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)

Official title

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

Overview

Researchers want to learn if using a study medicine called MK-1084 can help treat Non-Small Cell Lung Cancer (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.

Interventions

• Drug MK-1084
  Oral Administration
• Biological Pembrolizumab
  Intravenous administration
• Biological Cetuximab
  Intravenous administration
• Biological Sacituzumab tirumotecan (sac-TMT)
  Injection powder for intravenous infusion
• Drug Rescue medication
  Participants receive the following rescue medications, per approved product label, as premedication to study treatment to prevent hypersensitivity and/or infusion reactions: diphenhydramine (or equivalent histamine-1 \[Hl\] receptor antagonist), H2 receptor antagonist, acetaminophen or equivalent, dexamethasone or equivalent infusion, and granulocyte colony-stimulating factor (G-CSF). A steroid mouthwash (dexamethasone or equivalent) will be given as prophylaxis for stomatitis/oral mucositis.

Primary outcome measures

• Percentage of Participants with a Dose Limiting Toxicity (DLT) [Time frame: Up to approximately 21 days]
• Percentage of Participants who Experience at Least One Adverse Event (AE) [Time frame: Up to approximately 84 months]
• Percentage of Participants who Discontinue Study Intervention Due to an AE [Time frame: 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) [Time frame: Up to approximately 84 months]

Secondary outcome measures (6)

• Duration of Response (DOR) per RECIST 1.1 as assessed by BICR [Time frame: Up to approximately 84 months]
• Progression Free Survival (PFS) per RECIST 1.1 as assessed by BICR [Time frame: Up to approximately 84 months]
• Overall Survival (OS) [Time frame: Up to approximately 84 months]
• Area Under the Concentration-Time Curve (AUC) for MK-1084 [Time frame: At designated timepoints (up to approximately 44 days)]
• Maximum Concentration (Cmax) of MK-1084 [Time frame: At designated timepoints (up to approximately 44 days)]
• Trough Concentration (Ctrough) of MK-1084 [Time frame: At designated timepoints (up to approximately 84 months)]

Eligibility criteria

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 history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing
• 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 (ILD) that required steroids, has current pneumonitis/ILD, or has suspected ILD or pneumonitis that cannot be ruled out by standard diagnostic assessments at screening
• Has a history of stem cell/solid organ transplant
• Has not adequately recovered from major surgery or has ongoing surgical complications

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Ukraine · 9 centers

• COMMUNAL NONPROFIT ENTERPRISE CLINICAL CENTER OF ONCOLOGY, HEMATOLOGY, TRANSPLANTOLOGY AND — Cherkasy
• Medical Center "Mriya Med-Service"-Clinical Research Department ( Site 0465) — Kryvyi Rih
• Communal Non-Commercial Enterprise "Prykarpatski Clinical On-Surgery department #2 ( Site — Ivano-Frankivsk
• Limited Liability Company Ukrainian Center of Tomotherapy-Department of Chemotherapy ( Sit — Kropyvnytskyi
• Lviv Territorial Medical Union Multidisciplinary Clinical Hospital ( Site 0133) — Lviv
• Communal Noncommercial Enterprise "Podillia Regional Oncolog-Cardiothoracic department ( S — Vinnitsya
• Uzhhorod Municipal Multidisciplinary Clinical Hospital of Uzhhorod City Council ( Site 013 — Uzhhorod
• VISION PARTNER Medical Centre ( Site 0135) — Kyiv
• … and 1 more center

Turkey (Türkiye) · 5 centers

• Erciyes University ( Site 0145) — Talas
• Baskent University Dr. Turgut Noyan Research and Training Center ( Site 0141) — Adana
• Koç Üniversitesi Hastanesi ( Site 0142) — Adana
• Liv Hospital Ankara ( Site 0146) — Ankara
• Hacettepe Universite Hastaneleri ( Site 0140) — Ankara

China · 4 centers

• Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School ( — Nanjing
• The First affiliated hospital of Nanchang University (Xianghu campus) ( Site 0306) — Nanchang
• Zhongshan Hospital Fudan University ( Site 0319) — Shanghai
• West China Hospital, Sichuan University ( Site 0315) — Chengdu

Finland · 4 centers

• Kuopion Yliopistollinen Sairaala ( Site 0261) — Kuopio
• Vaasan Keskussairaala ( Site 0263) — Vaasa
• Turku University Hospital ( Site 0262) — Turku
• HYKS Syöpätautien klinikka ( Site 0260) — Helsinki

United States · 3 centers

• Clermont Oncology Center ( Site 0041) — Clermont
• Sanford Health Roger Maris Cancer Center ( Site 0039) — Fargo
• Sanford Cancer Center Oncology Clinic ( Site 0038) — Sioux Falls

Hong Kong · 3 centers

• Hong Kong Integrated Oncology Centre ( Site 0232) — Central
• Hong Kong United Oncology Centre ( Site 0231) — Kowloon
• Queen Mary Hospital ( Site 0230) — Pokfulam

Chile · 2 centers

• Fundacion Arturo Lopez Perez ( Site 0167) — Santiago
• Centro de Oncología de Precisión ( Site 0160) — Santiago

Netherlands · 2 centers

• Deventer Ziekenhuis ( Site 0272) — Deventer
• Leids Universitair Medisch Centrum ( Site 0273) — Leiden

Thailand · 2 centers

• Bangkok Metropolitan Administration Medical College and Vajira Hospital ( Site 0351) — Bangkok
• Faculty of Medicine Siriraj Hospital ( Site 0350) — Bangkok

Greece · 1 center

• Evangelismos General Hospital of Athens ( Site 0200) — Athens

Italy · 1 center

• Fondazione IRCCS Istituto Nazionale Dei Tumori ( Site 0175) — Milan

South Korea · 1 center

• Severance Hospital Yonsei University Health System ( Site 0080) — Seoul

Spain · 1 center

• Hospital Universitario Virgen de la Macarena ( Site 0093) — Seville

Identifiers

NCT: NCT07252739 · 3475-01J · U1111-1321-3999 · 2025-521939-36-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗