiretroviral therapy (ART) if HIV-infected
• Has undetectable hepatitis B (HBV) viral load and have received HBV antiviral therapy for at least 4 weeks if hepatitis B surface antigen (HBsAg) positive
• Has undetectable hepatitis C (HCV) viral load if HCV-infected

Exclusion Criteria:

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

• Has a diagnosis of small cell lung cancer or, for mixed tumors, presence of small cell elements
• Has HIV-infection with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease
• Has uncontrolled, clinically 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 corrected 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
• Has received prior systemic anticancer therapy for advanced or metastatic NSCLC
• Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE) (except endocrine disorders that can be treated with replacement therapy) or was discontinued from that treatment due to Grade 2 myocarditis or recurrent Grade 2 pneumonitis
• Has received previous treatment with an agent targeting KRAS
• Has received prior systemic anticancer therapy within 4 weeks or 5 half-lives (whichever is shorter) and has not recovered to grade ≤ 1 or baseline from AE associated with anticancer therapy before allocation/randomization
• Has received radiation therapy to the lung that is >30 Gray within 6 months of start of study intervention
• Has a 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
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
• Has a known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Has a history of stem cell/solid organ transplant
• Has not adequately recovered from major surgery or has ongoing surgical complications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Participants receive 400 mg of Pembrolizumab every 6 weeks, Carbo platin every 3 weeks and 500 mg/m^2 of Pemetrexed every 3 weeks.	Drug: Carboplatin; Intravenous administration; Biological: Pembrolizumab; Intravenous administration; Other Names: Keytruda; MK-3475; Drug: Pemetrexed; Intravenous administration
Experimental: Arm 2; Participants receive 400 mg of Pembrolizumab every 6 weeks, and MK-1084 dose regimen	Drug: MK-1084; Oral Administration; Biological: Pembrolizumab; Intravenous administration; Other Names: Keytruda; MK-3475
Experimental: Arm 3; Participants receive 400 mg of Pembrolizumab every 6 weeks, 500 mg/m^2 Cetuximab every 2 weeks, and MK-1084 dose regimen	Drug: MK-1084; Oral Administration; Biological: Cetuximab; Intravenous administration; Biological: Pembrolizumab; Intravenous administration; Other Names: Keytruda; MK-3475

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants with a Dose Limiting Toxicity (DLT)	A DLT is defined as the occurrence of protocol-specified toxicities if assessed by the investigator to be possibly, probably, or definitely related to study intervention administration, excluding toxicities clearly not related to the drug.	Up to approximately 21 days
Percentage of Participants who Experience at Least One Adverse Event (AE)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.	Up to approximately 84 months
Percentage of Participants who Discontinue Study Intervention Due to an AE	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.	Up to approximately 84 months
Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 as assessed by Blinded Independent Central Review (BICR)	ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experience CR or PR as assessed by BICR will be presented.	Up to approximately 84 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR) per RECIST 1.1 as assessed by BICR	For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.	Up to approximately 84 months
Progression Free Survival (PFS) per RECIST 1.1 as assessed by BICR	PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first as assessed by Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1). PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by BICR will be presented.	Up to approximately 84 months
Overall Survival (OS)	OS, defined as the time from first dose or randomization (depending on study period) to death due to any cause. OS will be presented.	Up to approximately 84 months
Area Under the Concentration-Time Curve (AUC) for MK-1084	Blood samples will be collected to determine the AUC of MK-1084.	At designated timepoints (up to approximately 44 days)
Maximum Concentration (Cmax) of MK-1084	Blood samples will be collected to estimate Cmax of MK-1084.	At designated timepoints (up to approximately 44 days)
Trough Concentration (Ctrough) of MK-1084	Blood samples will be collected to determine the Ctrough of MK-1084.	At designated timepoints (up to approximately 84 months)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2025
• Primary Completion (Estimated): January 14, 2033
• Study Completion (Estimated): January 14, 2033

Study Registration Dates

• First Submitted: November 20, 2025
• First Submitted That Met QC Criteria: November 20, 2025
• First Posted (Actual): November 28, 2025

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Programmed Cell Death-1 (PD1, PD-1); Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1); Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
• Additional Relevant MeSH Terms: Neoplasms; Parkinson Disease 4, Autosomal Dominant Lewy Body; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Coordination Complexes; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Dicarboxylic; Pemetrexed; Cetuximab; Carboplatin; pembrolizumab
• Other Study ID Numbers: 3475-01J; U1111-1321-3999 (Registry Identifier: UTN); 2025-521939-36-00 (Registry Identifier: EU CT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No