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

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Trial Details

Sponsor: Merck Sharp & Dohme LLC (industry)

Phase: 2

Start date: Dec. 19, 2025

Planned enrollment: 130

Trial ID: NCT07252739
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More trial details at ClinicalTrials.gov More info

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Goal: To evaluate the safety, tolerability, and preliminary antitumor activity of adding the investigational KRAS G12C inhibitor MK-1084 (with or without cetuximab) to pembrolizumab-based first-line therapy for advanced/metastatic nonsquamous NSCLC harboring KRAS G12C mutations, and to estimate response rates with these regimens.

Patients: Adults with histologically/cytologically confirmed advanced or metastatic nonsquamous NSCLC with a documented KRAS G12C mutation in tumor tissue or ctDNA, who are systemic therapy–naïve for advanced/metastatic disease and can provide archival or newly obtained (non-irradiated) tumor tissue. Key exclusions include prior KRAS-targeted therapy, prior systemic therapy for metastatic disease, active CNS metastases/carcinomatous meningitis, significant uncontrolled cardiovascular disease, active autoimmune disease requiring recent systemic treatment, active IBD requiring immunosuppression, and history of steroid-requiring pneumonitis/ILD.

Design: Randomized, phase 2, umbrella substudy with three experimental arms in the first-line setting. Safety is assessed early for dose-limiting toxicities, with longer-term follow-up for adverse events and efficacy endpoints; tumor response assessments are performed per RECIST 1.1 with blinded independent central review.

Treatments: Arm 1 receives standard first-line chemoimmunotherapy with pembrolizumab 400 mg every 6 weeks plus carboplatin every 3 weeks plus pemetrexed 500 mg/m^2 every 3 weeks. Arm 2 evaluates pembrolizumab 400 mg every 6 weeks combined with MK-1084. Arm 3 evaluates pembrolizumab 400 mg every 6 weeks plus MK-1084 combined with cetuximab 500 mg/m^2 every 2 weeks. MK-1084 is an investigational selective KRAS G12C-GDP inhibitor that covalently binds the switch II pocket cysteine of KRAS G12C in its GDP-bound state to suppress oncogenic signaling. In early clinical testing, MK-1084 monotherapy produced an overall response rate of about 22% in previously treated solid tumors, and in first-line NSCLC combined with pembrolizumab showed high response rates (approximately 71% overall, with higher activity reported in PD-L1–high disease). Common toxicities observed to date have included transaminase elevations and diarrhea, with higher rates of grade 3–4 events in combination regimens than with monotherapy.

Outcomes: Primary endpoints are dose-limiting toxicities within approximately the first 21 days, overall incidence of adverse events over extended follow-up, discontinuation due to adverse events, and objective response rate by RECIST 1.1 per blinded independent central review. Secondary endpoints include duration of response, progression-free survival, and overall survival, as well as pharmacokinetics of MK-1084 (AUC, Cmax, and trough concentrations).

Burden on patient: Moderate-to-high. Participants must undergo molecular confirmation of KRAS G12C and provide archival or newly obtained tumor tissue, which may require an additional biopsy if adequate archival tissue is unavailable. Treatment involves frequent infusion visits (every 2 weeks in the cetuximab-containing arm and every 3 weeks for carboplatin/pemetrexed during induction) in addition to pembrolizumab every 6 weeks, plus standard serial imaging for RECIST assessments. The MK-1084 arms add pharmacokinetic blood sampling at multiple early timepoints (up to roughly the first 44 days) and continued long-term safety follow-up, increasing clinic time and procedure burden beyond standard first-line care.

Last updated: Jan 2026

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Sites (2)

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Communal Noncommercial Enterprise "Podillia Regional Oncolog-Cardiothoracic department ( Site 0131)

Vinnitsya, Vinnytsia Oblast, 21029, Ukraine

No email / 380953105783

Status: Recruiting

Clermont Oncology Center ( Site 0041)

Clermont, Florida, 34711, United States

No email / 386-538-3169

Status: Recruiting

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