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Pembrolizumab plus MK-1084 for NSCLC with KRAS G12C mutation

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

Phase 2 Interventional Merck Sharp & Dohme LLC · NCT07252739

This trial tests whether adding the targeted drug MK-1084 to pembrolizumab helps people with advanced non‑small cell lung cancer that has a KRAS G12C mutation.

Quick facts

PhasePhase 2
Study typeInterventional
Enrollment130 (estimated)
Ages18 Years and up
SexAll
SponsorMerck Sharp & Dohme LLC Industry-sponsored
Drugs / interventionsimmunotherapy, radiation, prednisone
Locations22 sites (Clermont, Florida and 21 other locations)
Trial IDNCT07252739 on ClinicalTrials.gov

What this trial studies

This Phase 2 interventional trial enrolls people with advanced or metastatic nonsquamous non‑small cell lung cancer whose tumors or ctDNA harbor the KRAS G12C mutation. Participants receive the KRAS G12C targeted agent MK-1084 in combination with the PD‑1 inhibitor pembrolizumab, with protocol-defined use of other agents as specified by treatment arms. The study's main goals are to characterize safety and to measure how often tumors shrink or disappear on treatment. Participants must provide tumor tissue or ctDNA for mutation confirmation and will be monitored with regular safety assessments and imaging to track response.

Who should consider this trial

Good fit: Ideal candidates are adults with advanced or metastatic nonsquamous NSCLC confirmed to have a KRAS G12C mutation who can provide tumor tissue or ctDNA and have recovered from prior therapy‑related toxicities.

Not a fit: Patients without the KRAS G12C mutation, with squamous histology, or who cannot tolerate PD‑1 blockade or targeted therapy are unlikely to benefit from this regimen.

Why it matters

Potential benefit: If successful, the combination could shrink tumors or control disease longer in patients whose tumors have the KRAS G12C mutation.

How similar studies have performed: Selective KRAS G12C inhibitors have produced responses in other trials and combining targeted KRAS G12C agents with PD‑1 inhibitors is a promising but still relatively new approach.

Eligibility criteria

Show full inclusion / exclusion 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 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

Where this trial is running

Clermont, Florida and 21 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
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Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.