MK-1084 combined with other therapies for advanced non-squamous non-small cell lung cancer

KEYMAKER-U01 Substudy 01F: A Phase 1b/2 Umbrella Study With Rolling Arms of Investigational Agents for Previously Treated Participants With Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer (NSCLC) With KRAS G12C Mutations

This trial tests whether MK-1084 given with other anti-cancer drugs can shrink tumors in people with advanced or metastatic non-squamous NSCLC who have a KRAS G12C mutation and have progressed after prior platinum chemotherapy and PD-(L)1 therapy.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 190 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Merck Sharp & Dohme LLC (Industry-sponsored)
• Drugs / interventions: chemotherapy
• Locations: 4 sites (Clermont, Florida and 3 other locations)
• Trial ID: NCT07286149 on ClinicalTrials.gov

What this trial studies

This substudy of the KEYMAKER-U01 master protocol (MK-3475-U01) is a Phase 1/2 interventional program that gives MK-1084 together with one or more partner agents (including antibody-drug conjugates and monoclonal antibodies) to determine safety, tolerability, and anti-tumor activity. Participants must have advanced or metastatic non-squamous NSCLC with a confirmed KRAS G12C mutation by tumor tissue or ctDNA and have progressed after 1–2 prior lines of platinum-based chemotherapy and PD-(L)1 therapy. The study requires provision of archival and newly obtained tumor biopsies (from lesions not previously irradiated) and includes rescue medication guidelines as needed. Primary endpoints focus on dose-limiting toxicities and objective response rates, with additional monitoring of adverse events and pharmacodynamics.

Who should consider this trial

Good fit: Ideal candidates are adults with advanced or metastatic non-squamous NSCLC harboring a KRAS G12C mutation who have progressed after 1–2 prior lines of platinum chemotherapy and PD-(L)1 therapy and can provide required tumor biopsies.

Not a fit: Patients without the KRAS G12C mutation, with squamous histology, who cannot tolerate combination therapy, or who cannot provide the required biopsy samples are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could offer a new targeted combination option that shrinks tumors or delays progression for KRAS G12C-positive non-squamous NSCLC after standard treatments.

How similar studies have performed: Other KRAS G12C-targeted agents have produced meaningful responses in this population, but combining MK-1084 with the specific partner agents used here is a relatively novel approach with limited prior data.

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 non-squamous 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 (KRAS) mutation of glycine to cysteine at codon 12 (G12C) mutations
* Has documented disease progression after receiving 1-2 prior lines of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy and platinum-based chemotherapy
* Provides archival tumor tissue sample of a tumor lesion not previously irradiated
* Has provided tissue prior to treatment allocation/randomization from a newly obtained biopsy of a tumor lesion not previously irradiated
* Participants with human immunodeficiency virus (HIV) infection must have well-controlled HIV on antiretroviral therapy (ART) per protocol

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 clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease
* Has evidence of any leptomeningeal disease
* Has uncontrolled or significant cardiovascular disorder or cerebrovascular disease prior to allocation/randomization
* Has one or more of the following ophthalmological conditions: a) Clinically significant corneal disease b) history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* Has received previous treatment with an agent targeting KRAS
* Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
* Has known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has history of (noninfectious) pneumonitis/ interstitial lung disease (ILD) that required steroids or has current pneumonitis/ILD
* Has an active infection requiring systemic therapy
* Have not adequately recovered from major surgery or have ongoing surgical complications

Where this trial is running

Clermont, Florida and 3 other locations

• Clermont Oncology Center ( Site 0041) — Clermont, Florida, United States (Recruiting)
• Shaare Zedek Medical Center ( Site 0186) — Jerusalem, Israel (Recruiting)
• Sheba Medical Center ( Site 0180) — Ramat Gan, Israel (Recruiting)
• Severance Hospital, Yonsei University Health System ( Site 0080) — Seoul, South Korea (Recruiting)

Study contacts

• Study coordinator: Toll Free Toll Free Number

Conditions Lung Neoplasm Malignant